All right. Well, welcome everyone. Thank you for joining us. This is Gavin Clark-Gartner with the Evercore ISI Biotech research team. Really happy to be here with Scott Struthers, who's the CEO and co-founder of Crinetics Pharmaceuticals. We also have Alan Krasner, who is the Chief Medical Officer. Thank you guys so much for joining us. Thank you. Thanks for having us in a nice, warm place, too. Absolutely. You guys, welcome anytime. So a lot going on, maybe just for people who are not as familiar, maybe just give us a recap of the Crinetics story and where things stand today. Yeah, so, it's been a great year for us. It's kind of the culmination of efforts we've had for a long time now, with our first molecule passing its first Phase III study with flying colors, which allowed us to raise a nice chunk of money, so we're financially stable. And it also allows us to move the rest of our pipeline forward. So we're focused on endocrinology and drugs targeting peptide hormone receptors, but small molecule oral drugs that can modulate these systems. And everything we've made has been discovered in our labs in-house, and that means the patents go out into the 2040s, and we're playing a long-term game. We're trying to build a real company. With this program entering or finishing up phase 3, our plan is to launch it ourselves, and use those proceeds to continue to build the pipeline and advance the company. Sounds great. All right, so, I mean, most of my investor conversations have been around paltusotine and carcinoid, since we have data coming next month. Maybe we'll start there. Just remind us, what exactly is the trial design? And for the interim data, how many patients should we expect to see data from? Yeah, so paltusotine, for those who don't know, is a small molecule taken once a day that acts as a somatostatin receptor, and it's designed to replace the current somatostatin receptor ligands, which are administered as a once-a-month depot intramuscular injection that tend to wear off and have a variety of issues. And so we showed positive Phase III data in acromegaly. The other main indication is carcinoid syndrome. These are patients with neuroendocrine tumors who have a variety of symptoms, including diarrhea and flushing, and we're looking at reduction in diarrhea and flushing, as well as PK safety and other things. You want to go into more detail on that or kind... Yeah, no, that's good. All right, so, 30 patients total in the trial. I think you noted half or a little over half, we should expect to see data from in December. Yeah, sorry. So, yeah, but we'll finish about half, a little more than half for 8, the full 8 weeks. We're almost done enrolling the full 30. This will allow us to have a complete data release in the first part of next year. But I think that from the initial group, we'll have a lot to chew on and see, you know, share with folks whether or not the drug is working as expected and begin to help guide our thinking around phase 3 designs. There's two populations of patients enrolled in this trial. The first is the naive patients, and the second is the washout. What's the split between those two groups? Alan, maybe you want to talk about some of the details here. That's right. The more prevalent patient population are those who are already on treatment. And you're right, during our screening period in this trial, we washed them out of their treatment and randomized them when they're having active symptoms. Probably, I would expect roughly two-thirds of the patients would be in that category. One-third, though, will be naive, not previously treated. They start out with active symptoms and are randomized as soon as possible. Got it. Maybe let's go into a little more detail for that washout period then. How long is it? It sounds like there may be some flexibility in terms of when patients start to get worse. You don't want them to get too much worse before you enroll them. Maybe just give us a sense for what that criteria looks like. Yeah. Yeah. So basically, these are patients who come in on either octreotide or lanreotide with controlled symptoms, as defined quantitatively in the protocol. They then enter up to a 3-month period of washout. But you're right, if they qualify earlier than 3 months based on a pre-specified symptom worsening, they can randomize earlier than that. For the symptom worsening, does that need to be specifically diarrhea, flushing, both, any other symptoms? Well, I would say, many patients qualify on the basis of a frequency of bowel movements, others on the basis of flushing episodes, and a number of patients can have both, and that's really represents the real world of carcinoid syndrome. That's fair. And thinking about response in those different patient groups, should we expect any difference in response? Well, you know, I think only insofar as they may start at different baselines. As you can imagine, those who are naive, there is no cap to the frequency of either of their symptoms, and so you would expect higher baseline symptoms, symptom burden at that level. When we wash patients out of a successful treatment, we have to be judicious there for safety's sake. So we don't really allow them to get maximally symptomatic before we would randomize them. Yeah, I think that's explained pretty well. Is there any kind of bar for clinical meaningfulness you're willing to kinda lay out here, and taking into account what you just said about the different kind of baselines and the different groups potentially? Yeah, so this study isn't really designed to quantify things like that. I think actually the most compelling is the original study, this was the New England Journal paper, I believe, in the late eighties for short-acting octreotide, where it was a case series of just 25 patients. And what you could see is the majority of them had very significant benefits from the, from the treatment. So you expect somatostatin receptor agonist-... to have what we call self-evident efficacy in these populations. Now, in this particular study, we're looking at the washouts, the naives, the flushing patients, the diarrhea patients, and so there's different segments that we need to qualify and figure out how to quantify as part of a phase III design. But it doesn't lend itself well to a single bar or bogey or number that a lot of people wanna get out