Good morning, everyone. Welcome to Crinetics Pharma's 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 sweltering on your way here. For those of you joining virtually, welcome to the webcast. We will be making forward-looking statements today, so I'll pause for a few seconds on the slide for you to absorb all of the fine print. Let's see. The speakers today, you all know Scott Struthers and Dr. Stephen Betz, the co-founders and CEO and Chief Scientific Officer. I think the real superstars of today's presentation are our global product leaders, our GPLs. The GPLs are the CEO of their molecule, and they oversee the process from they chaperone the molecule from discovery all the way through clinical development to commercialization. They are 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 has been involved in a lot of prominent clinical trials and has published over 200 papers. Also, we have Toby Schilke, our newest CFO. He will be joining for Q&A. We have Jackie Kirby, our Chief Corporate Affairs Officer. We also have other people from Crinetics. 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 is that we wanted to talk about every molecule, every indication. Unless you want to come for a week of Crinetics summer camp, we thought we had to be efficient in what we actually cover. 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 the SST3 agonist for autosomal dominant polycystic kidney disease, 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. We will 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 will open the floor up for Q&A. For those of you here in person, we will have people running around the mics, and we invite those of you on the webcast to submit questions through the Q&A function. We ask that you hold your questions until the end. We will have plenty of time for Q&A. 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. You will see some of the reasons why today. I have to 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. 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 will spend a little time talking about kind of our philosophy around discovery and how we approach it. Honestly, I mean, this is not kind of an easy thing to say, but we 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 21st-century medicines for the diseases that they had. This seemed like a pretty tall order back in 2010 when we opened our first lab, but I think you are seeing some of the fruits of that labor over the last decade or so. We are not going to spend a lot of time talking about acromegaly. This is more about the stuff that is earlier in the pipeline. I wanted to point out, like Tracy in this slide, she is an acromegaly patient. She has talked to us about her disease and about her journey as a patient and about the needs that the acromegaly community has. This is something that we do all the time, is get to know our patients, get to know the people who have these diseases and the people that are treating these diseases. It is one of the core fundamental things, I think, as we have grown the company that we have tried to incorporate into everything that we do. You will see some of that today. Again, we are not going to talk about paltusotine, but I will just answer the question because I am sure it is one that everybody has. So far, so good on the NDA, and its PDUFA date is on September 25th. 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. 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. We wanted to get as many people as we could in person, so we thought we would come here to New York. We have kind of highlighted here what goes on in the building on a daily basis. You can always come and probably find a couple of dogs in the building, always willing to say hi and be friendly. The dog wall is there for perusal. Really, it is the scientists doing the work in the lab that are the real stars here. They are absolutely killing it. I am so grateful for the people that have been able to work in our labs. They are really remarkable. I wanted to spend a little time talking about Crinetics and the history in case some folks have not heard this story before. 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 four of us as co-founders, myself and Scott and Frank and Anna and our two dogs, Penny and Princess. We had always been a dog-friendly company. When you start a company, you have to do a lot of jobs that you are not trained to do. I was head of HR, which is terrifying to the people who work for Crinetics right now. We decided, like, well, we can bring our—why cannot we bring our dogs into work? They will do fine. It has been something that has remained part of our culture ever since. I think people really like that. We really did bootstrap our way. I do not know if you guys remember what it was like in 2008, 2009, 2010. It was a really tough economic time. It seemed like a crazy idea to start a company in that environment. It was actually, in some ways, kind of a good time to start a company. 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. We got a bunch of ideas, the fruition of which you will see later in this talk. One of the ones that took hold earliest was the somatostatin II program, which ultimately led to paltusotine. 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 the last part of 2015. That really catalyzed the company into a different stratus. 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. 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. The IPO in the summer of 2018 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. We started taking paltusotine into the clinic. Now, earlier, we've always wanted to be a pipeline company. 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. We used to have this saying that I think a lot of folks at Crinetics, this idea of no good idea left behind. We've been talking, as we think about how we make molecules and what we want them to do, one of these 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? We had this idea around, could we use this to make radionuclides and deliver radionuclides, both for imaging and for therapy? 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 that original picture, they went off and were part of the founding team of Radionetics. Scott is still on the board of Radionetics. They are off and running. You will see some of the fruition of that idea kind of in the story around 9682 and our non-peptide drug conjugates. Stacey Harte will tell you that story. Over the last couple of years, the Pathfinder studies for acromegaly, both Pathfinder I and Pathfinder II, have been completed. They were the basis of our NDA, which we submitted at the fall of last year. 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, the company continues to grow. I think fulfill this idea that Scott and I had when we started the company of making a 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. It is, I can't tell you how exciting it is to see it come to fruition. That's us today. Starting from four, we're now over 500. That's our new facility. Even though we're not there today, if you guys are ever in Southern California, I want you to stop in, say hi, see the lab, see the dog wall. I'll bring Enzo in. It'll be good. Thinking about where we are as a company, this is a tough couple of years for biotech. I feel very fortunate that Crinetics is in such a good position as it is. We're in a really good spot. The pipeline's doing really well. We're starting the phase III's in CAH and carcinoid syndrome. Today, we're going to talk about the pipeline, some of the stuff kind of below the fold if you're in journalism. It's this combination of kind of our understanding of endocrinology. We're rooted in endocrinology, and we understand the mechanisms of endocrinology and how that might affect diseases that maybe some people don't think of as endocrinological diseases. 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. We've got a good balance sheet. 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 at JP Morgan this year. This is kind of our idea around what we're thinking about for Crinetics and where it was founded in kind of pituitary science. You see paltusotine for acromegaly and originally for Cushing's disease, atumelnant. 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, 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. 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. Today, we're going to talk about the things that are here that are probably closest to clinical development for us. Actually, one of them is already in clinical development. We're going to talk about, as Gayathri said, our approach to Graves 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 they're 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. And the way that cells and tissues communicate with each other are through hormones. And too much or 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've spent decades making molecules and testing them against targets. This is what we do, and this is our expertise. We are particularly good, I like to think, at making these small molecule drugs that interact with these peptide receptors. There was a long time when we actually had to answer the question of, like, how do you do this? I think we've done it enough to suggest that we kind of have this. The current indications, I kind of showed that on, I think, what I think of as the solar system chart. These are a lot of important indications where patients need, really, they need new therapies. 