And then later I'll tell you about a thyroid-stimulating hormone antagonist for Graves and Graves' eye disease, which does not cause hearing loss, unlike this last blowout in the mics. But, you know, paltusotine is our lead for acromegaly that has the PDUFA date, but it's also starting up a phase III program for carcinoid syndrome. Our second molecule is atumelnant, which is starting up phase II, phase III, sorry, for congenital adrenal hyperplasia. Also, a phase II, III pediatric program for congenital adrenal hyperplasia. Cushing's disease, so a third indication for that. And then behind that, as I mentioned, four molecules in various stages of preclinical development. 9682 is the first in a whole new class of what we're calling non-peptide drug conjugates. It's got the best biodistribution data you've ever seen. It's kind of like an ADC, but using a small molecule payload, a small molecule targeting agent. And the whole thing is just synthetic chemistry, no fermentation, no bioconjugation. Really excited to take that into NETs. That IND goes in any day. And then, as I mentioned, a TSH antagonist for Graves' and thyroid eye disease is in preclinical. Pretty close behind that, or maybe right in front of it, it's a bit of a horse race, is a PTH antagonist or parathyroid hormone for hyperparathyroidism. You probably heard a lot about hypoparathyroidism, but this is the other. Too much parathyroid hormone, and there's nothing else out there in development besides us as a PTH antagonist. And then finally, in the space of endocrinology that's moving into kidney disease, there's a novel approach to polycystic kidney taking advantage of one of the tools of endocrinology. And that's just in IND-enabling work as well. So it's kind of a challenge in a group like this. I don't know where you're going to focus today, Tyler, but happy to talk about anything up and down the pipeline, and always there's some things cooking in discovery as well. This is exactly why we're back in coverage here recently, right? We covered Crinetics on the IPO, and we're watching from the sidelines for a little while. You know, when we came back to Cowen, and the productivity of their platform has just been so tremendous. Not only that, not only are they a leader in endocrinology, but a lot of these opportunities for their pipeline candidates are very large as well. Excited to try to knock each one of those off with you here, Scott. And as you in the audience have questions, feel free to raise your hand, and we'll do our best to get them answered. Starting with paltusotine, September 25th PDUFA date, probability of approval is incredibly high based upon the data. There's no reason it shouldn't get approved unless there's some unforeseen incident on the back end with respect to manufacturing or execution or something like that. But as you think about that launch, you know, you've got the $2.5 billion SRL market. Roughly half of that, a little bit less than half of that, I guess, is acromegaly, as far as I recall. And expectations by some of your top holders are pretty conservative, which isn't a bad thing. But how do you think about the early innings of this paltu launch and the opportunity and how you penetrate the market? Yeah, so for those of you who don't know, paltusotine, it's a once-a-day oral drug that's going after a $2.5 billion market of injectable peptide depots that are given every month. And octreotide, the long-running entrant in the field, is a 2 mL intramuscular injection with an 18-gauge needle that tends to wear off each month. And then because it's monthly, it takes three months before you know if your first dose level works. And there's three dose levels, so you can spend nine months trying to get that right. We showed phase III data last year where in two to four weeks, we get to steady-state levels of suppression. We also showed it's a once-a-day oral, so it's very consistent. And it's not an injection. So I think we're trying to position this, and I think most KOLs recognize it as kind of a whole new level of care. That being said, I think it has the opportunity to not just penetrate and take over the existing market, but to help grow that market, because there's really a lot of folks with acromegaly that are currently not being treated who should be, but that said, I do think it, you know, especially on the switching side, it may take a little time for that to grow. In terms of finding patients and bringing them back into care, that may take a little time and effort, so expect a slow and steady launch as we grow the market, and I think it's not just that we're launching paltusotine in acromegaly. We're also launching the company so that we're getting ready for the launches that come after that, next in carcinoid syndrome and then CAH and Cushing's disease and these other things I've been talking about. So, we're really trying to lay the foundation for a long-term growth trajectory that, if you look back at this in a few years, I think you're going to be pretty amazed. Do you think the low-hanging fruit for this launch is the patients who are uncontrolled on SRLs, who don't like being harpooned by the 18-gauge needle or have tolerability issues? Or is it naive patients, or is it truly both, and it's just going to be a mix? Yeah, I think we're going to find