Crinetics Pharmaceuticals, Inc. (CRNX) Earnings Call Transcript & Summary

Good morning, everyone. Welcome to Crinetics first R&D Day. For those of you joining us in person, I'm so glad the weather has calmed down a little bit, so you're not swelltering on your way here. And for those of you joining virtually, welcome you to the webcast. So we'll be making forward-looking statements today. So I'll pause for a few seconds on the slide if we absorb all of the fine tech print. Let's see. So now the speakers today, you all know Scott Struthers and Dr. Stephen Betz, the Co-Founders and CEO and Chief Scientific Officer. But I think the real superstars of today's presentation are global product leaders, our GPLs. So the GPLs are the CEO of their molecule, and they oversee the process from, a chaperone the molecule from discovery all the way through clinical development to commercialization. So really responsible for the strategy and execution and know everything there is to know about the molecule. Today, we have Rick Grimes here covering TSH and Stacey Harte for the NDC-9682. Providing a clinical perspective, we have Dr. David Metz, a neuroendocrinologist. He was the President of the North American Neuroendocrine Tumor Society and received the Lifetime Achievement Award from NANETS. He's been involved in a lot of prominent clinical trials and has published over 200 papers. Also, we have Tobin Schilke, our new CFO. He'll be joining for Q&A. And we have Jackie Kirby, our Chief Corporate Affairs Officer. We also have other people from Crinetics. So during the break and during lunch, we invite you to get to know the deeper bench of talent we have here. In terms of agenda, we will have Steve kick off with a strategic focus and discovery overview. The first session, when we were talking about what molecules we wanted to share, the feedback that we got from all of you was that we wanted to talk about every molecule, every indication. And unless you want to come for a week of Crinetics summer camp, we thought we had to be efficient in what we actually cover. So first, we'll be going through CRN-12755, which is the TSH molecule in development for Graves disease. We also have CRN-10329, which is SST3 agonist for autosomal dominant polycystic kidney disorder or ADPKD. We'll have a brief break. And when we regroup, we'll have the NDC or non-peptide drug conjugate platform as well as the first candidate from that platform, CRN-9682, and we'll go through the first indication, neuroendocrine tumors and other SST2 positive tumors as well as talking about how we position that with carcinoid syndrome. After closing, we'll open the floor for Q&A. For those of you here in person, will have people running around with mics, and we invite those of you on the webcast to submit questions from the Q&A function. We ask that you hold your questions until the end. We'll have plenty of time for Q&A. And with that, please welcome to the stage, Dr. Steve Betz.