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. The endocrinology in our preclinical models in rodents often mirrors the endocrinology that you see in a healthy volunteer study and a phase I study that mirrors the endocrinology that's going to arrive in a patient. One of the things that we've been able to enjoy or de-risk, 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. It's one of the things, like, people say, oh, like, when paltusotine worked in acromegaly, how excited were you? I'm like, well, I knew it was going to work. There was no doubt that it was going to work. There's always a doubt of, like, oh, you're going to get the PKU one, or you're going to have some weird thing, idiosyncratic thing that pops up. That's what I worried about. I never worried about whether it was going to work or not. Let's spend a little time talking about GPCRs. 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. I guess at a certain level, that's basically what you're trying to do. 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. We have programs where we have agonists and antagonists. You can see them. I've listed them here. Sometimes you're looking for the primary signaling that you might want out of G protein coupling. That's cyclic AMP or inositol phosphate. Most GPCRs, when they are activated by an agonist, a lot of times they will become internalized. 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 back to the cell surface. This dynamism in GPCR activity actually 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-arrestin recruitment and internalization? We'll talk about 9682, our NDC. That's actually, we've designed that to get internalized because we want that process to pull the payload we want into the cell. 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 for patients in the end, but how do we get there? What does that look like? I'll show you a little bit of the data from the SST2 agonist program that led to paltusotine. Part of the reason here, I don't want to take any of the thunder away from Rick or Stacey or any of the other programs we're going to talk about today. This is a complicated slide because, honestly, discovery is a complicated business. The one thing here, there's a whole bunch of stuff here for in vitro pharmacology, in vivo pharmacology, for safety, for drug-like properties. Frank, one of our co-founders from that picture of the four of us and our two dogs, he used to call this a water balloon. Frank, he'd 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. You're always trying to optimize all these things all at the same time in probably 10 or 11 dimensions. The other thing here is this is the assay cascade for SST2. It doesn't look like any of the other assay cascades 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. This goes back to, so this was actually kind of fun putting this slide together because I got to go back and look at some of the really old data that we had from the bootstrapping era. 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. The structure of 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. 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. As we think about making molecules, I guess there's a point where, like, do we take that one forward? Do we not take that one forward? We actually, our philosophy is you've got to make, you've got to have the right target. You've got to have the right molecule that's going to solve for what we're trying to do here. 351 was close, but it wasn't quite right. We wanted to really dial out that SST4 activity. 351 was actually good enough. This was the molecule in the data that actually prompted our Series A because we were able to convince folks in the investor community that we were on the track to making a non-peptide somatostatin agonist. That was probably a good investment from our Series A folks. 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 the one that we did in rodents. If you go on, the data in Acrobat and the data in Pathfinders especially speaks for itself. 808 did in patients exactly what it was designed to do, which is very gratifying to see. I wanted to show this here. This kind of goes to Frank's water balloon. This is fun for me because I get to go into the database and pull stuff out of the database, and I do not get to do that as much as I used to. I made a chart here of every molecule we made for our SST2 program. I highlighted 808 there in Crinetics Green. You can see that it's potent. It's somewhere, it was the 808th molecule that we made. It came out of this cascade. 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. In terms of the water balloon, it solved just about everything. That was the one that we moved on. I think that's something that I think a lot of people who don't work in discovery probably don't appreciate. 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. You could have a whole course on how this molecule came to be. It does exactly kind of what we were hoping for it to do. 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, ethylamine, 12755, whatever we're going to talk about. 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% sure, right? You're always like, OK, I'm going to push this forward because I think it's worth the investment to push this forward. What if something happens? Sometimes things happen. I brought up two examples here, and this is the program we're not talking about today. In the paltusotine program, we decided we needed to make a backup because, A, it was the company's lead program at the time. We wanted to, we knew that if 808 failed for some reason, that we needed a backup for the company, right? It was an existential threat to the company to lose its lead assets. We actually came up with 1941, which is another molecule that we made. It was ready to go. We actually took it all the way through the end of phase I because we wanted to make sure we had something ready in case something happened to the lead molecule. Paltusotine performed, and it performed, and it performed, and now it's in registration. We had a clinical class compound sitting on the shelf. A couple of years ago, we got together with some folks that we used to work with back in the bootstrapping era. They're like, oh, talk to these guys who are working on the endocrinology of aging, and they're using dogs as a model species for that. We actually licensed out 1941 to this company called Loyal for dogs. It's been a real pleasure to work with them. 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 breaks. This is a great opportunity. We had a backup. We didn't need it. Now we're going to use it for something else. 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. 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. 4599 looked great until it had a problem, a developability problem around stability in a solid form. We do not need to go into that part. We had 4894, which became atumelnant, right behind it. We probably lost, I do not know, a month or two in that development program for Cushing's and CAH. Having these backups ready to go is part of what we do. In fact, it is kind of its own little water balloon. It 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? That is one of the things that we always talk about. How many backups do you have? How far do you take them? What do you do with them once the lead molecule is off and running? That is a little behind the curtain there. The last thing I want to come back to is patients. I think it is easy to say that we are a patient-focused company. I remember going to the Endocrine Society meeting in 2015 and meeting Jill Sisco and the members of the acromegaly community for the first time. This was before we ever had, we had data from compound 351 that I showed you. We were not going into the clinic yet. We wanted to understand patients because I'll tell you, one of the things I've learned 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. If you want to understand medical need, talk to patients because they live it every day. They understand their disease differently and better than anybody. We incorporate, by talking to the folks in the acromegaly community and, of course, in the Cushing's community and, of course, in these other communities, 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're doing and what they need and what patients are experiencing. 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. Always happy to talk about this stuff. For now, we're going to get on the main events. We're going to talk about TSH receptor antagonist. I'm going to bring up the Global Product Lead, Rick Grimes, for that. Thank you, Steve. 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. 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. 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, or about 3 million people. It has two main manifestations. That's hyperthyroidism and Graves' orbitopathy, also known as thyroid eye disease. For Graves' hypothyroidism, there's a number of significant symptoms: irritability, tremors, fatigue, and can cause major complications, including atrial fibrillation, heart failure, and thyroid storm. This has significantly negative impacts 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. 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%-50% of patients with Graves' disease. 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 tissue and connective tissue. In severe cases, it can lead to vision impairment and vision loss and blindness. 