Good morning. Thank you again for attending the Citigroup Global Healthcare Conference, first time in Miami, Florida. I'm happy to have with us on stage here CEO and President Founder Scott Struthers of Crinetics. Before we start digging in, and this has obviously been a very eventful year for the company starting. I only initiated about, literally, I think about a year ago. Good time. It was by design, of course. You have a big year. Tell us about the company itself, the overall strategy of what you're trying to do, and certainly specifically in the endocrine space. Yeah, thanks, David. Great to be here in Miami with you and the crew. So Crinetics is a company that was founded actually some time ago, and we've been focused on endocrine systems and peptide hormone receptors since the inception. And the thing about these endocrine systems is they touch every cell in the body. And so as things can go wrong, it gives you ways of trying to fix those pathophysiologies using the tools of endocrinology. And what we've done then is build mostly non-peptide, small molecule ligands that bind and either activate or block these hormone receptors, and are using that then to treat both endocrine diseases and now moving into some things that, while endocrine in its approach, are actually not likely to be treated by the endocrinologist. And so this has led then to an internally developed pipeline of compounds. The lead is now in registration. We anticipate a decision next year, all the way down to four new molecules entering IND enabling work and ongoing work and discovery, and I'm sure we can kind of talk through parts of that as much as we can cover in this short period. Absolutely. One question I would ask, and this is more from the top level, is you have a variety of indications that you're targeting across your entire pipeline, and many of these treatments, these indications have treatments available on the market, albeit flawed treatments available, where many of these markets haven't evolved much over a very long period of time and have been pretty static. Is that your overall goal to look at specific markets where there is some history, but it's just insufficient? Or are you also going to look at more developing markets and opportunities that have nothing available? Yeah, I think we take an approach more of what is the medical need in the field of endocrinology and/or where can our endocrinology impact other fields? And I don't know if I've told you, but I started working on these peptide hormones when I was an 18-year-old freshman undergrad. And it kind of leads you in lots of different directions. But much of what we've done now is driven by our friends and what they tell us they need for their patients. And so, yes, we started in an area where there's, I think, a high unmet need, even though there are drugs available for acromegaly and neuroendocrine tumors. But then as you look at our second program, which is an ACTH antagonist, this is something that nobody else in the world has that is, I think, super innovative since Harvey Cushing first described Cushing's disease in 1910. And there hasn't been anything that directly addresses this mechanism in those 100 years. So I think it's a mix of improving standard of care where there is some care or creating whole new ways of approaching treatment of diseases if we see an angle. Now, a lot of pipeline products. Where would you like to start? Oh, boy. People ask me variations on that, and I also say I have four grandkids, and I love them all. So let's see, which grandkid should I talk about first? Maybe the newest one. How's that? Let's do it. We announced a few weeks ago at the North American Neuroendocrine Tumor Society meeting a whole new platform that we developed based on these non-peptide ligands and peptide receptors. And we call it non-peptide drug conjugates or NDCs. And this molecule has completed most of its IND-enabling work. We plan on taking it into the clinic early next year for neuroendocrine tumors that express somatostatin receptors, but also other tumor types that express somatostatin receptors, and there's quite a few of them. And what it does is it allows us to use the tools of small molecule chemistry to optimize a targeting ligand that's low molecular weight, that drives internalization of the receptor, that can be cleared quickly and be manufactured chemically, unlike the ADCs where you're kind of stuck with the properties of antibodies and bioconjugation. And I'm really excited to see what it does in humans. In mice, it's almost a perfect delivery system where you can accumulate the payloads in tumor cells with very little, if any, exposure systemically. And if this translates into humans, then it should have a very good therapeutic window. Have there been prior efforts that you know about with small-molecule drug conjugates in the past, and what have you learned from those? There's been a couple, but really where we learned this came out of the whole radiopharmaceutical space. So you may know that a lot of the recent excitement in radiopharmaceuticals came out of Lutathera, which is a somatostatin-targeted lutetium