of this, but I hope you can tell whether the drug is working or not. Yeah, that makes sense. Are you taking tumor scans as part of this trial? Any plans to present that data? Yes, as for the safety monitoring of the carcinoid syndrome patients, they have regular CT or MRI scanning, according to their pre-trial schedules, largely. That wouldn't be a short-term endpoint in the eight weeks of the core study, but certainly, those patients who complete the core study are eligible for a long-term extension, and during the long-term follow-up, certainly they have their scanning. Have you said anything about the rates of patients that are rolling over into the long-term follow-up? It might still be a little bit early there. Yeah, I think we would probably announce that with the data, the interim data. And again, we are just getting very close to completing enrollment, so the full cohort will be next year. Yeah, that makes perfect sense. All right, so thinking a little about this population commercially, it's kind of the broader group of neuroendocrine tumors, and then there's also carcinoid. So at least based on your conversations with doctors and how they view these patient groups, how are you defining that, and how is that guiding your development? Yeah, well, so I mean, I think that the carcinoid syndrome patient population probably have the highest use SRL therapy the most, because if they don't, oftentimes their acute symptoms are not adequately controlled. There are some patients who use, with non-functional tumors, who use SRLs for long-term sort of maintenance of their tumors, but that's kind of a cytostatic sort of effect. There are a number of patients who really are observed rather than being treated with these burdensome painful injections once a month. Yeah, I do think there's still a real opportunity in the field for truly targeted anti-tumor agents. But SRLs themselves, naked SRLs, aren't really it. There's been a lot of progress in the radiotherapy field, and that is providing additional, you know, quality years of life to these patients who you know, it's almost becoming a chronic disease. But I think that, you know, the main use would be symptomatic. Yeah. So with that in mind, as we're still early, of course, but as we're thinking about phase 3 development plans, should our expectation be that this is going to be probably a carcinoid symptoms trial, so a shorter endpoint, and is that gonna be placebo-controlled or head-to-head versus injectable? Yeah, I mean, so, generally, I can speak to the regulatory history in this area, and the most recent approval for carcinoid syndrome was a three-month prospective placebo-controlled trial. I think that's a reasonable expectation when we go in to meet with the FDA to talk about this. There are, of course, other trial design options to be considered, but this would not be unexpected, I would say. And yeah, I think the primary endpoint for such a trial for an indication in carcinoid syndrome would be directly relevant to the symptoms, diarrhea and flushing, either frequency, intensity, or something related to the symptoms of the disease. Yeah, and I guess that regulatory precedent aside, would you guys have any interest in running a head-to-head carcinoid syndrome trial versus the injectables? I mean, you can make the argument that, hey, maybe some of the injectables wear off at the end of the treatment period, and if you're sticking with the FDA-approved dose, you guys might actually have better coverage. So some of those, you know, bowel movement and flushing flares essentially kinda get caught in the injectable arm, whereas you guys could make out better. Yeah, I would like a way to be able to do some comparison to, quote, "standard of care," 'cause I don't think it works for a lot of patients. You know, these intramuscular injections are very burdensome, and if you gotta go to every two weeks or every three weeks for that, that's a big problem. And it's expensive for payers too. So I'd like a comparator, but I'm not sure a head-to-head is the way to do it. We are trying to figure out if there's a way to get a good baseline in these patients. You know, even if they're on every two or three weeks, you know, maybe putting them on the indicated label frequency for a while and measuring, if the patients are willing to do that. Again, it's really symptomatic. I mean, some of these patients, just, you know, I gotta give this some perspective 'cause we're just talking, you know, vague numbers here. But imagine trying to deal with running to the bathroom 10, 15 times a day, every day of the week, or, you know, maybe you just have a few bad days, you know. You know, that is life-altering, and you're probably not willing to get there... If you've found some treatment, you're probably not willing to go there again, right? So we need to come up with a design that is patient-friendly, shows the benefit of a consistent therapy, and meets the regulatory hurdles that, you know, basically gets it approved, and then people can vote with their feet on, you know, which drug they prefer. That makes sense. Like, also thinking outside of carcinoid to the broader neuroendocrine population, do you think you need to run some type of PFS or other trial to kind of, in neuroendocrine tumors specifically, to unlock the full opportunity? ... Well, like I kind of alluded to earlier, I think there's a huge need for symptomatic control in the carcinoid population. I do think there's needs for better therapies for neuroendocrine tumors beyond radiotherapies, because radiotherapies can only be used a couple times. And, I just don't think that for us, with paltusotine, that investing in a PFS-like study is the right use of capital. It's gonna be a very long study, many, many years, many, many patients, with a somewhat ambiguous endpoint, you know, in a, in a slow-growing tumor that's generally being controlled fairly well. Now, that said, our discovery group is. We've learned a lot about neuroendocrine tumors. We're developing a franchise there. We have an idea or two in the discovery group about what might be a whole better platform, and you can always count that there's things cooking in our discovery kitchen that may not have made it to the surface yet. That makes sense. More to come. More to come. All right, I don't, I think that's good. Let's move