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 diplopia, but also bulging of the eye, also known as proptosis. This can lead to significant anxiety and depression and can lead to a lot of social withdrawal. The vision impairment can also impact just daily tasks, such as reading and driving. For Graves' hypothyroidism, there has not been a new therapy for these patients since the middle of the last century. The standard of care has been stagnant for decades. Although it is relatively effective, it has imperfections and significant limitations. Recently, the oral antithyroid drugs have become the highly preferred standard of care and first-line treatment for Graves' hypothyroidism, accounting for about 90% of first-line therapy. This is due to the risks associated with the ablative therapies. Ablative therapy is where there is ablation of the thyroid function, either through dosing with radioactive iodine, which destroys the thyroid cells, or surgical removal of the thyroid, known as a thyroidectomy. Although it is definitive treatment, it has limitations, such as it renders the patient permanently hypothyroid, which leads to the need for lifelong thyroid hormone replacement therapy. As you can see here on the slide, there are a number of other risks associated with these procedures, including with radioiodine. There is an increased risk of incidence and exacerbation of underlying thyroid eye disease. Turning to antithyroid drugs, these oral antithyroid drugs work by inhibiting thyroid hormone synthesis. Although they are effective, especially if the patient is compliant, they have a number of significant limitations. Firstly, although they do not exacerbate thyroid eye disease, they do not treat or prevent orbitopathy. As I mentioned, this affects 30%-50% of patients. 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. A new therapy that is able to control the hypothyroidism while also co-treating and preventing orbitopathy, that does not have the adverse effects associated with antithyroid drugs and would be hugely valuable and also well co-treated and treated in TED, has potential as a really important new therapy for Graves' patients. Turning attention to Graves' orbitopathy, with the approval of Tepezza, the anti-IGF-1 therapy in 2021, this really changed the treatment paradigm and is the first and only approved treatment for thyroid eye disease. It is relatively effective. It does improve the symptoms associated with thyroid eye disease. 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 mm reduction in proptosis. However, many patients do experience a relapse and a recurrence of 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%-20% of patients, some of which is permanent, and secondly, hypoglycemia. There are a number of other safety risks that I've noted here. It is also not suitable for all patients, including those that have irritable bowel syndrome, diabetes, or any pre-existing hearing impairment. There is really a need here for a treatment that is as effective as these first-generation products or anti-IGF-1s, but with much improved safety. As I am sure many of you know, Graves' disease is an autoimmune disease that is characterized by the production of thyroid-stimulating autoantibodies, also known as TSAbs. It has two major manifestations, which are hypothyroidism and orbitopathy. The core driver of these manifestations is the overstimulation of the TSH receptor by these stimulating autoantibodies. 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 hypothyroidism. In the eye, in the orbital fibroblast, these TSAbs also bind to and stimulate the TSH receptor. 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 significant inflammation, a lot 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' hypothyroidism 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-IGF-1 therapies block only the activation through the IGF-1 receptor. IGF-1 activation is not required for thyroid hormone synthesis. Therefore, it has no effect for hypothyroidism. The TSH 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. That changes us to our approach, so TSH receptor antagonism. TSH receptor antagonism has the potential as a targeted novel mechanism to treat all of the manifestations of Graves' disease, including hypothyroidism 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 autoantibodies. In the middle panel, in hypothyroidism, in the thyroid, it would block the activation of the 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 autoantibodies. By that crosstalk, 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. Essentially, one therapy to treat all manifestations of Graves' disease. At Crinetics, we are developing small molecule TSH receptor antagonists. 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. It has predicted human PK to support once-daily dosing. As I'll show you in a moment, it was demonstrated efficacy in a preclinical model of Graves' hypothyroidism. We have demonstrated its ability to inhibit the activation of the TSH receptor in Graves' patient orbital fibroblast. It is currently going through IND-enabling studies, which are in progress. As you can see here on the right panel, 12755 is a potent antagonist of the human TSH receptor of approximately eight nanomolar. It is also slightly less potent as an antagonist of the TSH receptor, which is great because it enables us to put this and study this in our preferred Graves' model. At Crinetics, we have studied 12755 in our in-house rat model of Graves' hypothyroidism. 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. 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 a vehicle or an ascending dose of 12755 orally. You can see here we get a rapid dose-dependent response and reduction of the T4 thyroid hormone levels. You can see at the higher doses, within that first day, there's a return to baseline. 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' hypothyroidism in the clinic. We have also studied the ability of 12755 to not only inhibit the TSH receptor in the thyroid, but also its ability to block the stimulation in the eye. Just as a reminder, one of the effects of TSH stimulation by these autoantibodies in the eye is production of hyaluronic acid. Hyaluronic acid attracts and binds 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 TSAb. You can see here in the center panel that 12755 is able to dose-dependently suppress the production of hyaluronic acid when stimulated by this human-stimulating antibody. Not only is it able to block the stimulation by this isolated antibody, it is also able to block stimulation by autoantibodies from 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 of the TSAPs themselves. Finally, it leads to increased cellular proliferation, differentiation, and adipogenesis. 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 fibroblasts from patients as an isolated antibody in the middle and from the autoantibodies from a number of patient samples on the right panel. 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, 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 hypothyroidism and while treating and preventing Graves' orbitopathy. Our vision for the product is it has potential for the hypothyroidism 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 anti-thyroid drugs. It will preserve the thyroid and spare the need for ablative therapy. For orbitopathy, again, it will be an oral once-daily therapy. Because it blocks that same axis, the TSH receptor IGF-1 complex, we have a strong reason to believe that it has potential for equivalent or better efficacy than the currently approved IGF-1 for thyroid eye disease. More importantly, with that improved safety. None of those on-target hearing impairment or hypoglycemia. This improved safety could enable longer treatment duration and therefore improved durability. It has very much potential as a single therapy to address limitations in current standard of care for both hypothyroidism 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 Graves' hypothyroidism. We still believe that a TSH receptor antagonist still has potential advantages over these emerging new products. As you've heard me go through the profile, one of the major classes that's in development is the second-generation anti-IGF-1s. These are either 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, on whether they will be able to thread that needle and overcome the on-target side effects of the anti-IGF-1 additions, such as hearing impairment and hypoglycemia. The second major emerging class is the IgG degraders. These come in two major forms. Firstly, the anti-FcRn monoclonal antibodies and small molecule bispecific degraders. These work by reducing the levels of these circulating thyroid-stimulating autoantibodies by promoting their degradation. However, they are not specific to the stimulating autoantibodies. They broadly degrade IgGs. Data is suggesting that they may require large and sustained and deep IgG reductions to maintain efficacy. Finally, they are all high-dose, once-weekly subcutaneous injections. The population itself, 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' hypothyroidism and orbitopathy. Hypothyroidism affects approximately 1% of the population, which is approximately 3 million people. Studies have shown that there's up to about 1.2 million people who actively have Graves' hypothyroidism. We see this as the potential addressable patient population for the right new therapy for Graves' disease that addresses limitations of standard of care. It has an annual incidence of new diagnoses of up to 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%-50% of patients with Graves' disease. And it's approximately 150,000 patients with moderate to severe as a prevalence and about 9,000-10,000 of moderate to severe incidents per year. A very large population with a high or met need. What's next for this program that we're excited about at Crinetics? Next month, 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. As Steve touched on earlier, with this being the endocrine target, we do expect to see the modulation of the thyroid hormones in healthy volunteers. 