Welcome to Jefferies Healthcare Conference. My name is Dennis Ding, biotech analyst here at Jefferies. I have the great pleasure of having Crinetics Pharmaceuticals here with us, and CEO Scott Struthers will give a brief presentation, and then maybe we can do a little bit of Q&A afterwards. Thanks, Dennis, and thanks, everybody. It's a little loud, so I'll stand back a bit, but I see a bunch of folks I know and a few I don't know, so I'll just say a few words of intro, and then we can get into some Q&A and whatever you want to know. I'm joined today by Isabel Kalofonos, our Chief Commercial Officer, and I think many of you know we're getting ready for a PDUFA date on September 25 of our first molecule, paltusotine, for the treatment of acromegaly, and obviously that's a big thing for a company. One of the things I'm most proud of is it's not that often that a company conceives of a drug, makes it in-house, develops it in-house, and commercializes it themselves, and so it's a huge milestone for us, but it's just the first because we've got a deep pipeline underneath that of another indication for paltusotine, our second drug atumelnant for congenital adrenal hyperplasia and Cushing's disease, and on and on. We'll have a—I should put in a plug for an R&D day coming up a couple of weeks from now here in New York City. We'll talk about the things that are now in preclinical. We have four more programs in preclinical that'll be hitting the clinic in the coming year or so, and maybe as background for those who don't know us, everything we've built in-house, we haven't licensed anything in or out except we've licensed rights to paltusotine in Japan, and we've licensed a technology platform out to form Radionetics, which is a small molecule targeted radiopharm company that last summer did a great deal with Lilly, where Lilly bought an option to buy the company supporting our R&D efforts for various solid tumors for $140 million with the right to buy it for a billion, and Crinetics still owns about 25% of that company. We've also out-licensed rights to one of our backup molecules in the somatostatin space to a very exciting animal health company called Loyal that's developing that molecule to improve the lifespan of large- breed dogs, so you might go look into that, and I think these are all illustrations of the rich areas of endocrinology that have yet to be tapped. One of the beauties of this system is endocrinology touches every cell in every animal on the planet, and it's highly conserved amongst all mammals and even other species, so the things we learn in preclinical models in rats and mice are very translatable into the things we'll learn in the clinic, and the things we measure in rats and mice are often the biomarker endpoints for registration. I think it's a bit of a unique risk-reward profile, and we're really just getting started, so think about the things coming this year and next, but we're building a company to last into the 2030s, 2040s. Our patents don't expire; it starts expiring until the 2040s, and we're in a very strong financial position today. We've never been stronger. We've got $1.3 billion in the bank that lasts us till 2029, assuming we don't choose to partner something, and with that, maybe I'll turn it to Dennis, and we can figure out what you want to talk in some more detail about. Yeah, perfect. That's a great overview. In the near term, you obviously have paltusotine with the FDA under review for acromegaly, so talk a little bit about the dynamics there, maybe remind us a little bit about the data, the market, etc. Yeah, so maybe I'll do a little bit of intro and then let Isabel talk in some more detail. First, just a reassurance that I guess is common lately at this meeting, but everything seems on track with the timing of the activities going on with the FDA towards our PDUFA date. We also had an IND open for 9682, our newest program to enter the clinic, and that opened on time, and we've got multiple mid-cycle meetings going on with other clinical programs, and those seem to be happening on time with kind of the normal types of interactions you get, so reassuring on that front. From a market dynamic, I think it's—I'm super encouraged. I've spent the week here in New York riding along with our New York MSL. We've got an MSL team that's been out in the field for the last several months. We're onboarding our sales team now, getting ready for the training them and getting them out there to profile accounts and start making introductions. I think there's a lot of receptivity to the next level of care in acromegaly, and certainly that's well appreciated. One of the things I've been learning is it's not enough to just provide a better drug. We also have to spend a lot of time improving the delivery of healthcare because the acromegaly patients that are out there are not being managed as well as they should with the existing drugs, and many of them are not getting those drugs who should. We're building a system not just to help get paltusotine out there, but to improve the state of care of acromegaly, and this is part of our long-standing partnership with the endocrinology community. We're not just a sponsor selling a drug. I've been in endocrinology since 1980. Many of our people in the company have spent their whole careers on it. We have, I think now, almost a dozen MD endocrinologists in the company. It's a huge powerhouse of endocrinology thinking, and we're trying not just to make drugs that are going to advance endocrinology, but help the delivery of endocrine drugs in general. That is a high-level view. Now, Isabel and her team are deep on the ground and in the weeds, and maybe she can give you a little bit of characteristics of that. Yes, so the acromegaly market has approximately 11,000 addressable patients, and we are—we had segmented them in some groups that we can immediately address and others that are additional market expansion in the future. From those 11,000, we have some patients that are new to therapy every year, and we are fortunate to have not only Pathfinder 1, but Pathfinder 2. For those of you that have seen the data, Pathfinder 2 is looking at the naive population, which will give us an advantage on the label if the FDA approves the label the way we have