agent for the treatment of neuroendocrine tumors. And it's transformed the treatment of neuroendocrine tumors. And then there's been a lot of follow-on activity in that area with probably dozens of companies developing new radio approaches to neuroendocrine tumors. But you can only give so many rounds of radiation, and you need to get to a center that can handle these things. And so a non-radioactive, smaller molecule approach that can kind of democratize that access to care, whether you live near a high center or you just have a local infusion center in a small town. Now, could you run us through what you think some perceived potential advantages could be versus an antibody drug conjugate? But conversely, what also are the potential risks that might be if you're comparing these to each other? The antibody drug conjugates have transformed the practice of oncology for many different tumor types. So no knocks against them. They have done some remarkable things. But the whole class of GPCRs are very difficult to get to with antibodies. And then just conceptually, driving internalization, driving clearance of a molecule out of the systemic circulation are things that I think improve the therapeutic window of a potential drug targeting system. And by using small molecule chemistry and chemical manufacturing, you have access to the whole range of chemical space for optimizing these characteristics. With an antibody, you've got an antibody. You can tune some aspects of it, but in the end, you've still got kind of some core properties that you can't get past. Got it, so you have a lot of INDs that are going in. Some have already gone in. Could you tell us about some of these new candidates and what we should expect to see? Certainly, polycystic kidney disease is one area. Graves' disease, TED. Yeah, it's a toy store full of fun things that I'm really excited to move forward. We've got a great discovery group, and it's nice to see these things now maturing on their way to the clinic. Probably after, so the drug conjugates I mentioned are in the lead for the next IND because we've already completed most of the IND-enabling work there. After that will be the PTH antagonist for hyperparathyroidism. And I know there's quite a bit of activity in the hypoparathyroidism space, so not to confuse that, but there's actually even more patients that have too much PTH, whether it's through benign tumors of the parathyroid gland or through hypercalcemia of malignancy where these tumors release excess parathyroid hormone-related hormone. So that's in the middle of IND- enabling work, should come out next, an IND next year. After that, there's, as you mentioned, a candidate for polycystic kidney. And you might say, well, what does polycystic kidney have to do with endocrinology? But endocrinology touches everything, including the kidney. And already the one drug that's out there is tolvaptan, which is a blocker of vasopressin, a peptide hormone that controls water excretion in the kidney. And it blocks the formation of cyclic AMP to an extent, but it also results in very high urine flow, which is a problem for patients if you need to use the restroom all day long. So we had discovered, well, we hadn't discovered, but we had found a large number of different somatostatin receptor ligands. There's five receptors for somatostatin, SST1 through 5. And as part of our paltusotine efforts, which is SST2 targeted, we found things at SST3. And we're looking for what do we do with them. And then we noticed that the field of ciliopathies and ciliary biology was using SST3 as a histological marker for this organelle. And somatostatins inhibit cyclic AMP wherever they act. And in polycystic diseases like polycystic kidney, the disruption of polycystin causes imbalance of too much cyclic AMP signaling in the cilia. And our hypothesis was that then activating somatostatin receptors there would lower cyclic AMP levels and potentially treat the disease. So we've got some great preclinical data there. We've got a good molecule. We're scaling it up. We hope to get that IND in next year as well. For those not acquainted, can you run us through what the path towards market is for a drug to treat polycystic kidney disease? Fortunately, there's been some innovation in that field recently. What the current conversation or guidance from the FDA is that total kidney volume is adequate or should be adequate for a preliminary approval. You need to follow through with kidney function studies as a post-marketing type of confirmatory trial. We would anticipate some sort of a phase one program to make sure you understand the PK and tolerability. Then going into a kidney volume study where you're measuring a variety of things, but kidney volume being kind of part of the key endpoint, placebo-controlled, probably fairly long, fairly big study. With an endpoint that in the field of polycystic kidney, tolvaptan has done okay. It's the only thing out there, but it's not a great drug. We think there's a huge market opportunity for us. So the initial IND, would that be something that'd be more geared towards healthy patients in determining the