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. Thank you for your time and letting me share an overview of our exciting TSH program. I'm going to hand back to Steve to talk about and share with you our ADPKD program. Thanks, Rick. I did, actually, in all my free time yesterday, I was reviewing that 755 poster for ENDO. I think it looks great. I'm excited to see that one. We're going to spend a little time talking about ADPKD. This is one where I think of as kind of endocrinologically adjacent. This is one where, kind of as I was talking about before, the infrastructure of endocrinology can play a big role here. ADPKD is actually the most common inherited renal disease. It affects nearly about 150,000 people in the U.S. It is 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. Over time, you actually lose kidney function. It has a very rapid drop-off at the end. In other words, early in disease, the kidney kind of chugs along and manages to get by. Later in the disease progression, it really falls off. That leads to patients requiring dialysis and 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. It is only used in about 10% of patients. The reason for that is some on-target pharmacology as a mechanism, tolvaptan. I'll go into this a little bit. That causes frequent urination for patients, so much to the fact it becomes actually debilitating for them. This is a disease with a lot of people that need a good option and just don't have one. 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. 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. 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. That homeostasis is maintained for healthy kidney function. What happens in ADPKD, there's a mutation either in this protein called PC1 or PC2. What that does is those mutant proteins do not allow the influx of calcium. What happens is then you start to get this disproportionate ratio of cyclic AMP to calcium. This has downstream effects of turning on cystogenic signals within the kidney. This leads to the development of cysts, which leads to bad renal function in the end. Our hypothesis about this disease, 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. Let's spend a little bit talking about tolvaptan. Tolvaptan is a vasopressin receptor antagonist. Vasopressin is found on the kidneys. The thing is, vasopressin receptor activity causes an increase in cyclic AMP. 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. If you block the effect of antidiuretic hormone, what happens? You're no longer able to reabsorb water from the kidney into the system. You end up having frequent urination, very high volume urination, and very high urgency of urination. This can be 3x or more frequently than healthy individuals can have. This ends up being so debilitating, I think people would rather not be on therapy than to have to put up with this. In some ways, tolvaptan is, and this is not a side effect. This is actually the pharmacology of vasopressin in action. This is not an unexpected outcome for this drug. As we thought about it, in some ways, the right idea was lower cyclic AMP, but not have these side effects. The right way to, as we think about it, the right way to lower cyclic AMP here is to turn on somatostatin III, which is also found in the kidney and specifically found in the cilia in the region where the mutations in PC1 and PC2 occur. We did some work here. As we were characterizing this idea, we went back and we characterized the expression of SST3 within the kidney. I will not go into it for purposes of time. 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. Somatostatin agonists have been looked at in ADPKD before, because it is a good idea to lower cyclic AMP. SST2, SST3, and SST5 are all found in the kidney. Why SST3? This is kind of one of the main underpinnings of our idea of developing a selective somatostatin III agonist. SST2, what I have here is some staining that we have done and looked at for ADPKD mice and also tissues from ADPKD patients. What they show is that in healthy individuals and normal mice, you get nice expression of both two, three, and five. When you go to disease mice or patients with ADPKD, you can see that SST2 expression goes down. The manifestation of that in treating disease is that an SST2 agonist, like octreotide 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. That activity will wane as the disease continues to progress a little bit. SST2, good, but not the right one. SST5 activity and expression remains high in both mice and patients with ADPKD. The problem there is if you treat SST5, it is an incredibly potent suppressor of insulin secretion. If you do that, you end up raising glucose. You end up raising people's HbA1c. You can turn them into diabetics. That is not what you want to do for an ADPKD patient at all. In the middle there is the expression of SST3, also highly expressed in the ADPKD mouse model as well as in ADPKD patients. We think that this consistent expression and 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 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 from the discovery that we did. We've run a lot of compounds in our SST2 and SST3 assays. 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. Here I highlighted both paltusotine and 1941, the molecule we licensed 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. Like all our molecules, we've got a bunch of different scaffolds that we're interested in. These are potent and selective for SST3. They've got all the ADME properties that we want, the once a day, the whole thing. 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. It is currently in IND-enabling studies. The model that we use for ADPKD, and go back to when I was talking about 25 minutes ago, I said how everything was translatable in endocrinology from preclinical models to healthy volunteers to patients. We don't quite enjoy that with ADPKD. This has been something that's been known in this arena for a while, that there's not a great model and that the mouse doesn't quite recapitulate what happens in patients. The best model that we know out there is one where we can induce cyst formation by knocking out PC1 in mice. You can see we have this model which takes about three weeks. We turn on cyst formation with tamoxifen. You can see in the lower left-hand corner, you can see a slice from a healthy kidney to one where we've started to form cysts. This is an incredibly fast, aggressive model. You can see kidney weight increases and cystic index increases. One of the things we've done is we've co-localized where these cysts are in the mouse model. These go exactly in the same places in the kidney that they do in ADPKD patients. This is a pretty reasonable model of cyst formation, even though the cyst formation is incredibly, incredibly rapid. 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. Even look kind of down at the molecular level for what's happening in the kidney. 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 MALDI experiment where we did it when we dosed mice with 10329. We're able to do a MALDI experiment where we can image the concentration of 10329 within the kidney. There's a nice overlap here with a cystic kidney in the right-hand picture. You can see that 10329 is co-localized exactly where you would need it to be throughout the kidney to affect cyclic AMP levels. This is exactly what we would hope for in this model. 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 tubule and collecting ducts. We looked at cellular proliferation in both highly proliferative cells and in the course of the whole kidney as well. That is in the right-hand set of graphs. 10329 is affecting all these things in the direction that you would want. One of the other things that we have looked at is a couple of markers kind of at the RNA level. One of these is, 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. You also get a decrease of this microRNA- 30a. What happens here is if you have an increase in periostin, you get increased cellular proliferation. You get increased cyst formation. The microRNA- 30a, its job is it blocks that. It inhibits that. Really, you've got kind of a double whammy in these mice because periostin's going up. The thing that stops periostin is going down. You get this really rapid growth of cysts. After 10329 treatment, you can see that periostin levels go down to baseline. You get a very nice increase in microRNA- 30. 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. We think that this actually has the chance to be, an SST3 agonist has a chance to be, kind of a new standard of care. 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 normalize 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. We think this 10329 is capable of treating patients at any stage of the disease and clearing 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 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 hyponatremia that you see in what you can manifest in rodents and is what keeps people from taking tolvaptan. 