I hope everybody can hear me. Welcome to everybody here. Thanks for coming out. My name is Steve Betz. I am not Scott Struthers, but I am one of the co-founders of Crinetics and its CSO, which most days is a pretty great job, and you'll see some of the reasons why today. I have to make -- let you guys know that Scott was kind of laid up by a little GI flu this morning and was unable to make it here in person. So I get to cover his duties a little bit here today. Hopefully, I can be a good stand in for him. As Gayathri was saying, we wanted to give you guys a bit of an idea about Crinetics, give us an overview. And I'll spend a little time talking about how kind of our philosophy around discovery and how we approach it. And honestly, I mean, it's kind of an easy thing to say, but we've founded the company around endocrinology and the mechanisms of endocrinology to serve patients that we thought were very kind of underserved by the pharma community and kind of needed a 21st century medicines for the diseases that they had. And this seemed like a pretty tall order back in 2010 when we opened our first lab, but I think you're seeing some of the fruits of that labor over the last decade or so. And we're not going to spend a lot of time talking about acromegaly. This is more about the stuff that's earlier in the pipeline. But I want to point out like Tracy in this slide, she's an acromegaly patient, she's talked to us about her disease and about her journey as a patient and about the needs that the acromegaly community has. And this is something that we do all the time is get to know our patients, get to know the people who are -- who have these diseases and the people that are treating these diseases. And it's one of the core fundamental things, I think, as we've grown the company that we've tried to incorporate in everything that we do, and you'll see some of that today. Again, we're not going to talk about paltusotine, but I'll just answer the question because I'm sure it's one that everybody has. So far, so good on the NDA and its PDUFA date on September 25. Our interactions with the agencies have been routine. And so far, everything is going as planned. I wanted to share a little bit of Crinetics with you. We did -- we -- actually, when we first thought about having R&D Day, we thought, oh, we just bring everybody into San Diego and we opened a new facility last year. And -- but we wanted to get as many people as we could in person, so we thought we would come here to New York. And we've kind of highlighted here what goes on in the building on a daily basis. And we've got -- you can always come and probably find a couple of dogs in the building always -- well, willing to stay high and be friendly. The dog wall is there for perusal. But really, it's the scientists doing the work in the lab that are the real stars here. They're absolutely killing it, and they -- I am so grateful for the people that's been able to work in our labs. They are really remarkable. I wanted to spend a little time talking about Crinetics in the history in case some folks haven't heard this story before. We actually -- we incorporated the company in 2008, but we started raising money on grants and contracts. We opened our first lab in 2010 in January. It was the 4 of us as co-founders, myself and Scott, Frank and Anna, and our 2 dogs, Penny and Princess. We've always been a dog-friendly company. When you start a company, you have to do a lot of jobs that you're not trained to do, and so I was Head of HR, which is terrifying to the people who work for Crinetics right now. But we decided like, well, we can bring -- why can't we bring our dogs into work. They'll do fine. And so it's been something that has remained part of our culture ever since. And I think people really like that. We really did bootstrap our way. I don't know if you guys remember what it was like in 2008, 2009, 2010, it was a really tough economic time, and it seemed like a crazy idea to start a company in that environment, but it was actually, in some ways, kind of a good time to start a company, and we were able to raise enough money to keep the company going and get these ideas of how we can make molecules that work at these endocrine receptors and do the things that we need them to do for the patients who need them. And we've got a bunch of ideas, the fruition of which you'll see later in this talk. And we actually -- one of the ones that took hold earliest was the somatostatin 2 program, which ultimately led to paltusotine. And based on the data we had earlier, and I'll actually share a little bit of this data with you later, we raised a Series A in -- in the last part of 2015, that really catalyzed the company into a different status. We were able to move the program forward. We eventually came up with paltusotine. Paltusotine, we started our Phase I at the end of 2017. And that Phase I and the SAD and MAD data from that Phase I propelled us to a crossover round at the beginning of 2018. Some of you guys actually participated in that, and then the IPO in the summer of 2018. And that really was quite a remarkable run for us in terms of growing the company in terms of -- we went from kind of being a discovery company to being a development company, and we started taking paltusotine into the clinic. Now as earlier, we've always wanted to be a pipeline company, and we started developing the pipeline, the next compound that we went into the clinic with was atumelnant. This is another first-in-class molecule ACTH receptor antagonist for CAH and Cushing's disease. That compound went into the clinic in 2021. And we've -- we used to have this -- we had this saying that I think a lot of folks at Crinetics -- we like this idea of like no good idea left behind. And we've been talking -- as we think about how we make molecules and what we want them to do. One of the ideas that we came up with was, can we use what we know about making molecules and GPCRs and find ways to deliver payloads to tumors. And so we had this idea around could we use this to make radionucleides and deliver radionuclides both for imaging and for therapy. And that program, that project was actually so successful, we decided in the fall of 2021 to actually spin that out as Radionetics. Frank and Anna from the lower part of -- from that original picture. They went off and were part of the founding team of Radionetics. Scott's still on the Board of Radionetics, and they are off and running. And you'll see some of the fruition of that idea kind of in the story around 9682 and our non-peptide drug conjugate, Stacey Harte will tell you that story. And then over the last couple of years, we've -- the PATHFNDR studies for acromegaly, both PATHFNDR 1 and PATHFNDR 2 have been completed. They were the basis of our NDA, which we submitted at the fall of last year, and as well as the atumelnant data, which we showed at Endo last year and showed some more at the beginning of this year, I think, has really set us up for kind of the next stage of the company as we went from discovery to the clinic. Now we're going from clinic to commercial. We're -- the company continues to grow. And I think fulfill this idea that Scott and I had when we started the company of making company that makes its own molecules, can get them into the clinic, can commercialize them and bring them to patients. This was the vision at the start and it is -- I can't tell you how exciting it is to see it come to fruition. And that's us today. So starting from 4, we're now over 500, and that's our new facility. And even though we're not there today, if you guys are ever in Southern California, I want you to stop in and say, "Hi, see the lab, see the dog wall, I'll bring Enzo in, it will be good. And thinking about where we are as a company, this is a tough couple of years for biotech. And I feel very fortunate that Crinetics is in such a good position as it is. We're in a really good spot. The pipeline is doing really well. We're starting Phase IIIs in CAH and carcinoid syndrome. But today, we're going to talk about the pipeline. Some of the stuff is kind of below the fold, if you're in journalism. And this combination of kind of our understanding of endocrinology and we're rooted in endocrinology, and we understand the mechanisms of endocrinology and how that might affect diseases that maybe most -- some people don't think of as endocrinological diseases. And we'll talk -- hopefully highlight a little of the science that most investors don't get to see until compounds are pretty further along in development. And we've got a good balance sheet. We can -- we've got a really good buffer to take us to 2029 and beyond. This is a slide that I think we actually started showing versions of it at JPMorgan this year, and this is kind of our idea around what we're thinking about for Crinetics. And where it was founded in kind of pituitary science. So you see like paltusotine for acromegaly and originally for Cushing's disease atumelnant, but you can see how we've sort of taken those ideas and now we're growing them into new areas. Carcinoid syndrome for paltusotine, other SST targeted therapies, right, NDC for oncology and net an SST3 agonist for ADPKD and atumelnant of course, for CAH because it's the right molecule for that disease. And then you see some of the other things that we're thinking about in terms of other areas of endocrinology, other areas of oncology that we are pointing the company towards over the next several years. But today, we're going to talk about the things that are here, that are probably closest to clinical development for us. Well, actually, one of them is already in clinical development. But we're going to talk about -- as Gayathri said, we're going to talk about our approach to grades and the TSH receptor antagonist. We're going to talk about ADPKD, and then we're going to talk about our NDC program. All these I'm very excited for you guys to hear about today. With that, I will turn it over to me. And I'll tell you a little bit about what we do in the labs because this is something I don't think we get to talk about that often in this sort of setting. I won't spend a lot of time talking about GPCRs. I think everybody knows there's such an important family for biology first of all, and certainly for disease modification in endocrinology. A lot of endocrinology was laid down hundreds of millions of years ago in the way that cells and tissues communicate with each other through hormones. And too much, too little of a certain hormone or too much or too little of activity of a certain receptor can cause disease. And so this is what we have dedicated ourselves to, Scott, myself, others in the company, we've spent decades working in endocrinology and GPCRs. We spent decades making molecules and testing them against targets. This is what we do, and this is our expertise. And we are particularly good. I'd like to think at making these small molecule drugs that interact with these peptide receptors. And there was a long time when -- we actually had to answer the question of like how do you do this? I mean I think we've done it enough to suggest that we kind of have this. And the current indications, I kind of showed that on, I think, what I think of as the solar system chart. But these are a lot of important indications where patients need really, they need new therapies. But I think the point here that I want to make is that this is just really scratching the surface of what we think we can do as a company and our approach to discovery. There's a ton of GPCRs and a ton of hormones out there where you can imagine that regulating their activity either up or down will make a difference for a patient. Now one of the things about endocrinology, I don't know how to put this quite right, is that I like working in endocrinology, especially as a discovery scientist, because as I said, endocrinology was laid down a long time ago. And the endocrinology in our preclinical models in rodents often mirrors the endocrinology that you see in a healthy volunteer study in a Phase I study that mirrors the endocrinology that's going to [ride] in a patient. And so one of the things that we've been able to enjoy or derisk or however you want to put it, is that when we have molecules that do what we think -- that have the pharmacology that we think they need to have in preclinical models, we know that they're going to do that in healthy volunteers, and we know that they're going to do what they need to do in patients. So it's one of the things like people say, "Oh, like when paltusotine worked in acromegaly, how excited were you? And I'm like, well, I knew it was going to work, right? There was no doubt that it was going to work. There's always a doubt of like, oh, are you going to get the PK you want, you are going to have some weird thing -- idiosyncratic thing that pops up. That's what I worried about. I never worried about whether it's going to work or not. And so let's spend a little time talking about GPCRs. And I'll nerd out a little bit here because most people think, oh, you make an agonist, you turn a GPCR on, you make an antagonist, you turn it off. And I guess at a certain level, that's basically what you're trying to do. But what I want to show here is that GPCRs actually are incredibly dynamic in the way that they operate, and they're incredibly dynamic in the responses that they can have. And we have programs where we have agonists and antagonists. You can see them, I've listed them here. And sometimes you're looking for the primary signaling that you might want out of out of G-protein coupling that's cyclic AMP or an osteo phosphate. But most GPCRs, when they are activated by an agonist, a lot of times, they will become internalized and I show that on the right-hand side. Sometimes that internalization into the endosome can have its own signaling. Sometimes the receptor gets degraded. Sometimes it gets recirculated to the -- back to the self service. And this dynamism in GPCR activity actually has -- it defines what we look for in a drug because what are you looking for? Are you looking for something that's a slow off-rate antagonist? Are you looking for something that is biased for G protein signaling versus beta rested recruitment and internalization. We'll talk about 9682 or NDC, that's actually -- we've designed that to get internalized because we want to be -- we want that process to pull the payload we want into the cell. And so thinking about -- we think about this from the start of every program. It's like what are we trying to do? What do we think this molecule needs to do, both from -- for patients in the end. But how do we get there? What does that look like? And I'll show you a little bit of the data from the SST2 agonist program that led to paltusotine. And part of the reason here, I don't want to take any thunder away from Rick or Stacey or any of the other programs that we're going to talk about today. But -- and this is a complicated slide because honestly, discovery is a complicated business. And the one thing here, there's all a bunch of stuff here for in vitro pharmacology and vivo pharmacology for safety, for drug-like properties. And Frank, one of our co-founders from that picture of the 4 of us and our 2 dogs, he used to call this a water balloon. So Frank, you say, like making the right molecule is like a water balloon. Like you're always squeezing the water balloon, trying to get the right thing. Sometimes if you squeeze on bioavailability, selectivity goes wrong. And so you're always trying to optimize all these things all at the same time in probably 10 or 11 dimensions. And the other thing here is this is the assay cascade for SST2. It doesn't look like any of the other assay cascade for any of the other programs that we have. Everything that we do is customized for that GPCR biology that we are trying to elicit with the molecules that we make. And this goes back to -- so this is it was actually kind of fun putting this slide together because I have got to go back and look at some of the really old data that we had from the bootstrapping era. So one of the first really good compounds that we made that kind of told us we were on the right track to making a non-peptide somatostatin 2 agonist was this compound 351. And the structure 351 is shown there. 351, we do, like I said, the biology in a rat is going to mimic what we did in healthy volunteers and patients. We do a growth hormone releasing hormone challenge, and we see if our somatostatin agonist can suppress that. And you can see from the graph in the middle, 351 did a great job of that, just like it should, if you are a somatostatin agonist. The issue with 351 was that it also came along -- it was a really very good SST2 agonist, but it was also a really good SST4 agonist. And as we think about making molecules, I guess there's a point like, well, do we take that one forward? Do we not take that one forward? But we actually -- our philosophy is you've got to make -- you got to have the right target, you got to have the right molecule that's going to solve for what we're trying to do here. And 351 was close, but it wasn't quite right. We needed -- we wanted to really dial out that SST4 activity. But 351 was actually good enough. This was the molecule and the data that actually prompted our Series A because we were able to convince folks in the investor community that we are on the track to making a non-peptide somatostatin agonist that was probably a good investment from our Series A folks. So we went on, we churned the wheel a couple more times trying to figure out what to make. We came up with 808. The healthy volunteer challenge is there for 808, it looks amazingly just like you, the one that we did in rodents. And if you go on the data in Acrobat and the data in PATHFNDR especially speaks for itself, 808 did in patients exactly what it was designed to do, which is very gratifying to see. And so I wanted to show this here, and this kind of goes to Frank's water balloon. So there -- this is -- so this is fun for me because I get to go into the database and pull the stuff out of the database, and I don't get to do that as much as I used to. But I made a chart here of every molecule we made for our SST 2 program, and I highlighted 808 there in Crinetics green. And you can see that it's potent. It's somewhere -- it is the 808th molecule that we made. It came out of this cascade. But 808 in terms of the water balloon, it's not the most potent molecule we ever made. It's not the most bioavailable molecule we ever made. It's not the most selective molecule we ever made. But in terms of the water balloon, it's solved just about everything. And so that was the one that we moved on. But I think that's something that I think a lot of people who don't work in discovery probably don't appreciate. And this is a molecule -- this is actually paltusotine 808. This is sort of an encapsulation of what we would call that water balloon. Every atom here tells a story, every atom was poked and prodded and tested to look at in vitro, in vivo, drug-like properties. And you could have a whole course on how this molecule came to be, and it does exactly kind of what we were hoping for it to do. And I think one of the other things that I wanted to get across here because a lot of times when we're talking about development, you're talking about a specific compound, right. 808, 12755, whatever we're going to talk about. But the thing is when we find those molecules, we know we're not quite done because when you make something that's going to be a development candidate, you're never 100% short, right? And you're always like, okay, I'm going to push this forward because I think it's worth the investment to push this forward. But what if something happens? And sometimes things happen. And so this is -- I brought up 2 examples here for -- and this is the program we're not talking about today. In the paltusotine program, -- we actually -- we decided we needed to make a backup because, a, it was the company's lead program at the time. And we wanted to under -- we were -- we knew that if 808 failed for some reason, that we needed a backup for the company, right? It was an existential threat of the company to lose its lead assets. We actually came up with 1941, which is another molecule that we made and it was ready to go. We actually took it all the way through the end of Phase 1 because we wanted to make sure we had something ready in case something happened to the lead molecule. And paltusotine performed and it performed and it performed and now it's in registration. And so we had a clinical class compound sitting on the shelf. And a couple of years ago, we got together with some folks that we used to work with back in the bootstrapping era and they're like, "Oh, talk to these guys who are working on the endocrinology of aging, and they're using dogs as a test -- as a model species for that. And so we actually licensed out 1941 to this company called Loyal for Dogs. And it's been a real pleasure to work with them. And if you ever want to hear about that story, it's a great story I'll talk about that. We can talk about that at the break. But this is a great opportunity. We had a backup. We didn't need it. Now we're going to use it for something else, and we're going to probe endocrinology, we're going to probe biology in a way that I think is meaningful and is going to be super interesting to see the answers out of that. And if it helps dogs live longer, I am 100% behind that. In our ACTH antagonist program, our first development candidate was a compound called 4599. And 4599 looked great until it was -- it had a problem -- a developability problem around stability in a solid form, and we don't need to go into that part. But we had 4894, which became atumelnant right behind it. And so we probably lost, I don't know, a month or 2 in that development program for Cushing's and CAH. So having these backups ready to go is part of what we do. And in fact, it's kind of its own little water balloon is how far do you push these backup molecules. Do you take them all the way to the clinic, do you take them to an IND -- and so that's one of the things that we always talk about, how many backups do you have, how far do you take them? And then what do you do with them once the lead molecule is off and running. So that's a little behind the curtain there. The last thing I want to come back to is patience. And I think it's easy to say that we're a patient-focused company, but I remember going to the Endocrine Society Meeting in 2015 and meeting Gilsisco and the members of the Acromegaly community for the first time. And this is before we ever had -- we had data from like compound 351 that I showed you. We weren't going into the clinic yet, but we wanted to understand patients because I'll tell you, one of the things I've learned in this -- in my journey at Crinetics is you know a lot about biology. You talk to really good doctors, you understand about the practice of medicine, you can get a lot of data out of prescription databases about how medicine is practiced. But if you want to understand medical need, talk to patients, because they have -- they live it every day. They understand their disease differently and better than anybody. And we actually -- we incorporate by talking to the folks in the acromegaly community and, of course, in the Cushing's community and of course, the other communities. We actually -- it actually helps us decide what we want that molecule to look like. What's going to be the right molecule for these patients because there's sometimes a discrepancy between what doctors say they are doing and what they need and what patients are experiencing. And -- that's something that we try to incorporate. That's a vision and a view that we incorporate from the get-go. I'm going to pause there. I think that is a little look behind the curtain, both of the history of the company, and as part of how we do discovery. We'll be happy to answer any questions at the end of the thing, of course, catch me at the break. I'm always happy to talk about this stuff. But for now, we're going to get on the main events. We're going to talk about TSH receptor antagonists and going to bring up the Global Product Lead, Rick Grimes for that.