on from carcinoid, go over to acromegaly. And maybe less so to recap all the data, but maybe more frame expectations for the naive trial. The response rate's gonna be lower, so just based on prior studies, what would be a reasonable range to expect? Alan, you wanna talk about it? Well, as you can imagine, there's a range from the literature on published trials. But I would say that in general, the naive patient population, you can see responder rate, as defined by normalization of IGF-I, being in the 20%-45% range or so. Now, there are other patients involved in the trial, and as has been done in the past, including those who have recently washed out or have not recently been treated with SRL. They're kind of lumped together with the naive patient population in our Stratum 1 and PATHFNDR-2 because their responder rates are expected to be similar, but a bit higher in that second group. This is based on the data from the lanreotide registrational trial. So the final overall quote, "response rate" from the trial will be sort of a blend across the patient mixes. We also have the washout group, Stratum two, which would be expected to have the highest responder rate. So the blend of those three groups will be the ultimate responder rate. I would expect it to be, you know, sort of closer to the naive side. Yeah, and at this point, it's been a couple months since the previously treated acromegaly data has come out, so I'm sure you're kind of in the middle of some market research still. But at least from some of your early provider KOL interactions, do you have a sense for the existing injectable patients, how many may be looking to switch? And then also, for the new patients coming on, where, you know, market share kind of falls, and whether you've kind of done any provider segmentations to gauge where that falls yet? Yeah, so as you say, we're really just getting started on a lot of that more formal work. But we have been presenting the data recently at the British Endocrine Society, and maybe yesterday at the Brazilian Endocrine Society. You know, when we were going into all this, we were a little worried about the physicians having some reluctance to try something new. I'm sure the patients would be happy to get rid of these injections, but you know, the physicians being maybe a little conservative. But responses to this data have been everywhere from, "Wow, that's really good," to, "Wow, that's amazing!" So I think we, with PATHFNDR-1 data, have eliminated a lot of reluctance to try something new because it's so compelling. We'll see how that turns into market data and how best to position it and all that type of thing, but, basically, the Phase III data so far couldn't have been any better. That makes sense. So let's shift gears quickly and go over to 4894, the ACTH antagonist, and focusing on CAH first. It's gonna be the phase II data coming in the second half of next year. I just wanted to confirm, is that gonna be for all three of the cohorts? Well, so to remind folks, this is a dose escalation, and the highest dose is the last cohort. If we floor the hormone levels in the earlier cohorts, we probably don't need to finish the last one. So it'll depend. But, you know, we just need to let it play out and see the data. Yeah. What about for the Cushing's trial? So Cushing's is being done at top group at the NIH, and it's, you know, onesie-twosie enrollment, so it's going a little slow, but really rich data source for each of those patients. Yeah. Sounds good. I'm gonna try and touch on all the other programs in the last couple minutes too, so, Good luck with that. We'll see. For the PTH antagonist, have you locked down a development candidate yet? Ask me again early next year, but you know, we're down to, like, a couple good choices. Yeah. Phase 1 plans for that one, would there be any type of challenge study, or would it just be pharmacodynamic effects in healthy volunteers? We were just talking about that. So likely, whether it's a challenge study or whether it's pharmacodynamics, there are things you should be able to see in the parathyroid calcium axis that should be indicative of pharmacodynamics as well as the normal pharmacokinetics and safety. Yeah. All right, TSHR antagonist, what's the current status? How close are we? Got molecules that will... In a mouse model, we can give them Graves' disease, watch their thyroid hormones go up, and we can bring them back to normal. Now, we just gotta make sure those molecules have all the right pharmaceutical properties for a drug that's safe to use, and 1%-2% of the population has Graves' disease. So we're honing in, you know, it's always a little bit unpredictable when you can find that last best molecule, but it's getting close. Yeah, and maybe the last area for today is, you've previously discussed pursuing multiple targets in obesity and with the interest to use different combinations. So maybe just kind of frame where your recent efforts, I understand you're not really gonna be saying too much publicly for a while. Maybe also just understand, how much investment is there going on behind the scenes that we don't really see? Well, so we've invested the last 15 years at Crinetics, and many of us, many years and decades before that, learning how to make small molecule drugs acting at peptide hormone receptors, with a focus in the field of endocrinology. So our whole company has been built around this notion of: how do we make this type of drugs? And now we have, you know, great proof of concept with some of the peptides out there, that perhaps one of the biggest problems in public health today, which is obesity, and the second biggest problem, which is diabetes, can be really altered by modulating these peptide hormone receptors. But you just can't do it with auto-injectors and peptides in enough patients in an economically reasonable way. So we're making small molecules at different of these receptors, different combinations, and I think that that whole story is just really beginning. Yeah. Awesome. Well, almost hit on everything. Pretty close. Missed polycystic kidney disease, but we'll, we'll do that next time. There's a couple other things going on that you don't know about yet. Yeah. Well, more to come. Awesome. Thanks, Alan, thanks, Scott. Really appreciate you guys joining. Thanks. Thank you. Appreciate you being here.