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. This is the hope for this SST3 program in ADPKD. I'm super excited about this opportunity. The vision here, I've kind of gone into this, so I won't spend a ton of time talking about the vision. We think 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 in ADPKD. There are new endpoints that are being used, including total kidney volume and 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. I think here the one that's also important is ADPKD is a ciliopathy. There is a lot of what happens at the cellular level and the molecular level in ciliopathies that is somewhat similar. ADPKD is a ciliopathy. There are other ciliopathies out there that we might be able to treat. One of the other ones is polycystic liver disease. We are curious to see and excited to see how SST3 agonists might perform in PLD as well as ADPKD. What is 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 are hopeful for IND clearance in the near future. We will be doing a phase I study. This will be done in healthy volunteers. We are 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 is all I have for the SST3 program at the time. Thank you for your attention. I think we have a break. I am going to turn it over to Gayathri for a little bit of housekeeping here. Thanks. Thanks. We're going to take a brief break now until 10:25. For those of you here in person, we still have coffee and snacks. There's a terrace out if you want to go mill around and talk to management. For those of you in the webcast, please be back in line at 10:25. We'll continue with the presentation at that time. Oh, and restrooms are out that way as well if you need. Hi everybody. Thanks. We're going to continue with the program here. The second half of our programs that we're going to talk about today is 9682 and 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. One of the things that prompted this idea around creating Non-peptide Drug Conjugates was a synthesis of two ideas that we had seen evolve in the oncology space over the last decade or so. One of these was the use of dotatate scans for patients who have SST2 expressing tumors. Here on the left-hand side, I've got an image of a NETs patient who, using a copper dotatate scan, you can see that the NETs are clearly indicated, as well as, unfortunately, some metastases as well. This is pretty standard. This is getting to be more standard. Of course, the growth of PRRT in oncology also kind of stems from this. 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 radionuclides either for imaging or for therapy. This idea, this program actually works so well. I said this a little bit earlier. We started Radionetics and spun that out in the fall of 2021. That is off and running and doing its thing. As we were thinking about it, we were like, radionuclide is not the only thing that you need to deliver or that you might want to deliver. We had thought about, what if you could, and you know, radiotherapy PRRT has some limitations. We will talk about that in a little bit. One of the things we thought, what if you could deliver kind of like a successful ADC? What if you could deliver a payload that was toxic to the tumor but without some of the hassles of ADCs? This is where this idea of a non-peptide drug conjugate sort of arose from in us. We thought that an SST2 targeted payload with a toxin would be a great way to kind of integrate ourselves. We've been working in carcinoid syndrome and neuroendocrine tumors. We knew this space. We knew that there was 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 to. They're very difficult to drug with ADCs. We, of course, have lots of ways to make molecules that will go to the receptors that we want, be selective for the receptors that we want. We tried to think about how we could get them to deliver payloads to the tumor cells specifically. We opted to go with MMAE as our first one because it's been used in ADCs very effectively. We'd done enough in vitro work to know that MMAE was effective at killing, at least in vitro, cells derived from neuroendocrine tumors and SST2 expressing tumor cells. A combination of an SST2 agonist and MMAE seemed 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. The figure on the right is supposed to indicate there is 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. NDCs are designed. 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. They're comprised of three components. One is the targeting ligand. One is a linker. The linker is not just a spacer between the targeting ligand and the payload. It actually has a lot of purpose as well. Then, of course, the payload. We think that this configuration has a lot of benefit compared to some of the therapies that are out there. Now, of course, chemotherapeutics are not going to be, you know, it is not very hard to think of something working better than many of the chemotherapeutics. They are not tumor specific. They have a low therapeutic window. They are across the whole system of the body. You know, we think about antibody drug conjugates, which have been, I think, waxing and waning in interest over the last couple of decades. They can be effective in a lot of areas. 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 in the circulating plasma circulation. This can actually help. It actually lowers their therapeutic window as well because if they get chewed up in the plasma, all you're releasing is the toxic payload into the system, which is what you don't want. Of course, we talked a little bit about the radiotherapy, radio imaging, and PRRT. I think, you know, some incredible data coming out of some of these things. There are limitations. You know, even as we were starting Radionetics, we knew there were some limitations here, which is one of the things that spurred this idea of NDCs. It really comes around, A, difficult to manufacture. You know, you've got a really difficult supply chain sometimes with some of these radionuclides. You've got to create them in situ in the place of in the clinic. Of course, patients are limited in how much radiation they can absorb over the course of their lifetime. We thought that NDCs sort of took the best aspects of radiotherapy, took some of the best aspects of ADCs, combined 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, you know, remember that cartoon I showed with the endosomal signaling? It is designed to do that and get the payload released. 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 that it is not just the spacer between the two active parts of the molecule. The linker actually has a lot of craft behind it in terms of how we make them. These are synthetic, right? Unlike biologic, we are not limited by how you can attach a payload to an antibody or a peptide or anything like that. We get to make these by chemical synthesis in the way we make all of our molecules. They are designed to be stable in plasma. They are designed to be cleaved specifically in the endosome. We can also use them to modify the physical chemical properties of molecules so that they are soluble, so that they have the tissue distribution that you want. All the things that you, 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. I do not want to go 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, and I don't love to use the word platform, but I'll 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, you know, as we talked about. 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. You know, 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. 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. The linker, 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. It's this whole combo of activity, payload, biophysical properties that is going to make an NDC, you know, kind of the best drug that it can be. These are optimized in the same way that we optimize every atom for every molecule that we make. I'm super excited about these. I think there's going to be a next generation of these. 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. I will turn it over to David Metz, neuroendocrinologist, who we've worked with from time to time. As Gayathri said, have been president of the 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'm going 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. Neuroendocrine neoplasms, they are rare tumors arising from neuroendocrine cells throughout the body. The correct term these days is neuroendocrine neoplasm. That's because the neoplasm consists of two different subgroups: neuroendocrine carcinomas or NECs and neuroendocrine tumors or NETs. As I suggested, they originate in a wide range of organs. Most of them, about 80% +, have somatostatin 2 receptors that can be identified with imaging so that they help towards the theranostic approaches that we've been talking about. The spectrum of disease, as I've just mentioned, spreads from well-differentiated indolent, slow-growing tumors that are there for a long time but are incurable in many cases to the very poorly differentiated, rapidly growing tumors that behave just like a cancer. That would be neuroendocrine carcinomas as opposed to the neuroendocrine tumors. The so-called carcinoid was an old term used to describe like a carcinoma but not quite as aggressive. These tumors often present, as I've suggested, at a very advanced stage. 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 and to 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. The bulk of the tumor actually is metastatic, often in the liver. That is what ultimately causes demise for these patients. Liver-directed therapies are reasonable approaches. These tumors can be functional or non-functional. Here we mean functional in terms of tumors that produce products that give you hormonal syndromes, various different kinds in various different locations. In that situation, there is a potential to diagnose these early if you have an astute physician who thinks about the syndrome. Even in that situation, often tumors are already metastatic. On the right-hand side, I have given a figure here of the more traditional approaches. We talk about GEPNETs, gastroenteropancreatic neuroendocrine tumors, the GI tumors on the left, and the pancreatic ones on the right. The pancreatic ones can be functional or non-functional, many different functional syndromes. The GI NETs, if they're 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 tract carcinoids are traditionally divided into foregut, midgut, and hindgut. That does have some relevance in terms of the clinical behavior. Sometimes you worry about the primary site more than the actual tumor. 