presented it. We are expecting a label that talks about treatment and maintenance of the disease. The second segment is, of course, the switching segment. There are patients that are currently on therapy, but there is significant admitted need. They continue to have uncontrolled symptoms. There is at least 20% of them have to take a higher number of injections than the 13 number of injections that they normally have. They have to take it almost every three weeks in order to have disease control or better control of their IGF-1 levels, and therefore we see a lot of opportunity of addressing the admitted need and engaging with patients and physicians to mobilize them to really go to the next standard of care that we believe is paltusotine. The third group is what we call right now lost to follow-up, and we want to re-engage them. Many of the patients actually discontinue treatment, and we presented some of this data at ACE when we look at longitudinal data based on IQVIA on how many patients were actually discontinuing their therapy within the first three years after treatment, and it's close to 80% of the patients that discontinue. Some of them switch, some of them change, but over time, at least 20% of them discontinue for the long term. We see a lot of potential there to bring them back into therapy, and we are working on evaluating how to address that, given that many of them remain under the care of endocrinologists, given that they have comorbid diabetes and other conditions. In the long term, we see the potential for expanding that, for addressing more patients that currently believe that maybe they have a cure with the surgery, which we are really identifying more like guidelines defining this surgical remission, meaning sometimes the tumor can grow back, they can have symptoms again, and right now they are not on therapy, and also the significant number of undiagnosed patients. We see that there is a lot of potential expansion in the future, but the immediate population is the one I described: naive switch and some of the patients that have been lost to follow-up. We are active in the field right now. We are engaging with the KOL community. We are engaging with the patients. In community, we have lots of activities going on, several local advisory boards. We think it's important that we understand the regional dynamics. We have a speaker series ongoing, and as Scott alluded to, we had already hired most of our sales force, and we are in the process of training them, and we would like to be in the field earlier than the launch so we can engage with the sites, start profiling the sites, start scheduling appointments with the key decision makers on those sites. That is very exciting for us. I was mentioning some of the one-on-ones. We had over 1,000 applicants for 32 jobs, so we are very excited that we got really good talent into the organization with significant experience in endocrine and rare diseases. From the patient perspective, we continue to have our disease education campaign. We continue to engage with the patients on local events. One more coming up in Boston on Saturday, and we have very good receptivity to the educational activities and the materials that we are providing to them. We took the decision to open our hub for patient services earlier, so we launched it with the objective of helping patients, as Scott mentioned, beyond just the drug. We want them to have the opportunity to find a place where they can find a physician that will have expertise in treating acromegaly, a surgeon that has conducted several surgeries, and they will have better outcomes from that, and the opportunity to engage with our case managers and nurses should they need any support and understanding better their symptoms. There is a lot of activity going on, and the commercial team is actively working in preparing and shaping the marketplace, and that is in coordination with the medical affairs team. Right now, we have 12 MSLs actively engaging with the community and the key centers. Great. In terms of you outlined three sort of buckets, the naive, the switches, and then the patients who are lost to follow-up. As you're going into the launch over the next 6-12, 18 months, which do you consider to be the lowest-h anging fruit in terms of getting patients onto paltusotine? Yes, so we believe that the first two segments will be like an immediate win. In our discussions with the doctors, any patient that is newly diagnosed with acromegaly and just finished the surgery is very likely to prefer, and that's the preference that we see in our market research, to prefer paltusotine over other therapies. We see that as an immediate opportunity. Of course, there are a few number of patients that are being diagnosed every year, so you have to account for that. In terms of the switching, there are so many patients that continue to have uncontrolled IGF-1 levels and uncontrolled symptoms that, of course, we are going to start with that subset of patients and work our way through. Our experience is not only on the two clinical trials, but we have open-label studies where patients had high adherence to treatment for over four years, and the majority of those patients chose to go into the open label. 93% of the patients chose to go into the open label and have remained adherent to treatment, in contrast to what I mentioned before, that injectable, so many of them discontinued rather quickly. We are very encouraged by the feedback we're getting from the field, and we believe that once we get a patient, we'll be able to retain a patient, and that's another way of growing up the market. Okay, and as you do your market research, and if we can talk a little bit about the switch portion, based off surveys and things like that, what percentage of patients are actually okay and well controlled on the injectables, but what proportion of them have those breakthrough symptoms where maybe paltusotine would definitely make sense for a switch? It's interesting. The definition of control is a little bit all over the place for physicians. According to guidelines, control is defined as IGF-1 levels less than one upper limit of normal, but many doctors are not necessarily treating to guidelines. A lot of our work in education right now is to educate