Good morning, everyone. Welcome to the Piper's annual conference. It's day three of our conference, and I'm so thrilled. I think you all know how much I love Crinetics. He's like, "Don't tell everybody," and I'm like, "I tell everybody about it," a nd I want it to be in the transcript as well. Scott, wonderful to have you. I want to start off the fireside chat, actually, to talk about a lot of the great discovery and work that's ongoing that's not getting the attention. T hen we'll go into all the hot topics. Wherever you want to go. L et's start off with Graves' disease and TED. A key objective into 2025 is going to be IND submission for the program. P ease tell us, how do you think about TSH antagonist in Graves' and TED, and how and where you are into IND clearance and getting it in terms of POC studies, so. Great. L et me start answering the last part. W e've got a molecule that we think is pretty good by all the straightforward preclinical models we usually do. But now we got to go through the IND enabling work and prove it's safe enough for first-in-human study. T hat's obviously a rigorous process. But backing up a bit, for any of you who aren't familiar with Graves' disease, it's actually one of the more common endocrine disorders in the world, and it affects 1%-2% of the population. A number of those patients with Graves' disease develop what's called Graves' ophthalmopathy, or since nobody can say that, Horizon branded it as thyroid eye disease or TED, which is a little easier to say. I t's all caused by these autoantibodies. It's an autoimmune disease, and these antibodies bind to and activate the thyroid-stimulating hormone receptor, TSH, and what we've made is an antibody or a small molecule oral drug that blocks the action of TSH and these TSH antibodies at the TSH receptor, and so from the point of view of what we want to do with the molecule, so Graves' when this antibody in the autoimmune state binds to the receptor, it does two different things. In the thyroid gland, it causes the release of excess thyroid hormone, and that causes hyperthyroidism. In the back of the eye, it binds to receptors and causes the cells to grow, which pushes out the eye and causes inflammation and other issues, and that's the ophthalmopathy component, so we expect if we block this receptor, you'll block both the hyperthyroidism and the eye disease. T he challenge is in development, okay. Do you do first? Do you do both? Do one or the other? The real answer is that down the road, if we can, if this plays out the way we think, then the right treatment for Graves' disease itself should prevent the onset of Graves' ophthalmopathy, and you shouldn't need to be treating the eye disease. But in the meantime, we need to think about treating the eye, treating the thyroid. W hat's the right thing for the patients? Very helpful. H ow do you think I mean, we've learned quite a bit on Graves' drug development, a s Immunovant had recently unveiled their study designs. Could you talk about the differentiation of your mechanism versus sort of the FcRn approach? FcRns have been a really fascinating approach to access antibodies in a variety of conditions because they'll lower, t he amount of antibody around that is binding and activating these receptors. But that's not a particularly specific mechanism for Graves' itself, whereas we're blocking at the receptor that is the target of that antibody, so we're only blocking that part of the immune response and nothing else. Plus, we're a once-a-day oral, which part of our goal in the company is to take the medicine out of the medical treatment out of patients' lives so they just can take a pill in the morning and get on with their day and not have to think about treating their disease as much. How soon after the IND submission could you get ready in terms of a clinical study? You guys have done a great job on getting POCs quickly from a phase 1b study. O ne of the great things about this program and many of our programs, as a good friend of mine will tell you, humans are essentially mammals without tails, and the work that we do in rats, the endocrinology in rats, is very much the same as the endocrinology in an adult healthy human, which is very much the same as the endocrinology in a patient with various endocrine diseases. W e know that with our candidate in a mouse, actually, model, we can induce Graves' disease by giving them the same antibody as causes it in humans. Their thyroid hormone levels go up, and we can bring them back to normal with administering this candidate. Now, in healthy volunteers, what we'll do is we'll give the candidate or give the molecule to the healthy volunteer. We would expect thyroid hormone to go down, thyroid-stimulating hormone to go up, and that'll tell us pharmacodynamics in addition to the PK and safety we'll get in a healthy volunteer study. I f we kind of go back to the history of our lead program, which has just finished its phase 3 and is now in registration, we had a very similar story there where we're modulating growth hormone. W e showed in rats and then healthy volunteers how we could control growth hormone secretion and how that would play out in patient studies. O f course, it's played out exactly as the phase 1 healthy volunteer studies predicted. Topic 2 would be, I think, at your last earnings call, really s urprised everyone with sort of the 9682 to kick off, like, the NDC programs. I guess, big picture