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. That would fit into the foregut group. You can talk about pulmonary neuroendocrine tumors and thymic neuroendocrine tumors as being in a separate group. At the bottom, I've listed the three most common sites: the pancreas, the GI tract, the alimentary tract, the so-called carcinoids, bad term, or the lungs. Depending on what grade of tumor you're talking about, you might be separating those out in terms of extrapulmonary or extrapancreatic. The reason I've made that distinction for you is that the extrapulmonary neuroendocrine tumors in terms of the NECs are very important because there's a different treatment paradigm for small cell lung cancer and NECs that are not in the lungs. On the other side of the coin, you talk about the extrapancreatic 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. 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 incidence and how it has increased over other malignancies in time. You can see in this figure that the increase of neuroendocrine neoplasms is outpacing the development of standard solid tumors. We do not really know 100% why this is. It is partly just because of improved imaging. It is partly because of increased endoscopy procedures. It is also just because we do not 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. The increase is in localized, regional, distant disease, as well as the various grades of severity. This is SEER grading, not the grading I'm going to be talking about in a minute. Let me just also mention that this study is from Arvind Dasari at MD Anderson from 2017. Yesterday, he republished the entire analysis, updating it to the modern era. It was published yesterday, showing that these trends have continued. I've alluded to the difference here between NECs and NETs. I just want to go into that a little bit more so that you can get an idea of where Crinetics is trying to pigeonhole or use the NDCs going forward and finding the various possibilities without leaving opportunities on the table. On the left, we've got the neuroendocrine tumors. They are all well-differentiated tumors. If you look at them under a microscope, they won't look like malignancies as such. They'll have few mitotic figures. They'll be very uniform, have pale cytoplasm with nice little nuclei. They don't look like they're going to really be an ugly sort of tumor. They are, and they do grow. They can be graded as grade one, grade two, and grade three. These gradings, depending on mitotic figures or what's called the Ki-67 index. The reason for that distinction was determined post hoc because GI grade one tumors tend to behave quite nicely and slowly. You do not need to get too excited about them. In the olden days, physicians would say, oh, do not worry about it. You will 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. Those are going to grow and will need therapy. 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. When you look at these under a microscope, you will see higgledy-piggledy looking cells. They're not all the same size. Some of them are dark. Some of them are light. They look like a malignancy. They all are high grade. There you need to think of two 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. The small cell lung cancer would be in the lung. Small cell NECs can be extrapulmonary. The current therapy differs between those two 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. On the other hand, as you can see in two 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? You have to sort of decide where you want to pitch your product over here. The SSTR expression, the somatostatin receptor expression, also is highest in the lower-grade tumors, less in the poorly differentiated patients. You don't want to leave that opportunity on the table until you've had a look at it. In terms of long-term outcomes, the NECs do poorly, and the NETs do better. It's dependent on grade. This is how I think about treatment for neuroendocrine tumors. No two 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 to approach treatments. 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 four major predictors of outcome. First of all, the stage and extent of disease. Whether that depends on tumor bulk greater than 25% or 50% in the liver is sort of still being studied. The amount of disease makes a difference. The grade certainly makes a difference. There have been many studies showing that. The differentiation obviously will make a difference. Poorly differentiated NECs definitely do 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. It may, but it may also be in part related to the Ki-67 and the behavior of that particular patient. We do not really know that completely. It has been shown to be an independent variable. Finally, the last issue is age of the patient, something that you obviously cannot change when they walk in the door to see you. The algorithm that I've tried to summarize over here on the right-hand side is as follows. You're 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. You might do that and then sit and wait and see what happens after surgery. You might want to put them onto some kind of a maintenance treatment, which you'll get onto in a little while. However, if you can't remove all of the tumor but you can debulk, it is also an opportunity. We now are starting to believe that if you 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. There will be a large population of patients who go to surgery, have their tumors resected. I'm talking more about the lower-grade group here. They 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 surgery is a done deal, your next step is to determine is this a poorly differentiated or well-differentiated tumor. If it's poorly differentiated, the standard of therapy are certain types of chemotherapies. There are different types of chemotherapies depending on if it's a NEC or a NET. That's an important distinction to make. There are different studies, sorry, pulmonary or extrapulmonary NEC. The extrapulmonary NECs, they're using different therapies like FOLFOX and FOLFIRI. 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 patient with metastatic disease that's rolling along there, might have comorbidities. You don't necessarily want to do anything. A large population are just being observed. Many of them are going onto somatostatin receptor ligand therapy. 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. That was a study limited to the pancreas specifically. On the right-hand side, what happens about the tumor? You've got progressive disease that's growing, that's symptomatic, that you think you need to get on top of and control quickly. Since liver bulking, liver-dominant disease often in these patients, there is a role for liver-directed therapy and hence multidisciplinary discussion. As far as systemic therapy is concerned, the traditional approach for NETs is to separate into pancreatic and non-pancreatic. The reason for that is that chemotherapy regimens with CAPTEM are felt to be better in the pancreatic group than in the non-pancreatic group. That's still open to some debate. There 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. 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 duration of response. There are issues with PRRT, as was alluded to by Steve earlier on. The kinase inhibitors and the mTOR inhibitors will block specific therapies. They have a lesser duration of efficacy. They have some side effects. There certainly is a role for those. Cabozantinib, as you all know, is something that is coming to fruition soon. Finally, there are various types of chemotherapies that can be considered here, the CAPTEM regimen specifically. There is also the FOLFOX, FOLFIRI, FOLFIRINOX group for the GI NETs. There are combination therapies with immunotherapies and PD-L1 inhibitors and all sorts of other treatments. There is still a lot of space to sort of improve on this. There is no consensus about appropriate sequencing of treatment. When one treatment ultimately fails, what's your next approach? To end off here, I've listed on the left-hand side the expected outcomes you would hope for with the various classes of systemic treatments that are available. These tumors, as we've suggested, are incurable when metastatic, regardless of the grade. It's just a matter of inexorable time. You don't want to use up all your therapies too soon and cause too much in the way of adverse events. 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. You need to go on to the next treatment. When you go on to 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 three lines of treatment, you would potentially expect some kind of response. The frequency or the rapidity with which you want a 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 effective but may not be as well tolerated. The kinase inhibitors have a defined response time. The cytotoxic chemotherapies also ultimately are going to have issues related to side effects and ultimately other issues limiting their use. There is a significant opportunity in the neuroendocrine neoplasm space, both NETs and potentially NECs, 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 cannot take it forever. You are going to get limitations with radioactivity. That will provide better risk-benefit ratios after patients have moved on from SRLs and ultimately improve the quality of life and survival. I tell my patients, or I told my patients when I was in practice, that we would grow old together. Hopefully, my aim was to keep them with the neuroendocrine tumor until I retired and they carried on living. Hopefully, that was achieved with many of the patients. With that background, let me now pass it on to Stacey Harte, who's the Global Product Lead for this very exciting molecule that we're going to hear about next. Thank you, David. Hi. I'm Stacey Harte. I'm the Global Product Lead for 9682. I'm really excited to be here today to talk to you about all the great progress that we've made so far in the program. 