that out. So I think there's good rationales for everybody. You know, a naive patient coming in on therapy the first time, why would your physician prescribe something that's going to take three-nine months to know if you're at the right dose level, as opposed to something easier to use that's two-four weeks? That seems like a no-brainer to me. But those folks who are having breakthrough symptoms or have stopped because they just can't tolerate those injections all the time, getting them back into care, I think actually that's where we'll have a huge impact, not just on sales, but on improving the care of patients with acromegaly. I think we have to address this as a holistic problem and really go after the 27,000 patients with acromegaly and try and improve diagnostic rates, because it takes five to 10 years for them to be diagnosed. And every day they're not treating their disease, they're getting long-term irreversible consequences. So this comes back to this philosophy about improving overall care of this patient community, not just selling them a drug. Yeah. I mean, canvassing the existing centers that are prescribing SRLs and endocrinologists has got to be, I say this without ever having operated a company, but relatively straightforward. And so I guess pulling these patients from the community who are off therapy, increasing diagnosis rates, how do you guys expect to do that? Yeah, so one thing just about getting into the centers of excellence, there's about 40 pituitary centers in the country, and we have now nine clinical pituitary endocrinologists in our staff. And I've been doing this since 1980 as a freshman undergrad, obviously not a clinician as a freshman undergrad, but as a scientist working in the area, so there's no center of excellence where we're going in where there's not some friend of ours that's a warm introduction into the unit. Now, as we get out more broadly into the community endocrinologists, you know, that's a little more of a broader reach that we'll have to figure out how do we efficiently address, but again, we're approaching this whole thing as members of the endocrine community, not just a sponsor trying to sell the latest drug they made. Okay. Maybe we'll move to carcinoid syndrome for paltu as well, so the phase III was recently initiated. Maybe you could talk about the potential timeline for data from this trial and what you hope to achieve to be successful with that trial. Yeah, so carcinoid syndrome is a consequence of neuroendocrine tumors. So 20%-30% of those tumors get past the liver and start secreting hormones into the circulation, which can cause severe flushing and diarrhea. And so it's really the secretory activity of these tumors that we're trying to treat with paltusotine. And that diarrhea and flushing can be very, very debilitating. And what we showed in our phase II is that within a day or days of starting paltusotine, you can start to see relief of those symptoms. And then we can provide consistent and durable symptom control over the course of therapy. So now the phase III is to show that at scale in a placebo-controlled setting. It'll be 16 weeks with a 12-week endpoint, again, looking at a combination of flushing and diarrhea endpoints. Then with an open-label extension where we'll be looking at progression of the tumors themselves because somatostatins have anti-proliferative activity as well. So it's always hard to say how long trials will take, and we try not to predict that too much. But we're ramping up full speed, and it's a global study around the world, many of the same two phase II sites we used, and then many of the same sites where we did our phase III trials in acromegaly. Carcinoid syndrome is the other, I guess, half, or maybe even a little bit more than half of the $2.5 billion SRL market. How do you think about that market opportunity in particular when it comes to the ability to expand the market with a therapy like paltusotine? Yeah, I think there's also a market where there's maybe 10,000 patients on treatment. We're still digging into those, but there's somewhere between 20 and 30 who should be on treatment, so if you look at the combo of both acromegaly and carcinoid syndrome, I think we have the potential to grow sales significantly compared to where they are at current levels today, and it's not just about new patients, but I'm beginning to realize, especially as we dig into acromegaly, that many patients are just giving up on therapy and coming off therapy, presumably because of the tolerability and the burden of the treatment, so this notion of improving healthcare for all these patients and growing the market, I think is a compelling way for us to really add some value to the ecosystem. Wonderful. Let's move to atumelnant. So the A4 and 17-OHP data released earlier this year decreased a little bit from the initial release, which was incredibly high numbers or really steep reductions, but still appear at least similar, if not superior, to Crinetics on the whole. I guess given the much greater A4 reductions comparatively, is there reason to believe that A4 could be more relevant than 17-OHP, or how do you put these results into context? I'm looking out in the audience, and you've probably seen 10, 20 companies over the next couple of days and probably have no