properties and then going towards a more diseased population? Yeah, I think, and this is a bit of an outlier in our programs where there's not a lot of information to be had in a healthy volunteer study except PK and safety. And it's really a gateway into a more traditional phase two program. What you see with our other programs, like what happened in paltusotine, is that in a healthy volunteer study, you can get great endocrine readouts. And we had proof of concept for paltusotine in the single ascending dose arm that has played out now through the phase three data. And you'll see that type of really meaningful healthy volunteer data in the PTH antagonist program for hyperparathyroidism, in the TSH antagonist program for Graves, but not in the polycystic kidney program. Got it, so let's jump from the early to the more recent. Paltusotine, obviously, it's been a big year. First coming on the pipeline and nearing the end of the pipeline, so to speak, is acromegaly. Just give us a rundown of what acromegaly is and how it is currently treated? Yeah, so maybe it's the end of the beginning for us, right? So acromegaly is a disease of the pituitary gland where you get a benign adenoma of the cells that normally make growth hormone. This results in too much growth hormone, which then acts at the liver and makes too much of another hormone called insulin-like growth factor or IGF-1. And while rare, if this happens in childhood, you end up with gigantism, right? It's also the same reasons why we're both dog lovers. It's the same reasons why Great Danes are so much bigger than our Maltipoos is growth hormone. But most of the time with acromegaly, this happens after people are an adult in their 30s or 40s. Their bones have already closed, so you're not getting excess height or bone length, but you are getting excess growth of soft tissues. You're getting growth of the heart and the liver, and you're getting metabolic disturbances, including insulin resistance, arthritis, facial changes. It can really be debilitating and shorten lifespan if left untreated. And what was discovered some time ago was that you could use a natural hormone called somatostatin, whose role in physiology is to limit the secretion of growth hormone. It's part of the natural brake system on growth hormone. And then artificial analogs of that have been developed, like octreotide and lanreotide, that are used as depot injections for the treatment of acromegaly, as well as carcinoid syndrome. And the problem with that is these are given as monthly depots that tend to wear off every month in a lot of patients. There's cyclicity. They're a monthly depot, so you don't get to steady state for a few months, and there's several dose levels. So it might take you three, six, or nine months to get to the right dose level of these injections. And then they're also quite painful intramuscular injections that are a bit difficult to give. So there's a number of reasons why people with acromegaly would really prefer a simple oral solution, not liquid solution, but an oral medication. And that's what we've developed with paltusotine. Now, you ran two pivotal trials, Pathfinder One and Pathfinder Two. Could you tell us about the differences between these two trials? Yeah, so Pathfinder One and Pathfinder Two were designed to address guidance from the FDA that in acromegaly, they viewed it as two different indications. One is the maintenance of therapy, so switching patients from standard of care to something that maintains their care. And then the second is the treatment of acromegaly where people who are not on current therapy receive a therapy and get control of their IGF-1 as the main marker. So we ran two trials. Pathfinder One was in switching patients from standard of care to paltusotine. Pathfinder Two was in taking patients who were untreated currently and switching them, or not switching them, giving them treatment with paltusotine. And then the endpoints in these studies were measuring IGF-1 levels, which is the way that physicians and regulators view control of the disease. What we showed in both cases was a remarkable level of efficacy, but not just on hormone levels, but also on control of symptoms, which is something we measured quite rigorously in these phase threes that had not been measured as part of other registrational programs. Now, given that SSA has been around for a while, you're thinking about launching. In a lot of ways, you're going against inertia just because it's been there. With that in mind, and given the data that's presented to date, clearly an oral and the challenges with SSAs can be something appealing. How should we look at it as far as when we're thinking about the launch, about what uptake looks like when you're talking inertia versus innovation? Yeah. So I think there is a groundswell of demand amongst the patient community for a better way to treat their disease. But that may take a little bit of time, as you say, because there is some inertia. One of the things that surprises me a great deal is that from the literature, the prevalence data in acromegaly is on the order of 27,000 patients in the