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. Let me walk you through how it works quickly. 9682 binds to overexpressed SST2 cells on the cell surface. It's then internalized where the linker is cleaved by lysosomal enzymes 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 delivering payload into SST2-expressing tumors. The data on this slide really demonstrate that we designed 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. On the right, we see that free MMAE has rapid uptake into the tumor, peaking at about 24 hours. It is 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 two small cell lung cancer xenograft mouse models typically used in NETs in a dose-dependent manner. We first studied lower doses in the H5 tumor model. 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. 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. We are showing that we have demonstrated significant antitumor activity with tumor inhibition at all dose levels and complete regression seen at the two highest dose levels, 1 mg and 3 mg per kg, with no impacts to body weight. 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 [Bravus] 2. It is a dose escalation followed by a dose expansion. In the dose escalation, we will evaluate escalating doses until we reach the maximum tolerated dose. We will select the best dose that we will take into the expansion phase, where we will 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 will 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. 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. We have talked a lot about 9682 today in the NDC platform. We want to remind you that we have paltusotine, which I should not have to remind you. We have paltusotine in the clinic for carcinoid syndrome. 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. Together, in the future, potentially, there is 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 NET 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 us approximately 200,000 patients diagnosed with neuroendocrine neoplasms. Of those, a majority of them are really not treated with medical management. They are in that kind of addressed by surgery, as David also mentioned. They are really those patients that physicians are doing watch and wait. They have those lower-grade tumors, or they have really non-functional tumors. On the other side, we have a smaller percentage of about 28,000-51,000 that are undergoing various types of medical management. 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. I'm really excited today to see for the future, for us to share this program with you and to think about the future of where the program's going. We announced earlier this quarter that we cleared the IND. We're on our way to the clinic. We're looking forward to enrolling patients in our phase I, II [Bravus] 2 study, then taking insights from the 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 NDCs the discovery group is going to bring forward from our pipeline. With that, I want to thank you. 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. Again, apologies. For those who were not here a little earlier, Scott's laid up a little bit with a GI bug and was not able to make it today, which I know will infuriate him because he's been looking forward to this for a long time. Again, I'll do the closing remarks here in his stead, hopefully do a good job. 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. 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 brief date for paltusotine and acromegaly in September. We've got carcinoid syndrome coming up. We've got all the work going on in atumelnant. Of course, the molecules and programs that we talked about today. In the discovery kitchen, we're always cooking up something new. We're always thinking about what the programs are that are going to be behind that. Maybe those are going to be the ones Toby's told me I probably had to do another one of these in the future. Maybe that'll be for the next R&D day. 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. That has been the continuing fruition of that vision, has been incredibly gratifying to me. 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. This kind of sets up the stage for the future. We've done a lot of transitions at Crinetics. You saw some of those in the timeline slide that I showed you. We are coming up on another big one. I do foresee the things that are not going to change. We have the, I think, like I said, I am incredibly proud of the people who do the discovery work in our labs. We have 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 Pathfinder studies and the way that they came out, just a remarkable achievement. We have R&D going really well. We are going to do very well as a commercial company. We are well capitalized right now. I look forward to having the revenue that we hope to generate to start funneling back into the company and funding the future. Like early, all of our IP stretches out into 2040 and beyond. 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 small, the long-term plans we were making were like, what are we going to, how are we going to survive next quarter or next year? Now the long-term plans we're making are into the 2030s and beyond. I am super excited about that. I hope I can convey that excitement to everybody here in the room and everybody at home. That is where I will leave it. Thank you all for coming here today. 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. Oh, and Toby. Doug. Thank you. Doug Tsao, H.C. Wainwright, right? 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 as one of those indications sort of prioritized over the other. 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. 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. Thank you. Thanks, Doug. Yeah, I'll answer briefly. 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 two different indications. It's the same mechanism that's manifesting in different ways for Graves. I think the right TSH antagonist is going to be able to treat both of those indications. I don't really see them as two indications. We're in the process, as we approach phase i, of course, we're always thinking about what happens in phase II. I'll let Rick answer that. Yeah, I think you touched on it really well, Steve. I think if 12755 works as we expect, you see it's got potential to be a really important new therapy for 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 not only treat hypothyroidism but prevent incidence of thyroid eye disease too. We will look to see that in the clinic. Alex. Awesome. Thanks, 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 index here, do you think you're going to need to drive patients to full hypothyroidism by blocking their 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's an insightful biological question. It's one that we've considered. I think one of the difficulties in treating thyroid patients is the fluctuation in thyroid patients. You can imagine a world where it might be easier to block and replace. We're thinking about that a lot. Rick, you can probably speak to that as well. Yeah, I think obviously this is a new mechanism of action. I think there's certainly benefits of a titration approach. Potentially, there could be upsides of a block and replace. I think that's something that we'll look to establish as we move into the clinic. We really understand the treatment effect and how this mechanism works in patients. I think it's something that we'll really define, what's the optimal approach as we move into, as we go through the clinic. I should go to the other side, Joe. Thank you. Thank you, Joe Schwartz from Leerink Partners. It doesn't seem like a lot of dose ranging work was done in Tepezza development. They might have just selected a dose that was safe and well tolerated. 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? Yeah, 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 agonists to know how much we need to have on board. So we're thinking about that pretty actively. I don't have a dose range or anything like that as a number that I'm looking for. 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. I mean, it's interesting to think about SST3 because it's found in the pituitary. It's found in the pancreas. We don't have a lot of data to 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. We are definitely keeping an eye on that. I feel pretty good about that margin. Great. Thank you. Max [Gore] with Morgan Stanley. I have a question around the neuroendocrine neoplasias' SST2 expression through the different lines of treatment and the potential for, let's say, selection for a resistant subclone if you are targeting SST2 and it is being internalized. Just thinking about how it changes over time through the course of treatment. Thanks. David, I'll let you speak to that. Or Stacey, you guys are probably best. Yeah, that's a very good question. I think what's being done currently with patients who've received PRRT is if you receive your PRRT, you respond. You go another year. You get another scan. You look like you're stable. You grow later. The current approach is to get another Dotatate scan 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. 