speaking, and you have also said you're going to go into neuroendocrine tumors first and then expand out. How do you foresee the success of the first neuroendocrine tumors expanding this entire portfolio, and what is the opportunity beyond neuroendocrine tumors? T his non-peptide drug conjugate idea, or NDCs as we call it, is something we've actually been playing with for quite a few years in the discovery group. I t came from two different areas. One, everything we do, we're thinking about what do these patients really need. W e know in the neuroendocrine tumor space that they needed an oral option to these very burdensome injections and, t hat don't work quite as well for their carcinoid syndrome, for example. T hat's paltusotine. But they also needed a targeted therapy for those patients who don't have functional tumors, who just have tumors that are growing and causing damage to the liver. T here's actually many more of those patients than there are with the carcinoid syndrome. O ne of the things that's revolutionized the care of neuroendocrine tumors are the radiotherapies. S omatostatin-targeted lutetium, for example, was Lutathera, which essentially kicked off the modern renaissance in radiotherapy interest. N ow there's, I don't know, a dozen different SST2-targeted radiotherapies, which work pretty well. But I didn't think the world needed another one of those. What they needed is a non-radioactive option. Once they've used up their limit of radioactivity, they could go on something non-radioactive and something that's a little more democratized. T he radiotherapies still require a lot of infrastructure at centers, and that leaves a lot of people who live out in rural areas or who r eally can't take the time out, leaves them out in the cold from a therapy option. T he idea behind this was a targeted therapy, new approach for NETs patients. W e've been watching the world of ADCs. Antibody drug conjugates have transformed breast cancer and some of the other types of cancers. The core problem with an antibody is that no matter what you do with it, it's going to linger around for weeks. It's going to be gradually releasing these toxins or being cleared in non-mechanistic ways to release these toxins in the periphery. With a small molecule, you can engineer this through typical organic chemistry so you can control all kinds of parameters that you can't really control with an antibody. For example, the targeting agent here, which is a small molecule, 500 molecular weight ligand of SST2, we optimize so it not only binds with super high affinity to the receptor, but it triggers that receptor to internalize very, very efficiently. W e optimize the linker so it's cleaved by a couple different enzymes that are only in the intracellular environment so it's only cleaved after it's been internalized by the ligand. T he net of this is, at least in our preclinical models, that when we give this agent, it's cleared rapidly from the systemic circulation. Toxin payload accumulates rapidly and prolonged into tumors, and there's little, if any, of the free toxin in the systemic circulation. I f this plays out in humans, it should be a good therapeutic window. I'm sorry, I could talk for days on this, but you'd ask me about going into other tumor types, I think. T hat's helpful. For just housekeeping purposes, you guys have said IND is expected in early 2025. You've also said when you think about the study design, it's going to be more like a cancer-type study, phase 1 healthy volunteer. When will you be able to communicate sort of more on the trial design? You could just go a little bit beyond that. I don't know if you have that right now at the end or maybe later. Sure. T he reason we're communicating early next year is we've completed most of the IND enabling work. We're still working on some of the manufacturing for clinical supplies and writing the IND. W e've talked about essentially a basket study design where we're bringing in patients with SST2-positive tumors, both neuroendocrine tumors, neuroendocrine carcinomas like small cell lung, and other tumor types that express SST2, many head and neck cancers, small cell lung, I mentioned, pheochromocytomas, meningiomas. There's a variety of different tumors that express SST2. W e'll do a typical dose escalation study for tolerability, and then we'll branch into different expansion cohorts in either NETs or NECs, neuroendocrine carcinomas, or a basket of other SST2-positive tumors. T hen it's just how do these accrue and when do we start seeing results. What is traditionally, like, when you look at, are these slow-growing tumors, fast-growing, somewhere in between, like, as we think about not without having to give guidance, but, like, sort of thinking about the event rate? That's where it gets really interesting as you get into these different clusters. N euroendocrine tumors like a mid-gut NET are typically grade 1 through 3. T he low-grade tumors have Ki-67 down to 1% or something. High-grade tumors can be 50%-60%. T here's a range of different growth rates depending on the individual tumor. W hen you get into small cell lung and NECs like that, they can be very, very aggressive. W e need to learn some things about where this is going to work best in different tumor types, we'll be able to expand out from there. Moving now to adrenal NET and CAH and Cushing's. W e're expecting the full data in early 2025. I think the expectation from