Thank you, Steve, and good morning, everybody. I really appreciate this opportunity to come here today and talk to you about our TSH receptor antagonist program at Crinetics. It's one of the early programs in our portfolio and one of our exciting programs, too. So over the next 30 minutes, I'm going to share with you a little bit about our scientific rationale behind the program and some of our preclinical data that gives us a really strong reason to believe that this could be a really important new medicine for patients with Graves disease. So, as I'm sure many of you in this room know, Graves disease is one of the most common endocrine diseases. It affects approximately 1% of people in the United States are about 3 million people. And it has 2 main manifestations. That's hyperthyroidism and Graves' orbitopathy, also known as thyroid eye disease. For Graves' hyperthyroidism has a number of significant symptoms, irritability, tremors, fatigue and can cause major complications, including atrial fibrillation, heart failure and thyroid storm, and this has significantly negative impact on patients. Firstly, not only emotional, mental and physical fatigue, but can cause significant anxiety. It can also create what's called difficulty concentrating due to what's known as brain fog. And all of this can come together and make it really difficult for patients to just complete daily tasks and conduct work. The second manifestation of Graves disease is orbitopathy, like thyroid eye disease. It affects about 30% to 50% of patients with Graves disease. And it results in a lot of inflammation and damage to the tissue around the eye and a lot of pressure around the eye, including the muscles and fatty acid, fatty tissue and connective tissue. And in severe cases, can lead to vision impairment and vision loss and blindness. And again, it has a lot of impact on a patient's quality of life, not only with the physical discomfort, the pain, the impaired vision such as double vision or Graves' orbitopathy, but also bulging of the eye also known as proptosis. And this can lead to a significant anxiety and depression and can lead to social withdrawal. The vision impairment can also impact this daily task such as reading and driving. So for great hyperthyroidism, there hasn't been a new therapy for these patients since the middle of the last century. And the standard of care has been stagnant for decades. And although it is relatively effective, it has imperfections and significant limitations. Recently, the oral antithyroid drugs have become the highly preferred standard of care in first-line treatment for Graves hyperthyroidism accounting for about 90% of first-line therapy. And this is due to the risk associated with the ablative therapies. The ablative therapy, this is where you were -- there was ablation of the thyroid function either through dosing with radioactive iodine, which destroys the thyroid cells or surgical removal of the thyroid known as thyroidectomy. Although it is definitive treatment, has limitations, such as it renders the patient permanently hyperthyroid, which leads to the need for lifelong thyroid hormone replacement therapy. As you can see here on the slide, there's a number of other risks associated with these procedures, including with radioiodine there's an increased risk of incidents and exacerbation of underlying thyroid eye disease. Now turning to antithyroid drugs. These oral antithyroid drugs work by inhibiting thyroid hormone synthesis. And although they are effective, especially if the patient is compliant, they have a number of significant limitations. Firstly, they don't -- although they do not exacerbate thyroid eye disease. They do not treat or prevent orbitopathy. And as I mentioned, this affects 30% to 50% of patients, and that typically occurs and presents itself within the first 18 months. They also have a number of serious adverse effects, including liver injury and potentially fatal agranulocytosis and other adverse effects such as itching rash and hives. And so a new therapy that's able to control the hyperthyroidism, while also co-treating and preventing orbitopathy that doesn't have the adverse effects associated with antithyroid drugs and it would be hugely -- well and also well [indiscernible] potential as a really important new therapy for Graves patients. Turning attention to Graves orbitopathy. With the approval of tepezza, the anti-IGF1 therapy in 2021, this really changed the treatment paradigm and is the first and only approved treatment for thyroid eye disease. And it is relatively effective. It does improve symptoms associated with thyroid eye disease, and it has a response rate of proptosis of up to 80% with a proptosis response being defined as a greater than or equal to 2-millimeter reduction in proptosis. However, many patients do experience a relapse and a recurrence of the disease within 18 months of therapy. Although it is effective, it comes with significant risks, including on-target risk of hearing impairment, which is experienced by 10% to 20% of patients some of which is permanent and secondly, hypoglycemia. There are a number of other safety risks that I've noted here, and it's also not suitable for all patients, including those that have irritable bowel syndrome, diabetes or any preexisting hearing impairment. So there's really a need here for a treatment that's as effective as these first-generation products or anti-IGF1s, but with much improved safety. So as I'm sure many of you know, Graves disease is an autoimmune disease that's characterized by the production of thyroid stimulating autoantibodies also known as TSABs. And it is 2 major manifestations, which is hyperthyroidism and orbitopathy. The core driver of these manifestations is the overstimulation of the TSH receptor by the stimulating auto antibodies. And just turning your attention here to the middle panel. In the thyroid, these thyroid stimulating autoantibodies bind to and stimulate the TSH receptor, which leads to overproduction of thyroid hormones and therefore, leading to hyperthyroidism. In the eye, in the orbital fibroblast, these TSABs also bind to and stimulate the TSH receptor. And by crosstalk, they also stimulate the IGF-1 receptor. This leads to a number of downstream effects, including increased cytokine production, including IL-6, an increase in production of hyaluronic acid and cellular differentiation and proliferation of adipocytes into myofibroblasts. This results in a significant inflammation of tissue expansion and fibrosis and a number of symptoms that I alluded to earlier in the presentation. None of the current therapies for Graves hyperthyroidism or for orbitopathy actually block this core driver of disease. Antithyroid drugs, as I mentioned, work downstream of the TSH receptor blocking thyroid hormone synthesis and therefore, have no effect on the orbitopathy. Anti-IGF1 therapy block only the activation through the IGF-1 receptor, an IGF-1 activation is not required for thyroid hormone synthesis and therefore, it has no effect for hypothyroidsm. So the TSH block -- directly blocking the TSH receptor can have some significant advantages and potentially be able to block the activation and the manifestation of Graves disease regardless of location within the body. And that changes as to our approach. So TSH receptor antagonism. So TSH receptor antagonism as a potential as a targeted novel mechanism to treat all of the manifestations of Graves disease, including hyperthyroidism and orbitopathy. On the left panel here, the key aspects of this mechanism is that a TSH receptor antagonist would bind to the TSH receptor and block the activation of the receptor by these thyroid stimulating auto antibodies. In the middle panel, in hyperthyroidism, in the thyroid, it would block the activation of a TSH receptor leading to suppression of the overproduction of thyroid hormone and resolution of the thyroid symptoms. In the eye, it would also block to the TSH receptor, it would block the activation of the TSH receptor by the thyroid stimulating auto antibodies. And by that cross-stock it would also inhibit at the same time, the IGF-1 signaling. This would then shut down those downstream processes, reducing inflammation, mitigate that tissue expansion and decrease the formation of fibrosis and resolution of all the symptoms that I spoke to earlier. So essentially, one therapy to treat all manifestations of Graves disease. So at Crinetics, we are developing small potent, small molecule TSH receptor antagonist. We have developed a number of these antagonists in our discovery labs that are structurally diverse. They're potent and selective for the TSH receptor with good pharmacokinetic properties. Our leading candidate is 12755 and as predicted human PK to support once daily dosing. And as I'll show you in a moment, it's demonstrated efficacy in a preclinical model of Graves hyperthyroidism, and also we demonstrated ability to inhibit the activation of the TSH receptor in Graves patient orbital fibroblast. It's currently going through IND-enabling studies, which are in progress. And as you can see here on the right panel, 12755 is a potent antagonist of the human TSH receptor with -- of approximately 8 nanomolar and it's also slightly less potent as an antagonist of the rat TSH receptor, which is great because it enables us to put this and study this in our preferred Graves model. So at Crinetics, we have studied 12755 in our in-house rat model graves hyperthyroidism. In this model, as you can see here on the right panel, the rats are dosed with a human thyroid-stimulating autoantibody known as M22. And you can see here on that right panel that following dosing of M22, you see a rapid increase in thyroid hormone T4, as you would see in a Graves patient. The rats are then dosed with either vehicle or an ascending dose of 12755 orally. And you can see here we get a rapid dose-dependent response and reduction of the T4 thyroid hormone levels. And you can see at the higher doses within that first day, there's a return to baseline. I mean as Steve was alluding to earlier, with these models being so translatable in the endocrine area, this provides very strong proof of concept that 12755 will perform equally in Graves hyperthyroidism in the clinic. We've also studied the ability of 12755 to not only inhibit the TSH receptor in the thyroid, but also its ability to block with the stimulation in the eye. Just as a reminder, one of the effects of TSH stimulation by these antibody -- autoantibodies in the eye is production of hyaluronic acid. Hyaluronic acid attracts and bind water and therefore, contributes to the increasing of the volume of the orbital tissue. In this model, we have obtained orbital fibroblasts from TED patients that have undergone orbital decompression surgery and differentiated those into adipocytes. They are then stimulated with a human T-cell. And you can see here in the center panel, that 12755 is able to dose dependently suppress the production of hyaluronic acid when stimulated by the human stimulating antibody. Not only is it able to block the stimulation by this isolated antibody, it also able to block stimulation by autoantibodies to a number of patient samples shown here on the right. Another effect of the stimulation of the TSH receptor in the eye is production of IL-6. IL-6 plays a number of roles in the pathophysiology of Graves orbitopathy. Firstly, it increases cytokine production. It also increases production to the TSABs themselves. And finally, it leads to increased cellular proliferation, differentiation and differ genesis. And as you can see here in the middle panel, 12755, is also able and we've demonstrated that it's able to dose dependently suppress production of IL-6 in these same orbital fibroblast from patients as an isolated antibody in the middle and from the autoantibodies for a number of patient samples on the right panel. So we've generated preclinical proof-of-concept data that's given us a very strong reason to believe that this has potential as a really important new therapy for Graves patients, addressing the key -- potentially addressing the limitations of the current standard of care. Our vision for this product -- is for it to be a single oral therapy that will treat both manifestations of Graves disease, be that hyperthyroidism and while treating and preventing great orbitopathy. Our vision for the product is it has potential to put for the hyperthyroidism as a once-daily therapy that will achieve rapid control of hypothyroidism symptoms while simultaneously treating and preventing orbitopathy. With none of those risks associated with antithyroid drugs and it will preserve the thyroid and spare the need for ablative therapy. For orbitopathy, again, it will be an oral once-daily therapy. And because it blocks that same access, the TSH receptor IGF-1 complex, we have a strong reason to believe that has potential for equivalent or better efficacy than the currently approved IGF-1 for thyroid eye disease. But more importantly, with that improved safety. None of those on-target hearing impairment or hypoglycemia and this improved safety could enable longer treatment duration and therefore, improve durability. So it has very much potential as a single therapy to address limitations in current standard of care for both hyperthyroidism and orbitopathy. As I'm sure many of you in this room are aware, there is a number of emerging new; therapies in the clinic for Graves disease, either for thyroid eye disease or for hyperthyroidism. And we still believe that a TSH receptor antagonist has still -- has potential advantages over these emerging new products. As you've heard me go through the profile. So one of the major classes that's in development is the second-generation and anti-IGF-1s. These are other subcutaneous monoclonals or oral small molecules. As I touched on earlier, because of their mechanism, they will only treat thyroid eye disease. Early data from the clinic is suggesting that the subcutaneous injectables have the efficacy of the current standard of care. The question still remains though whether they will be able to thread that needle and overcome the on-target side effects of the anti-IGF-1 inhibitions such as hearing impairment and hypoglycemia. The second major emerging class is the IgG degraders. These come in 2 major forms. Firstly, the anti-FcRn monoclonal antibodies and small molecule bispecific degraders. These work by reducing the levels of these circulating thyroid stimulating auto antibodies by promoting their degradation. However, they are not specific to the thyroid -- they're stimulating auto antibodies. They broadly degrade IgGs. And data is suggesting that they may require large and sustained and deep IgG reductions to maintain efficacy. And finally, they are all high dose once weekly subcutaneous injections. So the population itself, so switching to how big is this population and our opportunity here is, as you can see here, and I think many of you know, there's a very large patient population in both Graves, hyperthyroidism and orbitopathy. Hyperthyroidism affects approximately 1% of the population, which is approximately 3 million people. And recent studies have shown that there's up to about 1.2 million people who actively have Graves hyperthyroidism. And we see this as a potential addressable patient population for the right new therapy for Graves disease that addresses limitations of standard of care. And it has an annual incidence of new diagnosis of upto 170,000. For Graves orbitopathy or thyroid eye disease, we really see the addressable patient population as those with moderate-to-severe disease, which is the population of which tepezza is mainly used. As I mentioned, it affects about 30% to 50% of patients with Graves disease. And that's approximately 150,000 patients with moderate to severe to prevalence, and about 9,000 to 10,000 of moderate to severe incidents per year. So a very large population with a high unmet need. So what's next for this program that we're excited about at Crinetics. So next month, we will -- we have a poster presentation at the Endo Conference in San Francisco, where we'll share this and more data on 12755. As I mentioned, we are progressing through IND-enabling activities, and we'll have IND submission. What we're really looking forward to is the Phase I healthy volunteer study. And as Steve touched on earlier, with this being an endocrine target, we do expect to see the modulation of a thyroid hormones in healthy volunteers. So not only will we establish safety, tolerability and pharmacokinetics, but we'll also get initial proof of concept in terms of thyroid biomarker modulation of the TSH, T4 and T3 thyroid hormones, which actually will be our Phase III endpoints for Graves disease. So thank you for your time, and let me share an overview of our exciting TSH program, and I'm going to hand back to Steve to talk about and share with you our ADPKD program.