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. 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 a responsive disease. And here you've got a drug. This phase I trial, I think, is appropriately as broad as it can be. Ultimately, it might narrow down. That is the subsequent cohorts in the expansion phase. Stacey can comment about how they're going to move forward there. I think I described it when I presented. I think the data will drive what tumors we enroll in kind of in this escalation phase, what kind of PK and efficacy, early anti-tumor effects we see. That will help us inform what exact tumor types to take into the expansion phase. Yeah, Yaz in the back. First of all, great presentation, all of you. That was very, very helpful. I guess the first question is for Rick. Rick, are you envisioning the clinical development to be in Graves' patients who have been refractory to anti-thyroid medications? Or would you be just looking at patients who are just naive coming in with Graves'? The second one is I think the regulatory path has been paved with the NTFCRNs. I'm wondering if that's sort of the thought process for a future phase III would be. Or would it be slightly different? I know it's a little tough to ask. Maybe a question for Toby. Based on the modeling that you're doing, what assumptions are you making for these three programs that are in early stage? How far the cash could take you to sort of development? I'll pass the mic back to Megan. Thank you. That's a really great question. I think on your first question around uncontrolled and 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. Ultimately, our hope is that we can bring this to as many patients as we can. Obviously, exactly what the later-stage development program looks like and obviously exactly how we proceed for the clinic, we're still evaluating. I just don't remember the second part of your question. The pivotal trials, wasn't it? Yeah, that's really going to depend on obviously exactly what we go after and how we're going to sequence things. We're not envisioning focusing just on controls on ATDs at this point. Yeah, and thanks, Yaz. We're in a very fortunate position in this business right now to have over $1.3 billion of cash. The company has really demonstrated over its entire history to be very well disciplined on the allocation of that capital. As we've said, we've guided that cash will take us into 2029. That's with puts and takes. There are obviously things that happen in earlier stage that are exciting developments. There are setbacks as well. We think that when you balance all those puts and takes, balance the future commercial potential of paltusotine both in acromegaly and carcinoid, the investments we're making in our phase III programs in carcinoid and CAH in Cushing's disease, we feel that we really will capitalize to get us through 2029. Come back to the left. Thanks, 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 TSH receptor antagonist would result in reduction of autoantibodies. Then on the ADPKD program, just the tachyphylaxis of SST2 agonism, I'm just wondering, is there a redundancy between two and three? If maybe SST2 can get downregulated if you upregulate SST3. OK. Rick, why don't you address the autoantibody question for TSH first? Yeah, sure. Thank you for the question. I don't think we didn't show any data, I don't think, on reduction of thyroid-stimulating autoantibodies. 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 we'll measure and look to see the effects on those circulating antibodies from this mechanism as we move forward. You restate your second question again? It was just on that you had said that the SLRs result in waning efficacy. I was just wondering if you could see a, is there any concern you could see a similar effect of SST3 in ADPKD, that both of them are sort of upregulated, downregulated by each other? Yeah, 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, does not seem to wane with the progression of disease. That is 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. Then their efficacy wanes. We do not foresee that with SST3. We will obviously watch it. There is nothing from a receptor biology perspective that we know right now that is going to suggest that that is going to be the case. Thanks very much, Tyler Van Buren from TD Cowen. A couple of questions. Maybe I'll start with Steve's favorite child in 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? Is it possible that it could be higher and closer to the therapeutic range? The second question is related to the ADPKD program. Other than the advantage of being once daily oral with no titration, how would you expect 10329 to compare to the mRNA-17 inhibitor by Regulus, now Novartis, in terms of efficacy and safety? 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. I want to see it play out over time. I want to see what their safety looks like over time. Yeah, 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 1. I'll let Stacy talk about these are fairly prescribed ways that these starting doses get started. I'll let in phase Is in oncology. I'll let Stacey speak to that. I would just comment that we have an FDA-cleared starting dose. It has potential to be within the therapeutic range. With most dose escalations in oncology, you start with lower doses. You escalate up really until that maximum tolerated dose. The FDA does take a more conservative approach with wanting you to start with lower dose levels in patients. Hi, John Walburn with Citizens. Follow up on 9682. You showed a graphic about tumors with presentation of SST2. I am wondering, do you have a sense if there is a threshold necessary for effectiveness or if it is a binary present or not? Would that be kind of the best predictor of efficacy? Is there anything else along grade or tissue targeting that could factor in as well? Thanks, John. Yeah, 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. 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. I don't think of it in a quantitative way. I do think from a clinical practice standpoint, it's a well-accepted method now. I think we would feel very confident going to patients with positive images from dotatate scan. David, do you want to add any color to that? Yeah, I would say that you're talking about the Krenning score from the old PRRT trials. Those were based on octreoscans, which aren't done any longer. 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. 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 a Krenning three, four. 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. Corey? You have 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? 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? I guess as a follow-up, can you walk us through the rationale of not including symptomatic carcinoid syndrome patients in those initial studies? I can answer the question about 9682 and the choice for MMAE. Like we were kind of saying earlier, this was our first NDC. We wanted to use a targeting mechanism that we were very comfortable with. We knew that MMAE, as something that had been widely used in ADCs, we knew what to look for from a safety standpoint, which I think was really important for us and specifically for this first molecule. In our in vitro program, we went and made sure that MMAE itself would be cytotoxic to the cells and tissues that were tumor types that we were targeting. 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 the targeting. We'd be able to understand the toxicity. As a 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. Yeah, 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. We just wanted to kind of make sure that we do not have that noise in the first-in-human trial. We do anticipate in later studies enrolling patients that have carcinoid syndrome once we know the profile of 9682 in patients. Hi, 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 cysts with ADPKD? Or is this a complete label expansion opportunity? The question is around PLD versus ADPKD. A lot of patients who have PLD arise from having PKD. I look at this as sort of a specific subset of ADPKD patients, not entirely separate. Thinking about other, I guess, extrarenal manifestations of ADPKD, I know that CNS manifestations are also common. I know thinking about the locations of SST3, that it may not have a direct impact. Do you think there could be any indirect benefit on such as aneurysms that occur? That's a super fascinating question. I think the question 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 into. Got another question? Oh, in the back. Hey, Brandon Fritz 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 data 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. If you think of what happens in thyroid eye disease, that crosstalk is an activation of TSH, which causes downstream activation of a TSHR, IGF-1R complex. The underlying mechanism, the first thing that happens is activation of TSH. Everything after that comes after. In Graves, of course, having an antibody IGF-1 does not do you anything for Graves. It is mechanistically the right thing for TED. It is the right thing for Graves. If we get it right, you should be able to prevent the development of TED in the presence of Graves. It is definitely about the mechanism. Hi, Abdul Tahlil, JP Morgan. Can you just talk about the anticipated timelines for IND submission in phase I trials for CRN 12755? Yeah, 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. As that gets closer, I'm sure we will give you a refined timing on that. Anything else? Nope? Nope. OK, 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. We're super glad to be here. 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.