idea what A4 and 17-OHP are unless you've been following us real closely. But these are markers of adrenal activation in a disease where the adrenal is trying to make cortisol, but it can't because of an enzyme deficiency. So it's making these other adrenal steroids instead, which are androgenic and progestins. And they're causing hormonal excess syndromes in these patients who also have not enough cortisol because that's what they can't make anymore. And what we showed was in our phase II study in these patients was that in two weeks, we could take people from extremely high levels of adrenal androgens, A4 and 17-OHP, which is more of a progestin, and bring them down to normal or close to normal. There's a good dose response between 40, 80, and 120. At the 120, almost everybody was down at or very close to normal, and 80, most people were. What we're trying to show with this is that we have a drug here which can actually treat the excessive activation of the adrenal gland. Those patients can come back and use some glucocorticoids, but just for replacement, because you don't need glucocorticoids to try and treat the disease. You need glucocorticoids because you need that cortisol to survive. We're trying to change the treatment paradigm here to treat the disease with atumelnant and then just allow for replacement with other glucocorticoids. This is a bit different than the one option that people have today, which is really about lowering glucocorticoids. Because right now, current practices, you give people glucocorticoids to try and control those androgens. But if you give too much, you end up with what's essentially a disease called Cushing's disease. And glucocorticoids are like the main stress hormone, and too much of that causes weight gain, hypertension, fat deposition, metabolic problems. So obviously, too much bone problems. So obviously, too much glucocorticoids are bad. But getting the glucocorticoids down to normal and getting the adrenal products down to normal is the goal of therapy for us. That's kind of a long-winded answer about some nuanced pharmacology. But let me maybe put it in a little simpler point of view. In our phase II, what we showed also was that women who had stopped menstruating or had very irregular menstruation because of these androgens circulating started cycling regular. Their testosterone levels went down. It's a lot like these excess androgens act a lot like doping in athletes in some patients. So we had six patients with what's called polycythemia, elevated hemoglobin levels, and they all got back to normal levels. We're really starting to see some effects on the signs and symptoms that people actually see and feel, not just these biochemical markers. But the biochemical markers will be the registrational endpoints. Great. Thanks for that. And with respect to the data, did patient compliance have an impact on it, and is that something that you look to control as you go into phase III? You know, we always work very hard to control compliance. And there's been in this field some instances of very poor compliance for various reasons. And so, yeah, we will manage that super carefully. But I also think there's a tendency to blame patients sometimes, and they may or may not be the source of that problem. One thing I think really helps compliance is if you make a drug as simple to use as possible. And that's one of the things we do with all our drugs. So atumelnant is something you take once a day. You don't have to worry about whether you're having food or not. There's no special requirements. You just take it and move on with your day. Okay. Great. And the phase III CAH trial is expected to start in the first half of this year. While you've not disclosed the trial design, will the primary endpoint be similar to Crinetics' in terms of reduction in glucocorticoids or steroids? And do you believe it's possible to stop steroid dosing altogether while maintaining the improvement in A4 and 17-OHP levels? Yeah, so I think the short answer to the question is, you know, our endpoints, the primary endpoint in the Neurocrine study was glucocorticoid reduction. And yeah, that'll be an endpoint someplace, but it's not going to be our primary endpoint. That doesn't do justice to the mechanism of action of paltusotine. So what we've described is a drug that I think can take care of those excess androgens and other products of this dysfunctional adrenal and get those to normal. And then the glucocorticoids are only needed in physiologic replacement levels. And our endpoint cascade should capture that. The goal of therapy is if you have too much glucocorticoids or too much adrenal androgens, you want those to all get to normal, not just one or the other. You shouldn't have to make a choice. Now, I don't think we'll get everybody to normal, but I think we'll get a lot of folks to normal, and we'll get a lot of folks a lot closer to normal than they are today, and so our endpoint cascade and trial design will reflect that. I I think that gives you a sense of how we're planning to both differentiate the trial and potentially the label, but we're finalizing some of the statistical nuances, and until we do that, I don't want to get people locked into some detail that may change later, so what I did commit is that by our next earnings