Thanks, Rick. And I did -- actually, I was in all my free time yesterday, I was reviewing that 755 poster for Endo, and I think it looks -- I think it looks great. So I'm excited to see that look. We're going to spend a little time talking about ADPKD. And this is one where I think of as kind of endocrinologically adjacent, but this is one where kind of as I was talking about before, the infrastructure of endocrinology can play a big role here. So ADPKD is actually the most common inherited renal disease affects nearly about 150,000 people in the U.S. And it's actually quite incredibly debilitating here on the graph, I show you, as the disease progresses, you get these large increases in cysts in the kidney. And over time, you actually lose kidney function and kind of -- it has a very rapid drop off at the end. In other words, early in the disease, kidney kind of chugs along and manage it to get by and then later in the disease progression, it really falls off and that leads to patients requiring dialysis and kidney -- ultimately, kidney transplant, incredibly burdensome disease, especially as it comes to the end of its run. The only approved therapy for ADPKD is a compound called tolvaptan. We'll talk about that a little bit later. And it is only used in about 10% of patients. And the reason for that is some on target pharmacology from -- as a mechanism tolvaptan, to go into this a little bit, that causes frequent -- frequent urination for patients so much the fact it becomes actually debilitating for them. And so there is not -- this is a disease with a lot of people that need a good option and just don't have one. I'll spend -- let's talk about the kidney a little bit, especially in the cilia. This is a disease of disrupted signaling within the cilia of the kidney, and I've got a little diagram of it here. On the left-hand side is a healthy kidney doing all the things it needs to do. And really, what happens here is there's a balance within the cilia in the kidney of the concentrations of calcium and the concentrations of cyclic AMP. And that homeostasis is maintained for healthy kidney function. What happens in ADPKD, there's mutation either in this protein called PC-1 or PC-2, and what that does is those mutant proteins do not allow the influx of calcium. And so what happens is then you start to get this disproportionate ratio of cyclic AMP to calcium. And this has downstream effects of turning on cystogenic signals within the kidney, and this leads to the development of cyst, which leads to bad renal function in the end. And so our hypothesis about this disease, and thinking about this from kind of a disease burden and pathophysiological sense is if we could restore that cyclic AMP and calcium ratio, you would alleviate the disease and be able to treat these patients. So let's spend a little bit talking about tolvaptan. So tolvaptan is a vasopressin receptor antagonist. The -- and vasopressin is found on the kidneys. And the thing is if vasopressin causes -- vasopressin receptor activity causes an increase in [indiscernible]. And so the answer here is if you block the action of vasopressin, you actually lower cyclic AMP, which is what you would want to do for an ADPKD patient. The problem with vasopressin is it's also known as antidiuretic hormone. And so if you block the effect of antidiuretic hormone, what happens, you're no longer able to reabsorb water from the kidney into the system. And so you end up having frequent urination, very high-volume urination and very high urgency of urination. And this can be 3x or more frequently than healthy individuals can have. And this ends up being so debilitating, I think people would rather not be on therapy than to have to put up with this. So in some ways, tolvaptan -- and this is exactly -- this is not a side effect. This is actually the pharmacology of vasopressin in action. And so this is -- this is not an unexpected outcome for this drug. And so as we thought about it, and so in some ways, the right idea was lower cyclic AMP, right? -- but not have these side effects. And so the right way to -- as we think about it, the right way to lower cyclic AMP here is to turn on somatostatin 3, which is also found in the kidney and specifically found in the cilia in the region where the mutations in PC1 and PC2 occur. And we did some work here -- as we were characterizing this idea, we went back and we characterized the expression of site -- of SST3 within the kidney, and I won't go into it for purposes of time, but essentially SST3 is expressed in the cilia and in the kidney, exactly where you need it to be to normalize this cyclic AMP to calcium ratio. So actually -- so somatostatin agonist have been looked at in ADPKD before because it's a good idea, it's a lower cyclic AMP. The thing -- so SST2, SST3 and SST5 are all found in the kidney. So why SST3. And this is kind of one of the main underpinnings of our idea about developing a selective somatostatin 3 agonists. So SST2, what I have here is some staining that we've done and looked at for mice in -- for ADPKD mice and also tissues from ADPKD patients. And what they show is that in healthy individuals and normal mice, you get nice expression of both 2, 3 and 5. But when you go to disease mice or patients with ADPKD, you can see that SST2 expression goes down. And the manifestation of that in treating disease is that an SST2 agonist likeoctreotide and lanreotide has been used in the past, will often have some activity. They will work a little bit and they will help kidney volume or EGFR. And -- but that activity will wane as the disease continues to progress a little bit. And so SST2 good, but not the right one. SST5 activity and expression remains high in both -- both mice and patients with ADPKD. But the problem there is if you treat -- SST5 is an incredibly potent suppressor of insulin secretion and so if you do that, you end up having -- you end up raising glucose, you end up raising people's HbA1c, you can turn them into diabetics, and that is not what you want to do for an ADPKD patient at all. And so -- in the middle there is the expression of SST3, also highly expressed in the ADPKD mouse model and as well in ADPKD patients. We think that this consistent expression in the ability to lower cyclic AMP levels with SST3 gives all the benefit of restoring that ratio of calcium and cyclic AMP, hopefully without the safety -- the on-target side effects that you would find with an SST5. I went back in here, I just wanted to show you a little bit more in the -- from the discovery that we did. We've run a lot of compounds in our SST2 and SST3 assays. And what I did is I went back and I pulled out all of them just to show you kind of the selectivity of SST2 versus SST3. And here, I've highlighted both paltusotine in 1941, the molecule we sent to -- we license to loyal. You can see that they're very potent for SST2, very weak at SST3, For 10329, 10329 is very, very potent at SST3 activation, not much activity at SST2. And so like all our molecules, we've got a bunch of different scaffolds that we're interested in. These are potent selective for SST3. They've got all the ADME properties that we want that once a day and the whole thing. And 10329 is our leading candidate, it is predicted to have once-a-day human dosing. I'll show you some data in an ADPKD model, and it's currently in IND-enabling studies. So the model that we used for ADPKD and you go back and when I was talking about 25 minutes ago. And I said how everything was translatable in endocrinology from preclinical models to healthy volunteers to patients. We don't quite enjoy that with ADPKD, and this has been something that's been known in this arena for a while, but there's not a great model and then the mouse doesn't quite recapitulate what happens in patients. But the best model that we know out there is one where we can induce cyst formation by knocking out PC1 in mice. And you can see we have this model, which takes about 3 weeks, return on cyst formation with tamoxifen, you can see in the lower right -- lower left-hand corner, you can see a healthy -- a slice from a healthy kidney to one where we've started to form cyst. This is an incredibly fast, aggressive model. And you can see kidney weight increases and cystic index increases. And one of the things we've done is we've co-localized where these cysts are in the mouse model, and these go exactly in the same places in the kidney that they do in ADPKD patients. So this is a pretty reasonable model of cyst formation, even though the cyst formation is incredibly, incredibly rapid. And so because we don't quite have the biomarkers like we did for growth hormone or insulin or thyroid hormone that we've enjoyed for other programs, we've really taken the approach to characterize this model at several levels, starting from just the macro kidney, look at the kidney and the biology of the kidney, look at the histology and tissues, look at cellular proliferation and even look kind of down at the molecular level for what's happening in the kidney. And I'll walk you through just a little bit of this data so that you can see what we've been able to do. In the upper left-hand corner is a moldy experiment there where we did -- when we dosed mice with 10329, and we're able to do a moldy experiment where we can image the concentration of 10329 within the kidney. And there's a nice overlap here with cystic kidney there in the right-hand picture. And you can see that 10329 is co-localized exactly where you would need it to be throughout the kidney to affect cyclic AMP level. So this is exactly what we would hope for in this model. And you can see here some of the data when you treat these ADPKD mice with 10329, you get a decrease in kidney weight, you get a decrease in cystic index, both in the proximal tubular and collecting DUCs. And then we looked at cellular proliferation in both those -- in both highly -- highly proliferative cells in the course of the whole kidney as well. And that's in the right-hand side of the graphs. And so 10329 is affecting all these things in the direction that you would want. One of the other things that we've looked at is a couple of markers, kind of at the RNA level. And one of these is -- so when you knock out -- when you knock out -- when you create these PKD knockout mice, one of the things that happens is you get an increase in a marker called periostin. Periostin is known as a modulator of growth within the cell. And you also get a decrease of this microRNA30a. And so what happens here is if you have an increase in periostin, you get increased cellular proliferation, you get increased cyst formation and the microRNA30a -- it's job is, it blocks that it inhibits that. So really, you've got a kind of a double whammy in these mice because periostin is going up, the thing that stops periostin is going down, so you get this really rapid growth assists. And after 10329 treatment, you can see that periostin levels go down to baseline, and you get a very nice increase in microRNA30. So this is what you would hope to see in a molecule that could normalize this disease and bring the kidneys back to kind of a healthy state. And so we think that this actually has a chance to be -- an SST3 agonist has a chance to be a kind of a new standard of care, and this goes back to what I was talking about a little bit earlier, a lot of what we think about is how can the molecules that we make change the practice of medicine. This is one where if we had the right molecule that could normalized cyclic AMP and calcium levels within the kidney, retard the progression of disease and not have the side effects that kind of the current therapy tolvaptan does, I think this would be an incredible win for patients. So we think this 10329 is capable of treating patients at any stage of the disease, including earlier in the disease to help halt disease progression, that would be fantastic. We have every reason to expect based on what we know that this should be an efficacious in patients. We think that SST3 presents a really compelling case for being well tolerated and should not have -- some of the data that we have suggests that you're not going to see the hypernatremia that you see in what you can manifest in rodents and is what keeps people from taking tolvaptan. And of course, it would be everything that we always do kind of target oral once a day dosing, take it, forget it in the morning kind of thing. So this is the hope for this SST3 program and ADPKD is super excited about this opportunity. And the vision here, I've kind of gone into this, so I won't spend a ton of time talking about the vision. But we think this is -- this could be a new standard of care for this patient population. We've learned some of the things that are being done in this arena and ADPKD, there are new endpoints that are being used, including total kidney volume, an eGFR that the agency seems to be willing to work with. We can go into patients who are earlier in their disease than patients who are typically getting treated, especially those who are getting on tolvaptan. And I think here, the one that's also important is ADPKD is a ciliopathy, right? And there's a lot of -- and what happens at the cellular level and the molecular level in ciliopathies is somewhat similar. And so ADPKD is a ciliopathy. There's other ciliopathies out there that we might be able to treat. And one of the other ones is polycystic liver disease. And so we're curious to see and excited to see how SST3 agonist might perform in PLD as well as ADPKD. And so what's coming up next for us in this program. We are in the midst of our IND-enabling studies and getting that package together to submit to start a Phase I. We're hopeful for IND clearance in the near future. And we'll be doing a Phase I study. This will be done in healthy volunteers and we're thinking about what we might be able to see in healthy volunteers that convince us that an SST3 agonist is doing what we want it to do. That's all I have for the SST3 program at the time. Thank you for your attention. I think we have a break. I'm going to turn it over to Gayathri for a little bit of housekeeping here.