U.S. But best we can tell from the claims data, only less than 10,000 are receiving current standard of care medical treatment. And I can't believe that those other 17,000 plus patients have been cured through surgical procedures because it's just surgery is not that good. So there's a lot of patients still who are not receiving therapy for one reason or another who should be. So as we think about this opportunity from a commercial point of view, I think there's several different segments. One, the new patients coming into the system, they'll trickle in every month at the centers. And there's really no reason why a physician wouldn't put them on an oral to begin with. So I think there's a very low barrier there. The patients who are doing well on the injectables, there may be some reluctance to switch because they're doing well. But on the flip side, they're struggling with these injections and they're scheduling their lives around them, and there's demand. So they, I think, is a low-hanging fruit to use a misused or often overused expression. But then they'll need to schedule an appointment with their physician, and that may be sometime down the road. And so there's going to be some time evolving in getting that switching. But I think the real opportunity then comes as we think about how do we expand medical care to all those patients who really should be on therapy, but who are not currently. And I think that's the longer-term opportunity that really we want to strive for. Are a lot of those patients identified and out there? So you know where they are and they'll be easy to find, or what type of effort is it to get in contact with these people who are selectively not in the system? Yeah, so I think there are a lot of people that are identified. These ones who are coming in for their monthly injections are really easy to identify, and from claims data, you can see what the physicians are that they're seeing, so I think that part is fairly straightforward. The more difficult group are the patients who are not receiving routine care for their acromegaly, even though they should be, and so we need to develop strategies for reaching out to them through either patient communities or through their physicians or maybe through their surgeons who they might have seen earlier, so a little bit more difficult, but I think an important opportunity for us in the long run. So let's jump to carcinoid syndrome. Similar data in a similar timeframe, obviously earlier stage. You recently announced a phase three trial design for the Carefinder studies, which looks in my notes I wrote as Carfinder, but Carefinder's trial. It is Carefinder, yes. So I guess tell us about that trial design. Tell us about how that market is currently treated and I guess similar dynamics of what your expectations are relative to paltusotine. Yeah, so somatostatin as a peptide hormone inhibits the secretion of other things. And the pituitary inhibits the secretion of growth hormone. And that's why you can use that mechanism to treat acromegaly. In the gut neuroendocrine cells, many of these cells make serotonin or VIP or other factors. And when they become tumorous and they form these neuroendocrine tumors, some of them end up secreting excess serotonin, VIP, other things that cause carcinoid syndrome. And so it's a secretory disease in addition to a cancer. And the carcinoid syndrome cardinal symptoms are flushing and diarrhea. And the backbone of therapy for those patients with these functional tumors has been the somatostatin analogs, just like in acromegaly. So in our phase two program, what we showed is that if you give paltusotine to patients with these symptoms, you could rapidly and very clearly resolve a lot of the flushing and a lot of the diarrhea. And we reported that in February or March earlier this year. And so the phase three program essentially takes that same concept and expands it to a placebo-controlled setting in a larger number of patients. And basically, we will take patients who are either untreated or who are willing to switch and wash out of their current therapy. We'll measure bowel movement frequency, intensity. We'll measure flushing frequency, intensity. We'll treat them for 12 weeks and measure the effect compared to placebo of paltusotine. And then there'll be an open-label extension where we'll also be monitoring PFS and tumor control. How should we think about that trial in terms of timeline? So we're in the process now of site selections and finalizing the protocol and getting all the things ready to begin recruiting patients. It's going to be a global trial. It'll probably be about 100 sites around the world. We'll use many of the same sites that we used for acromegaly. Outside the U.S., actually, many of the treaters are the same endocrinologists that do treat acromegaly. In the U.S., it's more oncologists versus endocrinologists. But even so, it's many of the same centers. So we're deep in that process now and ramping up the whole study. Sounds great. Boston, earlier this year, you had some intriguing data for both CAH and for Cushing's with your next candidate. Tell us about what you