call, we'll flesh this out for you and give you plenty of things to chew on. Okay. Fair enough. You mentioned Cushing's, unfortunately, as a potential side effect of too much steroid use. But focusing on the actual indication of ACTH-related Cushing's, maybe you could just review the data there in those five patients, the pathway forward, and what you hope to see in phase III? Yeah. So with Cushing's disease, this is caused by a pituitary tumor much like acromegaly. And that tumor, though, is made by cells that secrete ACTH, which is your central stress hormone. That acts at the adrenal. In these patients, they have a healthy adrenal, so they make too much cortisol. This is all the stress response pathway. Imagine the most stressed you've ever been in your life, and then this happens day in, day out, 365 days a year. It's tough to sleep. There's malignant hypertension. There's weight gain. You get adipose deposition, so people get a hump or they get what's called a moon face. This is a really tough-to-treat disease. As we were kind of growing the company, we focused first on a global phase II for CAH. Then we partnered with Lynnette Nieman at the NIH. She's one of the top Cushing's people in the world. And she was getting patients from around the country who could not be controlled outside the NIH. So they'd send the patient there to spend two weeks where she'd do her most intensive management, measuring things every day, day in, day out for two weeks. And usually, at the end of two weeks, she could get people close to control or under control. What happened with our patients is something she'd never seen before, which is everybody except one got to normal within a day or two. And that one that didn't took 10 days, all of them. It was pretty remarkable and fast. And so now what we need to do is figure out how to translate that and this was an in-house study, right? An inpatient study. So now what we need to do is figure out how to translate that into a global registrational study. The primary endpoint will be normalization of urinary free cortisol. That's what was normalized in these patients. And we're gearing that up right now. So I've got a product team associated with atumelnant. Their priority is adult CAH, then pediatric CAH, then Cushing's. So that'll start a little later this year. But super excited to get started on that too. What was Dr. Nieman or Nieman using to try to get those patients to normal levels prior to, obviously, atumelnant? It would depend on the patient, but they could use things like ketoconazole or Isturisa. There's a couple of drugs out there on the market that have various limitations, particularly safety limitations or difficulty to use. What really seems to happen is because of that difficulty to use, even though they work well in somebody like Lynnette's hands, there's too many patients that aren't getting adequately controlled out in the community. Even in Lynnette's hands, those are very difficult to use, which is why I see such potential for atumelnant in the Cushing's space. Got it. How big of a drug do you think atumelnant can be across both indications? You know, I tend to think in patient numbers, but that's on the order of across both is on the order of 30,000, 40,000 patients total. But what that doesn't take into account is some of the potential things that we might explore later. There's a lot of challenges with overactivation of the stress response pathways. And so as we start to learn more and more how to use this drug, we'll start thinking about what other indications there may be. All right. Five minutes, four INDs from the pipeline entering the clinic this year. So I guess we'll start with NDCs, not ADCs, but NDCs, as you talked about in your opening remarks, entering the clinic first of the four. You know, I think targeting SST2 positive tumors and NETs is pretty straightforward mechanistically. Other solid tumors, the potential there is large as well. But I wanted to focus on the two things you talked about, which was biodistribution and the synthetic fermentation. Just the. Can you elaborate on the biodistribution that you're seeing with these and then the manufacturing advantages and the ability to scale these? Yeah. So just as a reminder, this is like an ADC, but using a small molecule ligand to drive selectivity towards the somatostatin 2 receptor. And so from the practice of medicine in neuroendocrine tumors, almost all patients now are imaged with somatostatin 2 receptor ligand PET studies. It's like called gallium scan or something. And many of them are treated with somatostatin receptor agonists, which you can use to treat carcinoid syndrome like we're doing, or they can be used in patients that are not symptomatic where they slow progression of disease. And then if that fails, patients are going on to somatostatin-targeted radiotherapies, and you've probably heard a lot about those lately. Lutathera was the first of the radiotherapies to really make it big, and that's targeted against the somatostatin 2 receptor. So it's a very well-characterized target in this population. We routinely know if a patient has somatostatin-positive tumors. So we'll be focusing the use of this drug in patients with proven targets. So I think that's a very defined use of a precision medicine approach. But