We're going to take a brief break now until 10:25. So for those of you here in person, we still have coffee and snacks, there's a terrace out if you want to go around and talk to management. For those of you on the webcast, please be back online at 10:25, we'll continue with the presentation at that time. Restrooms are out that way as well if you need. [Break]

Hi, everybody. Thanks. We're going to continue with the program here and the second half of our programs that we're going to talk about today is 9682, our non-peptide drug conjugate program. I'm going to kick us off kind of with a little bit of the concept behind it and the idea of how we got to the molecules we got to. So one of the things that prompted this idea around creating non-peptide drug conjugates was a synthesis of 2 ideas that we had seen evolve in the oncology space over the last decade or so. And one of these was the use of dotatate scans for patients who have SST2 expressing tumors. And so here on the left-hand side, I've got an image of a NETs patient who using a copper dotatate scan and you can see that the NETs are clearly indicated as well as, unfortunately, some metastasis as well. But this is pretty -- this is getting to be more standard. And then, of course, the growth of PRRT in oncology also kind of stems from this. And so that was one of the things as we were thinking about these conjugate ideas of delivering payloads to tumors. One of the first things we started with was this idea around creating non-peptide compounds that were delivering radio nucleides either for imaging or for therapy. And this idea -- this program actually works so well, and I said this a little bit earlier, we started Radionetics, and spun that out in the fall of 2021, and that is off and running and doing its thing. But as we were thinking about it, we're like, well, radio nucleide, isn't the only thing that you need to deliver or that you might want to deliver. And so we had thought about, well, what if you could -- radiotherapy, PRRT has some limitations, and we'll talk about that in a little bit. But one of the things that we thought, well, what if you could deliver like kind of like a successful ADC. What if you could deliver a payload that was toxin to the tumor, but without some of the hassles of ADCs. And so this is where this idea of a non-peptide drug conjugate sort of arose from in us. And we thought that an SST2 targeted payload with a toxin would be a great way to kind of integrate ourselves, a, we've been working in carcinoid syndrome and neuroendocrine tumors. We knew this space. We knew that there is still a need for better treatments there especially if you could deliver something because one of the things about GPCRs is they're very difficult to raise an antibody too. And so they're very difficult to drug with ADCs. But we, of course, have lots of ways to make molecules that will go to the receptors that we want to be selective for the receptors that we want. And we try to think about how we could get them to deliver payloads to the tumor cells specifically. And we opted to go with MMAE as our first one because it's been used in ADCs very effectively. And we've done enough in vitro work to know that MMAE was effective at killing at least in vitro cells derived from neuroendocrine tumors in SST2 expressing tumor cells. So a combination of an SST2 agonist MMAE seem like a great first thing to go for. Of course, we're starting in NETs because we know this area really well. There's still a real unmet need here. But the figure on the right is supposed to indicate there's a lot of tumors out there that express SST2 and an incredible amount of unmet need in a large population that could really probably benefit from a very specific and targeted therapy. So NDCs are designed. So I'm not showing you the atomic level structure of our NDCs, but this is actually a space-filling model of what one of our NDCs looks like. And they're comprised of 3 components. One is the targeting ligand. One is a linker. And the linker is not just a spacer between the targeting ligand and the payload. It actually has a lot of purpose as well. And then, of course, the payload. And we think that this configuration had a lot of benefit compared to some of the therapies that are out there. Now, of course, chemotherapeutics aren't going to be -- it's not very hard to think of something working better than many of the chemotherapeutics. They're not tumor specific. They've got a low therapeutic window. They are across the whole system of the body. But we think about antibody drug conjugates, which have been, I think, vexing and waning in interest over the last couple of decades. And they can be effective in a lot of areas, but they have a couple of liabilities, a, they're biologics, so they're hard to make. They don't get very good tumor penetration in solid tumors. The other thing is they last for a long time and in the circulating plasma circulation. And this can actually help -- it actually lowers their therapeutic window as well because as they get chewed up in the plasma, all your releasing is the toxic payload into the system, which is what you don't want. And of course, we talked a little bit about the radiotherapy, radio imaging and PRRT. Again, I think some incredible data coming out of some of these things. But there are limitations even as we were starting NETs, we knew there were some limitations here, which is one of the things that spurred this idea of NDCs. And it really comes around, a, difficult to manufacture. You got a really difficult supply chain sometimes with some of these radio nucleides, you've got to create them in situ in the place of -- in the clinic. And then, of course, patients are limited in their -- how much radiation they can absorb over the course of their lifetime. So we thought that NDCs sort of took the best aspects of radiotherapy, took some of the best aspects of ADCs, combine them together to get something that we think can be pretty transformative for patients. 9682, which Stacey Harte is going to tell you more about is the first of what I hope will be many NDCs to come out of Crinetics. It is an SST2 agonist with a linker and then the payload. The agonist, we've talked a lot about SST agonists. This one is specifically designed to go to the receptor, get internalized by the receptor in that kind of -- remember that cartoon I shared with the endosomal signaling is designed to do that and get the payload released. And here, the payload is MMAE, which we had shown in preclinical or in vitro experiments should be effective against tumor cells. The thing about the linker, I want to make sure and impress upon you guys, it's not just the spacer between the 2 active parts of the molecule. The linker actually has a lot of craft behind it in terms of how we make them, and these are synthetic, right? So unlike a biologic, we are not limited by how you can attach payload to an antibody or a peptide or anything like that. So we get to make these by chemical synthesis in the way we make all of our molecules, but they're designed to be stable in plasma. They're designed to be cleaved specifically in the endosome. And then we can also use them to modify the physical chemical properties of molecules so that they're soluble, so that they have the tissue distribution that you want. All the things that you -- the -- I guess I'd say NDCs have their own little water balloon that we work on to make sure that they do the things that we need them to do. But I don't want to go out into the future, but I do want to talk a little bit about the future before we go back to 9682, because I do think of all the things that we've been able to create, I think of this -- I don't love to use the word platform, but I am going to use the word platform because this gives us an opportunity to really think about from a targeting standpoint, what receptors are we targeting, how do we make the small molecules to target them. We have a lot of experience there. We understand these receptors as we talked about. So we can make a lot of -- we can make a lot of NDCs that target different GPCRs. The payloads, I think, are a fascinating thing. You can think about how you might deliver either different payloads, a different toxin than MMAE, maybe more than one different toxin. And you might not even think about this in terms of delivering toxins. There could be other things that you might want to deliver to a tissue of interest. And of course, we've got a whole group back in San Diego, thinking about this and making these different constructs and seeing what they can do in the lab. And then of course, the linker, of course, as I was talking about, gets really optimized so that it's stable in plasma so that the overall molecule has the properties that we're looking for, and so that it's this whole combo of activity, payload, biophysical properties that is going to make an NDC kind of the best drug that it can be. And these are optimized in the same way that we optimize every atom for every molecule that we make. And so I'm super excited about these. I think there's going to be next generation of these and sometimes it's almost like what do you want to make next is almost the hardest question because there's so many opportunities here. We could probably spend a whole R&D day just talking about NDCs. But I will turn it over to David Metz, neuroendocrinologist who we've worked with from time to time. And as Gayathri said, have been President of North American Neuroendocrine Tumor Society. He's going to talk to us a little bit about NETs and why this is still an unmet need in oncology.