presented. I guess we'll start with CAH and how this could be a game changer for these patients. Yeah, I alluded to some of this earlier. I got to say that I've been going to the Endocrine Society meetings since the mid-80s, and when we put up our posters at the same time, and I think you were there, and we put up our posters for both Cushing's and CAH, and the hallway among the posters was just filled with people waiting for them to be enrolled, and I've never seen anything like it, actually. It was pretty exciting, and it was exciting for us for a couple of different reasons. As I mentioned, Harvey Cushing, who was the father of Cushing's disease, had his first patient starting in 1910, and that data in Cushing's disease, we did a single-site study with top investigator Lynnette Nieman at the NIH. And the way it works for her is when sites around the country can't get their patient under control, they send them to Lynnette for two weeks of intensive inpatient therapy, and usually at the end of those two weeks, she can get them moderately under control, and what we started seeing with the patients that she was giving atumelnant is that within a day or two, they were getting control, and every one of them. It just blew us away, and then similarly with our CAH data, CAH is, so I probably should have backed up, so Cushing's is very much like acromegaly. It's a pituitary tumor, but these tumors make a hormone called ACTH, which is at the center of the stress response pathway. That ACTH goes to the adrenal and makes too much cortisol or glucocorticoids, which is a main stress hormone. And then in CAH, it's similar, except patients with CAH have mutations in the pathway in the adrenal where they're not able to make cortisol, but they make these androgens like A4 instead. And what we saw in those patients, we measured them out to 12 weeks, but in the first two weeks, all these patients were coming down from very high levels of cortisol of A4 down to normal levels, thousands down to 100. It was, again, just this remarkably profound effect. And people were lining up in the hall to see it. It was one of the high points of my career. We were actually having a doctor call the moment the abstracts came out, and we were having a conversation, and it was shaped around expectations for atumelnant relative to crinecerfont, and literally, the doctor was saying, "Well, finds the CRF1 mechanism intriguing, not so sure about ACTH," then boom, the abstracts came out, and he read it over there, and he literally did a 360, I guess it'll be a 180, and said that the data was very impressive. It changed his expectations about what could be possible for treating the disease, and one thing that he particularly zeroed in on was the impact on menstrual cycles for these patients as something that he never would have anticipated. Was that type of effect? I mean, initially, people were talking about weaning off of corticosteroid reduction as being the objective. When you see something like that, how do you think doctors will think in terms of what their expectations are for treating these patients? Yeah, so what David's referring to is in this first cohort of patients, we had two women who had not had regular menstrual cycles in a decade or more. And one of the big challenges with CAH is because you're making these excess androgens in women, it impairs fertility. And the two women who were shifted on to atumelnant began regular menstrual cycles and have continued to this day. And it just kind of opened our eyes. I mean, some of the other things you're seeing with CAH are hirsutism, particularly problematic in women, testicular arrest tumors in men. The excess androgens affect fertility in both men and women. And so these are outcomes beyond just hormone levels. Now, hormone levels tell you and the endocrinologist a lot about what's going on. But in the end, it's about, "I want to have a baby," or, "Man, these testicular tumors are really a problem," or, "I don't want to have to shave and figure out depilatory type of things every week." So I think the potential to really impact people's lives beyond the biochemistry is what I hope for for this drug. Similarly, in Cushing's disease, what did you see that, I mean, probably didn't exceed your expectations, but you think might have exceeded the expectations of practitioners? Again, as part of that, just getting to normal glucocorticoid levels so rapidly was pretty surprising. We really didn't expect it that quickly. Also in those patients, relatively small numbers, so we have to. This is preliminary data so far. Every patient was showing some improvement in some of the clinical signs and symptoms of their Cushing's disease, whether it was hypertension or getting off some other meds or other things. Again, while those are not primary endpoints in a registrational trial, those are important types of things to measure so that you truly get the sense of the impact of a medicine on the patient's life, not just the regulatory endpoints. So could you tell us about next steps when we expect to see data and what the path towards market might look like? Yeah, so we're just wrapping