investors is sort of the same observations that you've made on the interim just for that to continue in a larger population. Is that? Do you agree with that assessment as just a smaller derivative? Yeah, ballpark. Yeah. What do you want to? [Crosstalk] The main thing we're getting now is when we reported the data in the spring, it was interim data on a handful of subjects, not all of whom had gone through 12 weeks. But it was really remarkable because we were getting normal hormone levels in almost everybody, both in CAH and Cushing's disease. hat was at 80 milligrams. N ow we've finished or we're just finishing up with 40, 80, 120. There's about 28 patients total. E verybody will have completed 12 weeks. N ow we're going to see a much bigger data set. T he only difference is when you now start getting larger numbers of patients. I don't expect everybody to be quite as perfect as the first handful, but still, it was pretty remarkable this spring, and I'm eager to see the data coming out. There's not a reason to believe also everyone expects the data released to be from a type of data to be very consistent with the full results. W e don't expect, like, any divergence in the type of data that's going to be reported. G enerally we're going to do the same type of things we showed you before. There's not a lot of new types of information. Is it fair that at the time of the release you will also talk about the registrational study design, or is it you're going to have to have the meeting posted? W e'll talk about some of our general ideas. But when we finish this phase 2 and get the data from the dose response, that'll allow us to finalize our dose selection and then talk to the agency. W e'll need some alignment from the agency into the final endpoints that we're going to put into the phase III. T o illustrate that, so what we showed in the phase 2 is a really profound reduction in adrenal androgens like A4. W hat's been done with some of the other compounds in development is shown that they can get steroid sparing so you don't need as much glucocorticoids to get down those adrenal androgens. W e think that's great. That's going to help people. But we want to get people to normal glucocorticoids and normal adrenal androgens. T hey shouldn't have to compromise between the two. But how do you describe that in an appropriate statistical way for a primary endpoint? You don't really want a co-primary. T hat's the type of nuance we'll have to discuss with the agency. B efore we move on from CAH, where are you in terms of sort of feasibility studies to maybe expand into the pediatric population? Are you ready to also? Yeah. W e know ballpark what we want to do. The team is working on wrapping up the data for the adults, working on the adult protocol and submissions. They've started working on the pediatric protocol and program. W e hope to start the pediatric program next year as well. I s there any sort of formulation work that needs to be done or any clinical work that needs to be done? Yes, there is some pediatric because y ou can't give kids, especially small babies, the same type of pills that you'd give an adult. T here's a little bit of work on that. There's some wrapping up some of the juvenile tox for the youngest patients. But all that's coming together in the first part of next year. W e're on track to start a pediatric program soon. Perfect. Let's move on to paltusotine and acromegaly and carcinoid syndrome. Maybe talk about carcinoid syndrome. R ecently you initiated your phase 3 CAREFNDR study testing 80 milligrams of paltusotine in patients. It's a 16-week study. Endpoint is a 12-week. In your open-label study, you had phenomenal effects both in diarrhea and GI motility as well as flushing. But the primary endpoint is looking at flushing. What led to the decision to go with flushing instead of sort of a co-primary or? T he way to think about it is, so the primary endpoint is reduction in flushing. The key secondary is reduction in excess bowel movements. I t's not really that they're prioritized first and second. They kind of go together. T he intent of those together is to seek an indication for the treatment of carcinoid syndrome or maybe diarrhea and flushing associated with carcinoid syndrome. F rom just a practical point of view, statistically co-primary is getting complicated. F rom a symptoms of carcinoid syndrome point of view, flushing is a very hallmark symptom, cardinal symptom of carcinoid syndrome. It's hard to mistake those flushes for anything else. It's not like a postmenopausal hot flash will confuse you. On the other hand, in diarrhea, there's quite a few different things that can cause diarrhea, as we all know. But in these patients, there's also other things like pancreatic insufficiency, for example. T hat's why we put the flushing first. The diarrhea will be stratified so we get enough patients to power and test that endpoint as well. But think of it together as one indication. Have you publicly thought about or communicated what the powering is in the change in flushing frequency? Yeah. F or both those endpoints, it's well powered over 90%. I don't remember the exact number, but it's going to be a robust study. H ow many patients do you expect to enroll in the study? I'm looking at my group to remind me. Okay. We're not disclosing. I'm getting to the point with all these different programs. I think I might have mixed that up with CAH or something. That's all