Great. Thanks, Steve. Thank you, everybody. It's a pleasure to be here today. I want to be giving sort of a background on the status of neuroendocrine tumors and neuroendocrine neoplasms, just so that you can get an idea of the landscape that Crinetics is addressing. So neuroendocrine neoplasms. They are rare tumors arising from neuroendocrine cells throughout the body, and the correct term these days is neuroendocrine neoplasm. That's because the neoplasm consists of 2 different subgroups, neuroendocrine carcinomas or NEX and neuroendocrine tumors, or NETs. As I suggested, they originate in a wide range of organs, most them, about 80% plus have somatostatin 2 receptors that can be identified with imaging so that they help towards the [indiscernible] approaches that we've been talking about. And the spectrum of disease, as I've just mentioned, spreads from well-differentiated indolent slow-growing tumors that are there for a long time that are incurable in many cases, to the very poorly differentiated, rapidly growing tumors that behave just like a cancer. So that would be neuroendocrine carcinomas as opposed to the neuroendocrine tumors, the so-called carcinoid was an old term used to describe like carcinoma, but not quite as aggressive. These tumors often present, as I've suggested, at a very advanced stage. And in fact, about 50%, 58% of patients with neuroendocrine tumors present with widely metastatic disease. This is in contrast to normal carcinomas that you could think of normal solid tumors where you have a primary that is relatively large grows, develops lymphadenopathy and then spreads to other organs into the bones. In neuroendocrine tumors, it's an upside down kind of picture. You have a very small primary tumor. You have a conglomerate of lymph nodes around it, but the bulk of the tumor actually is metastatic, often in the liver. And that is what ultimately causes the mice for these patients. So that liver-directed therapies are reasonable approaches. These tumors can be functional or nonfunctional. Here, we mean functional in terms of tumors that produce products that give you hormonal syndromes, various different kinds in various different locations. And in that situation, there's a potential to diagnose this early if you have an astute physician who thinks about the syndrome, but even in that situation, often, tumors are already metastatic. On the right-hand side, I've given a figure here of the more traditional approach as we talk about [indiscernible], gastroenteropancreatic neuroendocrine tumors, the GI tumors on the left and the pancreatic ones are on the right. The pancreatic ones can be functional and -- or nonfunctional, many different functional syndromes. The GI NETs, if they functional tend to cause the carcinoid syndrome, carcinoid syndrome, which you know from related to paltusotine being the most common of all the functional neuroendocrine tumors and therefore, a good one to go for first. The GI elementary [indiscernible] are traditionally divided into forgot, midgut and hindgut, and that does have some relevance in terms of their clinical behavior. And sometimes you worry about the primary side more than the actual tumor. But as I'll show you in the next couple of slides, it's really the biological behavior of these tumors that is important. The lungs are an interesting offshoot. You can think embryologically as the lungs as being a derivative of the foregut. So that would fit into the foregut group or you can talk about pulmonary neuroendocrine tumors and thimic neuroendocrine tumors as being in a separate group. So at the bottom, I've listed there, the 3 most common sites, the pancreas, the GI tract, the elementary track, the so-called carcinoids bad term or the lungs. And depending on what grade of tumor you're talking about, you might be separating those out in terms of extra pulmonary or extra pancreatic. And the reason I've said that -- made that distinction for you is that the extra pulmonary neuroendocrine tumors in terms of the NETs are very important because there's a different treatment paradigm for small cell lung cancer and NETs that are not in the lungs. And on the other side of the coin, you talk about the extra pancreatic and the pancreatic neuroendocrine tumors because in the lower-grade tumors or the well differentiated tumors, there are different chemotherapeutic approaches depending on if it's a pancreatic primary or non-pancreatic primary. So with that background, it is important to recognize that neuroendocrine tumors are increasing rapidly and they're becoming really a prominent cause of patients seeking help. On the left is an example of the incidents and how it has increased over other malignancies in time. And you can see in this figure that the increase of neuroendocrine neoplasms is outpacing the development of standard solid tumors. And we don't really know 100% why this is. It's partly just because of improved imaging. It's partly because of increased endoscopy procedures, but it's also just because we don't understand why this is happening. On the right-hand side, I want to point out that although the biggest increase is in early-stage disease based on imaging and endoscopy, it's not limited to this. And the increases in localized, regional, distant disease as well as the various grades of severity. And this is sergrading, not the grading I'm going to be talking about in a minute. Let me just also mention that this study is from Arvind Desari at MD Anderson from 2017. And yesterday, he republished the entire analysis updating it to the modern era was published yesterday showing that these trends have continued. So I've alluded to the difference here between NEX and NETs. So I just want to go into that a little bit more so that you can get an idea of where Crinetics is trying to pigeon hole or use the NDCs going forward and finding the various possibilities without leaving opportunities on the table. So on the left, we've got the neuroendocrine tumors. They are all well differentiated tumors. If you look at them under microscope, they won't look like malignancies and such. So I'll have a few mitotic figures. They'lll be very uniform, have pale cytoplasm with a nice little nuclei and they don't look like they're going to really be an ugly sort of tumor, but they are and they do grow. And they can be graded as Grade 1, Grade 2 and Grade 3. And these gradings depending on mitotic figures or what's called the KI-67 index. And the reason for that distinction was determined post hoc because GI Grade 1 tumors tend to behave quite nicely and slowly, and you don't need to get too excited about it. And in the older days physicians would say, don't worry about it, you'll live with this tumor, which is not true. On the other hand, you have the G2s, which are relatively more aggressive. They have a higher KI-67 and those are going to grow and will need therapy. And more recently, this is really a new update is the G3 well differentiated group that we know are the highly aggressive, well-differentiated neuroendocrine tumors that often have somatostatin receptor positivity quite densely and would be a good target for a somatostatin directed drug. The neuroendocrine carcinomas on the other hand, are all poorly differentiated. So when you look at these under a microscope, you'll see [indiscernible] cells. They're not all the same size. Some of them are dark, some of them are light. They look like a malignancy and they all are high grade. And there, you need to think of 2 kinds. There's a small cell and a large cell. That in itself is not much of a distinction, large cell neuroendocrine carcinomas are really rare. But the small cell lung cancer would be in the lung and small cell NEX can be extrapulmonary and the current therapy differs between those 2 groups. As I've mentioned, as you can see in the purple arrow there, as you go from left to right, the aggressiveness increases, your likelihood to get a response with therapy is going to be easier to show. But on the other hand, as you can see in 2 lines down, the more frequent patients are those that have relatively lower grade tumors. Again, 58% with metastatic disease, they're ultimately going to succumb to the disease. When are you going to intervene? So you have to sort of decide where you want to pitch your product over here. The SSTR expression, the somatostatin receptive expression also is highest in the lower-grade tumors, less in the poorly differentiated patients, but you don't want to leave that opportunity on the table until you've had a look at it. And in terms of long-term outcomes, the NEX do poorly and the NETs do better and it's dependent on grade. So this is how I think about treatment for neuroendocrine tumors. No 2 patients are the same. I think that's something we really stress in the field. Everybody needs their own sort of thoughtful tumor board approach treatments. But it's based on what is going to make a difference in the long term. A recent study out of Europe suggested that there are 4 major predictors of outcome. First of all, the stage and extent of disease and whether that depends on tumor bulk greater than 25% or 50% in the liver is sort of still being studied, but the amount of disease makes a difference. The grade certainly makes a difference. There have been many studies showing that. And the differentiation, obviously, will make a difference with poorly differentiated NEX, definitely doing worse than well-differentiated NETs. Does the primary tumor site make a difference? It certainly does in terms of some of the approaches to therapy. And it may, but it may also be in part related to the KI-67 and the behavior of that particular patient. So we don't really know that completely, but it has been shown to be an independent variable. And finally, the last issue is age of the patient, something that you obviously cannot change when they walk in the door to see you. So the algorithm that I've tried to summarize over here on the right-hand side is as follows. You diagnosed with a neuroendocrine neoplasm, a NET or a NEC. If it's locally resectable or regional disease, you can take out the tumor, you can remove as much as possible. You can potentially cure somebody if you catch them early enough, even if they have lymphadenopathy. That is still a potentially curable situation. And you might do that and then sit and wait and see what happens after surgery or you might want to put them on to some kind of a maintenance treatment, which we'll get on to in a little while. However, if you can't remove all of the tumor, but you can debulk, it is also an opportunity, and we now are starting to believe that if we can reduce the tumor bulk by 70% or more. 70% is not that much, right? You can leave a lot of potential tumor behind, but make a significant impact. So that there will be a large population of patients who go to surgery have their tumors resected. And I'm talking more about the lower grade group here. And it will have tumor left behind that you then can watch or treat with a product that isn't going to be too onerous for the patient to take. Once you've decided the surgeries are done deal, your next step is to determine is this a fully differentiation or well-differentiated tumor. If it's fully differentiated, the standard of therapy or certain types of chemotherapies and there are different types of chemotherapies depending on if it's a neck or a NET. And that's an important distinction to make. So there are different studies -- sorry, a pulmonary or extra pulmonary neck. So the [indiscernible], they're using different therapies like FOLFOX and FOLFIRI and in the pulmonary small cell lung cancer, there's now immunotherapy being utilized. That's the IO therapy. For the well differentiated tumors, you get the slow-growing patients with metastatic disease that's rolling along the might be have comorbidities. You don't necessarily want to do anything. A large population are just being observed. Many of them are going on to somatostatin receptor ligand therapy and those that are receiving that in a recent paper that's just come out suggests that actually SRL therapy is better than watch and wait, even in small tumors, and that was a study limited to the pancreas specifically. On the right-hand side, what happens about the tumor has got progressive disease that's growing, that's symptomatic that you think you need to get on top of and control quickly. Well, if it's -- since a liver bulking deliver dominant disease often in these patients, there is a role for liver-directed therapy and hence, multidisciplinary discussion. But as far as systemic therapy is concerned, the traditional approach for NETs is to separate into pancreatic and non-pancreatic, and the reason for that is that chemotherapy regimens with Cap TAM are felt to be better in the pancreatic group than in the non-pancreatic group, that's still open to some debate. And then you have a bunch of different treatments. You can use the somatostatin receptor ligands. If it's low growing and slow and not a big worry for now. PRRT, as I'm sure you all know, has grown, and there are going to be lots of new PRRT molecules coming to clinic in due course. It has a tremendous advantage of being the best odds -- best duration of response, but there are issues with PRRT, as was alluded to by Steve earlier on. The kinase inhibitors and the mTOR inhibitors will block specific therapies and they have a lesser duration of efficacy. They have some side effects, but there certainly is a role for those. And cabozantinib, as you all know, is something that is coming to fruition soon. And finally, there are various types of chemotherapies that can be considered here. The cap TAM regimen specifically, but then there's all the FOLFOX, FOLFIRI [indiscernible] group for the GI NETs. And then there's all the combination therapies with immunotherapies and PD-L1 inhibitors and all sorts of other treatments. So there's still a lot of space to sort of improve on this. And there is no consensus about appropriate sequencing of treatment and when one treatment ultimately fails what's your next approach? So to end off here, I've listed on the left-hand side, the expected outcome, as you would hope for with the various classes of systemic treatments that are available. These tumors, as we've suggested, are incurable when we had a static regardless of the grade and it's just a matter of inexorable time. But you don't want to use up all your therapies too soon and cause too much in the way of adverse events. So the somatostatin receptor ligands are favored early on because they cause stability potentially of tumors, they're very well tolerated. They have a variable duration of response in patients. Some do well for many, many years. some change quite quickly and you need to go into the next treatment. When you go into the next treatment, you've got your options of PRRT, the kinase inhibitors with -- the mTOR inhibitors as well or cytotoxic chemotherapies of various kinds. Those 3 lines of treatment, you would potentially expect some kind of response and the frequency or the rapidity with which you want to response may also impact on your choices of therapy. They all have their potential issues with side effects, some more severe than others. The best duration of response at the moment is PRRTs. We're not sure what's going to happen with the future PRRTs that seem to be potentially more affected, but may not be as well tolerated. The kinase inhibitors have a defined response time and the cytotoxic chemotherapies also ultimately are going to have issues related to side effects and ultimately, other issues limiting their use. So there is a significant opportunity in the neuroendocrine neoplasm space, both NETs and potential NEX to find drugs that will kill tumor cells rapidly and effectively, that will improve the efficacy, especially in these rapidly growing aggressive tumors, that will address the limitations of PRRT which is excellent, but not the be all and end all, namely the fact that you can't take it forever, and you're going to get limitations with radiotherapy, radio activity. That will provide a better risk-benefit ratios after patients have moved on from SRLs and ultimately improve the quality of life and survival. I tell my patients, well I told my patients when I was in practice that we would grow old together. And hopefully, my aim is to keep them with the neuroendocrine tumor until I retired and they carried on living and hopefully, that was achieved with many of the patients. So with that background, let me now pass it on to Stacey Harte, who is the global product lead for this very exciting molecule that we're going to hear about next.