up the full phase two study in CAH. We've studied now 40, 80, and 120 milligrams. The data we presented at Endo was just 80 and not a complete cohort. So we'll see the full cohorts. We'll understand dose response and full duration of action. So I don't expect that to be a major change in conclusions, but it fleshes it out in a way that allows us to go to the agencies with a strong rationale for dose response and allows us to start the phase three program in the first half of next year. What would you say the phase three program would ultimately look like? Now, I got to remember some of the details. It's getting harder with the full pipeline, but it'll be very similar to the phase two study, except it will be a little longer, and that'll allow us to start to look not just at androgen reductions, but also reductions of corresponding glucocorticoids, so the challenge with CAH is that because they can't make glucocorticoids, they need to take exogenous glucocorticoids, and if you take physiologic levels of these glucocorticoids, that does not adequately for most patients lower the androgens, so they're still suffering from the androgens, and most patients or many patients end up with high levels of glucocorticoids, and what you really want is normal glucocorticoids, normal adrenal androgens, and not have to compromise one for the other. So what we'll be measuring then is initially lowering of adrenal androgens, but then also the ability to wean off those excess glucocorticoids and get to safe levels of glucocorticoids while maintaining normal low levels of adrenal androgens, and then all the other symptoms and things associated with that. Got it. When investors are comparing different approaches and mechanisms out there, anything you would highlight different between what's happening with the crinecerfonts of the world and people on that end of the spectrum with your mechanism? Yeah, no, I'm really excited for patients to at least get crinecerfont on the market. Hopefully, that goes smoothly. It's the first thing out there since glucocorticoids, and it shows that they can reduce their glucocorticoid use without making their androgens worse. And so that's a step forward that I think will help the field. And then, of course, our aspiration, though, is to not only get the glucocorticoids down to normal levels, but not just keep androgens the same, but get those to normal levels as well. And that'll take us a little while, but the goal is to really resolve the disease to the point where it fades into the background and people can live a normal life, have their kids, not worry about hirsutism, not worry about the testicular adrenal rest tumors, and just get on with life. And that's kind of our whole approach to all the therapies that we're developing, whether it's atumelnant or paltusotine. We're trying to take the medicine out and let people be people instead of patients. So we're getting towards the end here, and we have a couple of minutes left. You certainly, a lot of the questions I've given are probably questions you've gotten before. It's people educating on certainly what's the latest in the pipeline. If you were to freestyle here and want to talk about what do you want people to know, and it can be anything, what do you see as far as the overall direction going forward, not just with the INDs, but just directionally where you see this company moving? Yeah, no, that's a great lead-in, David. You know, I truly understand the challenges of being on the buy side and dealing with the quarterly and annual goals and trying to cover large numbers of companies. And it's important to understand what things we have upcoming this year and next. But I think the real opportunity with Crinetics is not about an acromegaly launch or a carcinoid syndrome launch or a CAH launch or a Cushing's launch. It's that we've built an engine that can create important drugs that can develop those drugs. And now we're on the verge of learning how to commercialize those drugs. And our goal is to build a sustainable, high-impact global pharmaceutical company that is a leader in the field of endocrinology and the areas that endocrinology takes us. So if you scroll forward to 2030, which is where my head is usually at, I think you're going to look back on us as a cute little company today, right? And if you scroll into the 2030s, when all of these things that are just entering the clinics are really fully maturing and you're starting to get to sales numbers there, if you work your models forward there, it starts to be a remarkably large enterprise. And since everything's been discovered internally, we have no obligations externally except to our great partners at SKK who have rights to paltusotine in Japan. And the patents go into the 2040s for paltusotine and beyond for the rest of the molecules. So we're playing the long game, not ignoring the short game, but come for the acromegaly, but stay for everything else is maybe my way of answering your question. Excellent. That was very helpful. It was great. And thank you very much for your time, and look forward to chatting again soon. Thanks, David. Great to be here.