right. Over 100. Over 100. That I'm sure of. Very helpful. Maybe the next few minutes is talk about the acromegaly, I think. What work is being done at Crinetics to really get ready commercially for acromegaly between now and the approval? A whole bunch of different work streams. There's the kind of mundane stuff that I think people in the buy side may not pay attention to, but it's your infrastructure on IT and compliance and SOPs and quality and all that stuff. T hat's a baseline. That's table stakes. But our market access group is fully fleshed out and out there talking to payers across the country, really understanding and teaching them about the market. We think we're getting great reception from them. We don't perceive that we'll have real pushback from them, and we'll work with them to help bring value to the healthcare system with this oral alternative. We're also working very hard, as we always have, with the patient communities to figure out how to make sure they know in an appropriate way, what they should be expecting of medical care and acromegaly. T hen we're at the detailed level of mapping out from a marketing and sales perspective who all the providers are, what patients they have, what messages communicate, and understanding the different segments of patients. T here's the patients that are going to about one of 40, 45 different centers of excellence in the country. That's a very well-described, well-cared-for group of patients. There's another group of patients that are going out into the community endocrinologists who might have two, three, four, five patients. T hat's going to be a little bit more challenging because it's more dispersed. T here's also a pretty large group of patients that are out there without getting scripts written to them. T hey're not getting medical care, and they should be. T hat's a real growth opportunity for us. But it's going to be difficult to find them and bring them into the fold. But I think we all know from other examples out there that when you have a good, easy-to-use new medicine, that tends to help grow markets. W e're trying to figure out paths to each of those different patient populations and how do we deploy our effort and our capital to efficiently address them. Are you in a position to maybe share how you think about the size of your sales force and the cadence of hiring that will occur between now and approval? A s kind of a baseline level, we think it's 25 to 30 salespeople. T hat'll cover the centers and the high-volume community prescribers. But really, sales these days, especially in a rare disease, is not just about the salespeople. We're building out a great medical affairs organization. We've hired a phenomenal head of medical affairs who's a longtime friend and endocrinology practitioner, former head of medical affairs at Sanofi and Amgen, and still treats patients a couple of weeks a year at the Mayo Clinic keeps his hands in tight. W e're building out that force. We're building out our patient-facing group. We're building out our patient and patient hub. W e're bringing all these pieces together. It's a pretty active time at the company. I think one of the questions that comes up with investors who do not own Crinetics is that feeling of, "I missed it." T hey feel like they missed buying into Crinetics, and they look into 2025 saying, "At the current stock, it's pretty good valued for acromegaly, for carcinoid, some for CAH, and I missed it. I 'm not going to make money on Crinetics because I will wait till the phase 3 readouts." F or those individuals who have an incredible shareholder base who's very excited about the future of Crinetics, but for those individuals who say that to me, what is your message to them as they think about their investments in 2025? I'm trying to be polite here. First, I got to say we have been super fortunate to build a base of owners of the company who believe in the long-term vision of what we can do. Our long-term vision is to build a super impactful global pharmaceutical company that pioneers new therapies in endocrinology and all the various things you can use endocrinology to treat. From a value creation point of view, I think we're just getting started. If you take all those indications in our pipeline and you look into what those peak sales may be in the 2030s, you're not going to believe your models. It's too big, right? Now, the slightly cruel part, I'll twist a little bit, is the same people who think we're expensive now thought we were expensive at 25. Yeah. Then they thought we were expensive when we financed at 30 and at 40-something and at 50. I don't know. Macro stuff, who knows what macro is going to do. If you have a long-term time horizon, I think we can continue to add value. We're making good molecules. They have patents into the 2040s. We have predictable biology. We're trying to do it right. Y ou are. I always urge them and fight with them that you didn't miss it, and we're going to have the same conversation in six months or three months from now that. Try a little bit. Yeah. Try a little bit. Join the club and hang out, and then you may want to add some more later. T hank you so much. It's been a pleasure covering your stock and seeing the tremendous progress. I can't wait for 2025. C rinetics will be a commercial company, so not only a power engine in development and clinical execution. L et's give a big applause to that. Thanks, Yas. It's been wonderful.