Hi, I'm Stacey Harte. I'm the global product leader for 9682. I'm really excited to be here today to talk you about -- to talk to you about all the great progress that we've made so far in the program. So 9682 is a first-in-class novel non-peptide drug conjugate. As Steve discussed, it's designed to selectively target and deliver payload to SST2 expressing tumor cells. So let me walk you through how it works quickly. So we have 9682 binds to overexpress SST2 cells on the surface of the -- on-cell surface. It's been internalized where the linker is cleaved by lysosomal enzyme specific to the tumor, releasing that MMAE payload, that payload MMAE is a tubulin inhibitor that stops cell division and eventually leads to cell death. Here, we use in vitro data to show that 9682 was purposely designed to be selective for and internalized by SST2. Using cyclic AMP production assay, we show that -- if you look at the blue line, we show that 9682 is both highly potent and selective for SST2 in comparison to the other somatostatin subtypes. Using the endosomal trafficking assay, we show that SST2 is trafficked into cells in a very similar fashion to the native somatostatin agonist SS14. These data give us confidence that 9682 has desirable pharmacology and trafficking properties for bringing -- for delivering payload into SST2 expressing tumors. The data on this slide really demonstrate that we design 9682 to do exactly what we want it to do, which is to deliver that payload into these SST2 expressing tumors with overall minimal systemic exposure to free unconjugated payload. In the left, you can see intact 9682 has both rapid uptake and clearance from the tumor and the plasma. And on the right, we see that free MMAE has rapid uptake into the tumor, peaking at about 24 hours and then it's retained in tumor out to 10 days, or longer. In contrast, we can see that the free MMAE in the plasma has a low concentration and is rapidly cleared, thereby minimizing that overall systemic toxicity that we would expect from unconjugated payload. Here, we're showing that 9682 inhibited tumor growth in 2 small cell lung cancer xenograft mouse models typically used in NETs in a dose-dependent manner. So we first studied lower doses in H52 tumor model, and we show antitumor activity in a dose-dependent manner with the highest dose showing some kind of tumor inhibition. On the right side, we show in the 869 model that we took higher doses in and we show induced tumor regression across all dose levels with higher doses. Here, this data got us really excited. Here we grew up large tumors in the xenograft mouse model, and we're showing that we have demonstrated significant antitumor activity with tumor inhibition at all dose levels and complete regression seen at the 2 highest dose levels, 1 mg and 3 mg per kg with no impacts to body weight. So these data are just a small subset of data that we have that gave us confidence in the 9682 molecule to bring it forward into the clinic and into patients. Our first-in-human Phase I/II basket study is named [BRAVESST2]. It's a dose escalation followed by a dose expansion. And the dose escalation, we'll evaluate escalating doses until we reach the maximum tolerated dose, then we'll select the best dose that we'll take into the expansion phase, where we'll study that dose across different types of tumor types by cohorts. Our eligibility criteria allow for the inclusion of patients with neuroendocrine tumors, neuroendocrine carcinomas or other SST2 expressing tumors. We'll be using the somatostatin Dotatate scan to confirm that patients have the right level or adequate level of SST2 expression in their tumors. We know that SST2 is a well-validated target for neuroendocrine tumors, and we look forward to the opportunity of how we can expand 9682 into other SST2 targeting tumors like you see here on this slide, metastatic breast, glioblastoma, et cetera. So we've talked a lot about 9682 today and NDC platform, and we want to remind you that we have paltusotine, which I shouldn't have to remind you, but we have paltusotine in the clinic for carcinoid syndrome. And we believe that both paltusotine and 9682 really have the potential to offer distinct and complementary treatment options for patients with neuroendocrine tumors. 9682 can really address those metastatic patients that have progressive disease, really eliciting that true antitumor response needed in that patient set, where paltusotine is really addressing carcinoid syndrome or patients with functional tumors providing that rapid and consistent symptom control with an oral therapy. And together, in the future, potentially, there's an opportunity for combination use where we can broaden the therapeutic approach with both therapies together. We believe our strategy with 9682 and paltusotine really unlocks the full potential for addressing patients for improving outcomes and enhancing quality of life in the broadest set of NETs patients possible. David mentioned that the incidence and prevalence of neuroendocrine neoplasms continues to rise. The latest data from the -- 10-year prevalence data from the analysis that we did in 2024 with the SEER data shows there's approximately 200,000 patients diagnosed with neuroendocrine neoplasms. Of those, a majority of them are really not treated with medical management. They are in the -- that kind of addressed by surgery, as David also mentioned, or they're really those patients that physicians are doing watch and wait. They have those lower-grade tumors or they have really nonfunctional tumors. On the other side, we have a smaller percentage of about 28,000 to 51,000 that are undergoing various types of medical management. And this is what we see as our first -- as our real initial opportunity for both paltusotine and 9682, with paltusotine really addressing the population of patients that are on SRL therapies and 9682, really addressing the population of patients that need that antitumor agents. So I'm really excited today for the future for us to share this program with you and to think about the future of where the program is going. We announced earlier this quarter that we cleared the IND. So we're on our way to the clinic. We're looking forward to enrolling patients in our Phase I/II BRAVESST2 study, then taking insights from this dose escalation to really determine the best tumor cohorts to expand into and what other tumor types we work in. And then looking to Steve and his team to see what kind of new indices this Discovery Group is going to bring forward from our pipeline. And with that, I want to thank you, and I think I'm turning it back over to Steve at this point.

Thanks, Stacey. I got to say I'm not allowed to have favorite children, but I really actually do love 9682 a lot. So again, apologies for those who weren't here a little earlier, Scott's laid up a little bit with a GI bug and wasn't able to make it today, which I know will infuriate him because he's been looking forward to this for a long time. So again, I'll do the closing remarks here in his stead, hopefully, do a good job. So you've heard today kind of what's coming next for the company and for the compounds that are either in the clinic or about to go into the clinic. But I wanted to take a minute and remind everybody here of the pipeline that we've been able to create over the last 10 years, and think about the upcoming milestones that are coming up for everything that's going on. Of course, the biggest one for us is the PDUFA date for paltusotine and acromegaly in September. But we've got carcinoid syndrome coming up. We've got all the work going on in atumelnant. And then, of course, the molecules and programs that we talked about today. And of course, in the Discovery Kitchen, we're always cooking up something new, and we're always thinking about what the programs are that are going to be behind that and maybe those are going to be the Tobi's told me, I probably had to do another one of these in the future. So maybe that will be for the next R&D day. But we really do think that, like I said at the beginning, we always had this idea that we could create a sustainable company that grew its own pipeline, that brought meaningful therapeutics to patients that really needed them, not just the next me-too things, but things that can meaningfully impact patients lives and maybe even change the practice of medicine. And that's been -- that -- the continuing fruition of that vision has been incredibly gratifying to me. And I'm excited as we transition hopefully into a commercial company, we're transitioning into even a larger pipeline company. I'm excited to see that and see what this company becomes over the last part of this decade and beyond. And really, this is kind of sets up the stage for the future. We've done a lot of transitions at Crinetics. And you saw some of those in the time line slide that I showed you. And we're coming up on another big one. And I do foresee the things that aren't going to change. We've got the -- I think I'm -- like I said, I'm incredibly proud of the people who do the discovery work in our -- in our labs. We've grown an incredibly effective and knowledgeable development team in terms of both the way we design our clinical trials and the way we execute them. I think that was crystal clear in the PATHFNDR studies and the way that they came out, just a remarkable achievement. So we've got R&D going really well. We're going to do very well as a commercial company. And we're well capitalized right now, and I look forward to having the revenue that we hope to generate to start funding -- funneling back into the company and funding the future. And I -- like early -- all of our IP stretches out to 2040 and beyond. So I think one of the real -- as a founder, one of the things that's probably the most exciting thing is the long-term plans -- when we were -- when we were small, the long-term plans we were making were like, what are we going to -- like how are you going to survive next quarter or next year? And now the long-term plans we're making are into the 2030s and beyond. And I'm super excited about that, and I hope -- I hope -- I hope I can convey that excitement to everybody here in the room and everybody at home. That's where I'll leave it. Thank you all for coming here today. I am -- I will invite the other speakers up here to the stage so that we can answer your questions that we might have left for you.

Doug Tsao, H.C. Wainwright. I guess on the TSH antagonist program, obviously, one of the attractive attributes of the molecule is its ability to potentially address both graves disease as well as Ted. I'm just curious how you're thinking at this point in terms of the development program and the sort of maybe is one of those indications sort of prioritized over the other. And I know you sort of alluded and in conversations with Scott in the past, you sort of alluded to the potential value being the opportunity to prevent the development of Ted. And I'm just curious if you have thoughts in terms of the practicality of running a clinical development program that would be able to demonstrate that?

Thanks, Doug. Yes, I'll answer briefly, and then I'll turn it over to Rick, who I think spends a lot of time thinking about this. I don't really see them as 2 different indications. It's the same mechanism that's manifesting in different ways for Graves. And so I think by the right TSH antagonist is going to be able to treat both of those indications. So I don't really see them as 2 indications. But we're in the process, as we approach Phase 1, of course, we're always thinking about like what happens in Phase II, and I'll let Rick answer that.

Yes. I think you touched on it really well, Steve. I think if 12755 works as we expect, you see it's got a potential to be a really important new therapy for both all aspects of Graves disease. I think the first step for us is to really get this into the clinic and really establish efficacy in both of those and then take it from there. I think as you mentioned, it has potential to only treat hypothyroidism, but prevent incidents of thyroid eye disease, too. And we'll love to see that in the clinic.

Alex Thompson from Stifel. I guess another question on TSH. As you're thinking about what you're going to be dosing, how to think about the therapeutic next year, do you think you're going to need to drive patients to full hypothyroidism by blocking the receptor completely and the signaling there? Or is there going to be a sweet spot? How do you think about that in the context versus ablation therapy?

Thanks, Alex. That -- it's an insightful biological question. And it's one that we've considered, I think one of the difficulties in treating thyroid patients is the fluctuation in thyroid patients. And so you can imagine a world where it might be easier to block and replace, but we're thinking about that a lot. Rick, you can probably speak to that as well.

Yes. I think obviously, this is a new mechanism of action. And I think this certainly benefits of a titration approach and potentially, there could be upside of a block and replace. And I think that's something that we'll look to establish as we move into the clinic, and we really understand the treatment effect and how this mechanism works in patients. So I think it's something that will really define what's the optimal approach as we move into -- as we go through the clinic.

Joe Schwartz from Leerink Partners. So it doesn't seem like a lot of dose ranging work was done in teprotumumab development. They might have just selected a dose that was safe and well tolerated. How -- another question on your TSH program, Steve, since you talked about how the SST3 receptor distribution might be advantageous relative to vasopressin V2. How high of a concentration do you need to achieve in the kidney to have adequate target engagement there versus how do you think about the therapeutic index of inadvertently targeting SST3 extra-renally?

Yes. Thanks, Joe. That's a good question. I think about this, one of the things that's been interesting is -- one of the things I really like about the study that we did that showed how we got into the kidney is seeing the levels -- the concentrations that we were able to achieve in the kidney with kind of the doses that we were using. I will say that one of the things we're thinking about is in comparison to -- we use a lot of the work we've done on other somatostatin agonist to know how much we need to have on board. So we're thinking about that pretty actively. But I don't have a dose range or anything like that as a number that I'm looking for. But looking at the data we have and the data we expect to see in Phase I studies, I'm pretty sure we'll be able to cover that. Now you think about what the on-target effects of SST3 activation in other parts of the body might be it's interesting to think about SST3 because it's found in the pituitary, it's found in the pancreas. But we don't have a lot of data that would suggest that there's going to be any deleterious on target effects that we've been able to manifest in any of our safety studies so far. But we are definitely keeping an eye on that, but I feel pretty good about that margin.

Max Skor with Morgan Stanley. So I have a question around the neuroendocrine neoplasia's SST2 expression through the different lines of treatment. And the potential for, let's say, a selection for resistant subclone if you are targeting SST2 and it's being internalized, just thinking about how it changes over time through the course of treatment?

David, I'll let you speak to that or Stacey, you guys are probably best.