what we're finding as these PET scans are being done more and more is that it's not just neuroendocrine tumors that express it. Almost all head and neck tumors express it. About a third of ER-positive breast cancers express it. Paragangliomas, meningiomas, and some others, glioblastomas, all express this. So I'm super excited to see. This is a basket study, fairly traditional type of dose escalation, tolerability, coupled with expansion phase. So I'm really excited to see where this can go from an indication point of view. Sorry, and I didn't answer your primary question, which was about the biodistribution. You know an antibody-drug conjugate. You put an antibody into an animal, and it lasts for weeks. And the gradual release of these payloads from those antibodies is what causes the peripheral neuropathies, the white cell depletion, things like that. So with a small molecule, you can tune every aspect of it using all the dimensions of medicinal chemistry. And then you can make it just using traditional chemical manufacturing, which makes it a little easier to produce. And so we tuned it so that if you look at free payload in a mouse model, you don't see any of the payload left after 24 hours. And even during that 24 hours, there's very low levels. But we've optimized it to bind to things on the tumor cells, get internalized into the tumor cell, and only be cleaved inside the tumor cell. And so if you look at the tumor load of that payload, we see it for 10 days, and it probably stays there even longer. We just didn't measure any longer than 10 days. So from a biodistribution point of view, which is what these whole targeting approaches are about, I think this is one of the best biodistributions you'll ever see. And we hope that translates into some of the really good efficacy. That's what we're trying to figure out now. That IND goes in any day. Great. Moving to PTH and TSH antagonist programs. Speaking with some of your investors, they love these programs. They think they could be multi-billion-dollar potential programs entering the clinic this year, hopefully soon. Can you just talk about how quickly you think you could get early kind of proof of mechanism data from these programs? Yeah. So one of the joys of endocrinology from a drug development point of view, especially the ones that are more pure endocrinology, is that the endocrine systems are conserved across mammals. Actually, some of these hormones go into starfish and all the other just early invertebrates. But we know from the endocrine systems in mice and rats that these compounds we're making are doing what they're supposed to be doing pharmacologically. We'll learn that in healthy volunteers if they're doing what we expect at the doses we expect in a single ascending dose study or maybe the multiple ascending dose study as well. So it shifts the risk curve way to the left in drug development, where you can take a molecule and de-risk it at very high levels in a single ascending dose. In fact, for those of you who know us from a long time ago, like Tyler, we did our IPO based on single ascending dose data or sorry, multiple ascending dose data in a healthy volunteer because it's so predictive. And so coming up, what we'll know in thyroid disease, Graves affects 1%-2% of the population, with the majority of those patients being women. And 20%-50% of those patients go on to get the Graves' eye disease, which you may know from Horizon and TEPEZZA. And so we expect in the healthy volunteer studies to make sure we understand our dose levels and to see whether the drug is able to suppress the thyroid gland, I think hugely de-risking. To measure the eye disease, then of course, we'll have to measure in patients with proptosis. And we're looking at how we're going to do that now. But there's also a need to treat the patients with the underlying hyperthyroidism. And so we're figuring out a development strategy to go after both populations. So I think that's the first of our real potential mega markets, if you will, although actually maybe 9682, the NDC, could be a very, very large drug too. Okay. We're up on time here, but GLP-1, GIP candidate nomination later this year. Can you say anything about what we should expect to learn or differentiation, or are you going to make us wait? I'm going to make you wait. Look, I've spent my entire career making and understanding how small molecules might work at peptide hormone receptors and how you can make drugs at it. That's what we've done the whole time at Crinetics. We wouldn't be taking this on if we didn't have a strategy for applying that and trying to come up with something that's potentially best in class. We won't be a first-in-class small molecule for that system. Maybe some of the other targets, but obviously not GLP. Super competitive. We'll probably be fairly quiet about how that plays out. Great. So Scott, to close out, what do you believe is the most underappreciated aspect of the Crinetics story by investors right now? That we're a dog-friendly workplace. We have been since day one. If you come in any day of the week, you'll see a handful of pups playing. So it's a great place to work and visit. So welcome you to come see us. I love that answer. I was not anticipating it. I got to keep you guessing. Thank you very much for your time.