So yes, that's a very good question. And I think what's being done currently with patients who receive PRRT is if you receive your PRRT, you respond, you go another year, you get another scan, you look like you're stable and then you grow later. The current approach is to get another data at scale before you determine whether you're going to be able to use PRRT again. Eventually, you run out of it, the repeated PRRT does have some effect, but not as durable and not as responsive as the first time around. The possibility of selecting clones, I think, is a real issue. And as you get to the higher grade tumors, you will start thinking about getting FDG pets as well as getting Dotatate PET scans because the higher grade lesions may be selected whether it's from prior treatment or just naturally occurring, I don't think it's been established. But that is a legitimate concern. On the other hand, you don't want to leave the possibility behind that you may well have an SST or responsive disease. And here, you've got a drug. So this Phase I trial, I think, is appropriately as broad as it can be. And ultimately, it might narrow down, and that's the subsequent cohorts in the expansion phase. But Stacey can comment about how they're going to move forward there.

Well, I think I described it when I presented, and I think the data will drive what tumors we enroll in kind of in this escalation phase, what kind of PK and efficacy, early antitumor effects we see. And then really, that will help us inform what exact tumor types to take into the expansion phase.

First, first of all, great presentation all of you. So that was very, very helpful. I guess as we -- first question is for Rick. So Rick, are you envisioning the clinical development to be in Graves patients who have been refractory to antithyroid medications? Or would you be just looking patients who are just naive coming in with Graves. Second one is, I think the regulatory path has been paved with the anti-Fc, anti-FcRns. I'm wondering if that's sort of the thought process for a future Phase III would be? Or would it be slightly different, and I know it's a little tough to ask. And then maybe a question for Tobi. Based on the modeling that you're doing, what assumptions are you making for these 3 programs that are in early stage, how far the cash could take you to sort of development, and then I'll pass the mic back to Megan.

So thank you -- that's a really great question. I think on your first question around uncontrolled ATDs, I think that -- as a clinical development option, that's a potential for us as maybe a first in-human proof-of-concept study as it enables a placebo-controlled trial, as you can see. I think as you sort of heard from the presentation, we see this as a really important new therapy potentially addressing standard of care for Graves disease. So ultimately, our hope is that we can bring this with many patients as we can -- and obviously, exactly what the late-stage development program looks like and obviously exactly how we proceed for the clinic. We're still evaluating. I'm just trying to remember the second part of your question, the pivotal trials was it? Yes, that's really going to depend on obviously, exactly what we go after and how we're going to sequence things. But we're not envisaging focusing just on controls on ATDs at this point.

Yes. And thanks, Yas. we're in a very fortunate position in this business right now to have over $1.3 billion of cash. And the company has really demonstrated over its entire history to be very well disciplined on the allocation of that capital. And as we've said, we've guided that cash will take us into 2029. And that's what puts and takes. There's obviously things that happen in an earlier stage that are exciting developments, and there are setbacks as well. But we think that when you balance all those puts and takes, balance the future commercial potential of paltusotine, both in acromegaly and carcinoids. The investments we're making in our Phase III programs in carcinoid and CAH, in Cushing's disease, we feel like we're really well capitalized to get us through 2029.

Brian Skorney for Baird. Maybe sticking with the TSH program. I'm just wondering -- I was a little surprised to see I think you showed slides showing autoantibody reductions preclinically. I was just wondering what would be the mechanistic rationale for why TSHR antagonist would result in reduction of autoantibodies. And then on the ADPKD program, -- just the tachyphylaxis of SST2 agonist, I'm just wondering, is there a redundancy between 2 and 3? And if maybe SST2 can get down regulated if you operate [indiscernible] SST3?

Okay. So Rick, why don't you address the auto antibody question for TSH first?

Sure. Thank you for the question. I think -- I don't think we didn't show any data, I don't think, on reduction of thyroid stimulating auto antibodies. Obviously, clearly, that's not something we can directly expect with this kind of mechanism. But it's certainly going to be something that we're going to be monitoring in the clinic, especially as we think about -- as we move through, that's going to be one of the important endpoints or measurement look to see the effects on those circulating antibodies from this mechanism as we move forward.

Can we listen to your second question again?

[indiscernible] So I was just wondering if you could -- is there any concern you can see a similar effect that both tumor-related [indiscernible]?

Yes. So what we know so far in ADPKD and somewhat in PLD is that SST2 highly expressed and healthy wanes with progression of disease. SST3, highly expressed and healthy doesn't seem to wane with the progression of disease. And that's why we think an SST2-based agonist like some of the ones like some of the peptide agonists some of the depots kind of work early and then their efficacy wanes. But we don't foresee that with SST3. We -- we'll obviously watch it, but there's nothing from a receptor biology's perspective that we know right now that's going to -- that suggests that, that's going to be the case.

Tyler Van Buren from TD Cowen. A couple of questions. Maybe I'll start with Steve's favorite child, 9682. Can you talk about the starting dose that was approved by the FDA? Is it an abnormally low dose like we've seen with some of the novel bispecific platforms because it's a new technology? Or is it possible that it could be higher and closer to the therapeutic range? And then the second question is related to the ADPKD program. So other than the advantage of being once-daily oral with no titration, how would you expect 10329 to compare to the miRNA 17 inhibitor by Regulus, now Novartis in terms of efficacy and safety?

So I'll start with the ADPKD question first. That data is so young. I want to see more data there before I can weigh in on what I expect there. I mean I'm intrigued by their data, but I want to see it play out over time. I want to see what their safety looks like over time. But -- Yes. So I don't think there's a comparison. There's honestly not a comparison to make there. I think we feel that SST3 is going to be beneficial period there. To your question about the dose, I don't think we're going to talk about specific doses in the Phase I, but I'll let Stacey talk about this is a -- these are fairly prescribed ways that these starting doses get started. So I'll let in Phase I in oncology. So I'll let Stacey speak to that.

I would just comment that we have an FDA-cleared starting dose, and it has potential to be within the therapeutic range. But with most dose escalations in oncology, you start with lower doses and you escalate up really until that maximum tolerated dose. So the FDA does take a more conservative approach with wanting you to start with lower dose levels in patients.

Jon Wolleben with Citizens. A follow-up on 682. You showed a graphic about tumors with presentation of SST2. And I'm wondering, do you have a sense if there is a threshold necessary for effectiveness or if it's a binary present or not. And would that be kind of the best predictor of efficacy? Or is there anything else along grade or tissue targeting that could factor in as well?

Thanks, Jon. Yes. So I mean we sort of have a little bit of a slang in the lab. It's like if you can see it, you can treat it, -- but certainly, SST2 expression is that level of SST2 expression as much as you can get a quantitative versus a qualitative feel, I think, could be instructive for how the therapy might be effective in patients. But I don't think of it in a quantitative way. I do think from a clinical practice standpoint, it is -- it's a well-accepted method now. And I think we would feel very confident going to the patients with positive images from Dotatate scan. David, do you want to add any color to that?

Yes. I would say that the -- you're talking about the [indiscernible] score from the old the PRRT trials. Those were based on Octrea scans, which aren't done any longer. So in terms of the Dotatate scans or the PET CT scans, there is some suggestion that maybe higher SUV counts imply a better receptor density and more efficacy. But I don't think that has really been shown. The idea is that you have to -- we would have in this trial, a density greater than liver sort of like [indiscernible] and that way, you'll know that there's enough density there to get a response. In the higher grades, where you may find some heterogeneity the issue is going to be to actually look at known lesions that are higher than liver and to compare those, whereas your point is well taken, that it might be the marker is actually the density of the response not studied.

Cory?

So you've obviously taken an extensive iterative approach to molecule design across the pipeline. Thinking about this as it relates to the options available for cytotoxic payloads for the NDC program. How did you specifically land on MMAE as a match for 9682. And is there any -- coming back to your water balloon analogy? Is there anything specific about MMAE that pairs well with either the NDC approach or specifically in SST2 expressing tumors? And I guess as a follow-up, can you walk us through the rationale of not including symptomatic carcinoid syndrome patients in those initial studies?

So I can answer the question about 9682 and the choice for MMAE. Like we were kind of saying earlier, this is our first NDC we wanted to use a targeting mechanism moiety we were very comfortable with. And we knew that MME -- as something that has been widely used in ADCs, we knew it was -- we knew what to look for from a safety standpoint, which I think was really important for us and specifically for this first molecule. And then in our in vitro program, we went and made sure that MMAE itself would be cytotoxic to the cells and tissues that we were -- tumor types that we were targeting. So that combo gave us confidence that this was the right thing to go for as a first NDC to make because it gave us -- we would be able to understand them targeting, we'd be able to understand the toxicity. And as the first NDC out of the gate, that seemed like a great choice to us. Stacey, I'll let you talk to the inclusion of carcinoid.

Yes. So for our first in-human study, we decided to not include patients with carcinoid syndrome because we really wanted to get the cleanest profile that we can with 9682. As you know, carcinoid syndrome patients have a lot of complications. And we just -- we wanted to kind of make sure that we don't have that noise in the first-in-human trial. But we do anticipate that later -- in later studies enrolling patients that have carcinoid syndrome once we know the profile of 9682 in patients.

Catherine Novack from Jones. I have a question on the ADPKD program. When you mentioned polycystic liver disease, are these patients who have concurrent liver sets with ADPKD? Or is this a complete label expansion opportunity?

So the question is around PLD versus ADPKD. So a lot of patients who have PLD arise from having PKD. So we look -- I look at this as sort of a specific subset of ADPKD patients not entirely separate.

Thinking about other, I guess, ex renal manifestations of ADPKD I know that CNS manifestations are also common. And I know thinking about the locations of SST3 that may not have a direct impact, but do you think there could be any indirect benefit on -- such as aneurysms that occur?

That's a super fascinating question. So I think -- so the question is, is does the effect arise from the mutation? Or does the effect arise from the disease? That I honestly don't know the answer to and is probably worth looking -- it is worth looking into. Another question at the back.

Brandon Frith with Wolfe Research on behalf of Andy Chen. In regard to the Graves and Ted opportunity, I believe you commented on being equal to or better than Tepezza. Does that confidence stem from primarily the mechanism? Or is there a quantitative piece of that in the clinical -- in the mouse models that you can point to that you think will translate well to in the clinic?

No. This comes from an understanding of the mechanism, right? So if you think of what happens in thyroid eye disease, right? So that cost that is an activation of TSH, which causes downstream activation of a TSH or IGF-1 or complex, right? So the underlying mechanism, the first thing that happens is activation of TSH, right? Everything after that comes after. In Graves, of course, having an antibody IGF-1 doesn't do anything for Graves, right? And so it is the -- mechanistically, it's the right thing for Ted. It's the right thing for Graves. And if we get it right, you should be able to prevent the development of Ted in the presence of Graves. So it is definitely about the mechanism.

[indiscernible], JPMorgan. Can you just talk about the anticipated time lines for IND submission in Phase I trials for CRN-12755?

Yes. So I think everything that we have guided to since our last call still is in place. We are driving towards IND, hopefully, by the end of the year. And as that gets closer, I'm sure we will give you a refined timing on that. Anything else? Okay. No, going once, going twice. I will invite everybody to have a little bit of lunch out on the patio. Thank you all for coming and for your participation. This was very exciting for us. It was super glad to be here. And as always, feel free to stop and ask us any other questions, especially ones about nerdy science. Happy to talk about that. All right. Thank you very much.