on guidelines on what control really means. Over 70% of patients continue to have breakthrough symptoms, and in one of the posters we presented at ACE, we showed that while many of them, the historical data, many of them had expressed that most of those symptoms manifest towards the last week of the treatment; actually, they are having peaks and valleys, and they continue to experience symptoms throughout the cycle, which will be completely different with paltusotine where they have that daily control. I'm not going to mention market shares and percentage of patients, but I think that gives you a picture. Okay, if I can comment. Yeah, Scott. That was a very kind of analytical and clinical answer to how many patients are well controlled, but I would argue that patients have only really accepted what they have as their only choice, and nobody is really perfectly happy with an injection that you got to schedule and deal with every month. You got to figure out your vacation schedule, and then you have a very large, painful injection that is hard to administer if you do it yourself and wears off, and all these other things. Just think about it in your own life. How would you manage that? How would you go on vacation? How would you sit down for a couple of days? The best market research you could do is to go watch my favorite video on YouTube by a guy named Tumornator who films himself and his wife trying to give him his first octreotide injection. You will never ask the question again about these injections and what it means for somebody's daily life. We are going to take the burden of care off of these patients, hopefully also provide a next level of control of their disease. Really, go do a few minutes on YouTube. It is the best research you could do on this program. Given that the PDUFA is only a handful of months away, have you talked with payers and just maybe make some comments around access, what that could look like, step edit, et cetera? Something like that would be really helpful. Yeah, so we have a very strong payer team, and we had been engaging with all the key plans, national and regional plans, and presenting our data to them. We are also doing advisory boards with payers to get feedback on the best messaging and elements to present the program. The feedback has been very positive, and there are a few things that are coming from those discussions. Number one, they recognize that there is a significant, I'm going to use the word, wastage with the injectables because either the patient is taking too much drug, 20% of them are taking more injections, or many of them are skipping dosings, so they do not have really good efficacy, and they continue to have breakthrough symptoms. Many of the patients on those treatments anyway end up having surgeries, whether it is the knee surgery or hip surgery, and there are many costs associated to that. They recognize that. They also really respond very well to the fact that we have fast onset of action. You very quickly know if the patient is going to respond or not respond to the treatment and how well it is going to respond. That has been very positive. In terms of the discussions, I think you all know, once you know a payer, you know one payer. Each plan has a little variations, but so far what we had seen is that they are very open to just working prior authorizations based on our label, meaning we are first-line treatment. We can have naive patients, we can have switch patients, and they will not object to that or put any step edits. Frankly, they are just asking for the basic confirmation that the patient has acromegaly and meets the criteria for the drug. At this point, we have not had any feedback from any of the discussions we had about the step edits. This is one of those things that many of the other products have faced in the field because they have a second-line label in particular, and therefore they have to first have the injectable before they can be on drug, and that is the case that we will be facing, that many of the agents are facing today. Okay, and then how are you guys thinking about price? Because that's obviously an important factor for any kind of biotech launch going into a competitive landscape with injectables. There is a lot of value add with an oral, but in terms of pricing and maybe some of the feedback from payers and their sensitivities around various pricing points. That's right. Pricing is a very important question, and I think obviously we are not going to be announcing our price strategy at this stage. We are, of course, discussing what is the willingness to pay, the different brackets and price points, and we are evaluating all of that in research. Fundamentally, you want to define your price based on value. We will be working on that. Okay, and as you go into the end of the year in 2026 and 2027, with any kind of new drug launched, there's going to be a period of time where formularies have to be updated, et cetera. There's going to be a little bit, perhaps, of a lag between patient starts and actual product revenue. Should investors, as we go into 2026, be more focused on patient starts and patient forms and things like that instead of the actual revenue realized by clinics? Yeah, as any new-to-market drug, there is a lag on formulary coverage that you have to account for. In this particular market, also, the patients tend to visit the doctors only once a year. We really need to activate them, mobilize them to have those discussions and move those appointments. Yes, I think it's important to start with looking at patient starts. We'll have a bridge program, but this is going to be, I guess, similar to Crinetics Pharmaceuticals. Over time, you will see ongoing growth and ongoing coverage, which will accelerate the process in 2026. Okay, and if we can kind of talk a little bit about shifting topics, maybe we can talk about CAH, right? Scott, maybe talk a little bit about the progress there. You guys are going to start a phase three very soon. Talk about the rationale around the trial design and why it's differentiated relative to some of the competitors on the market. Yeah, thanks, Dennis. CAH and also Cushing's disease are both diseases of ACTH excess. In both of those, we've had some remarkable phase two data in that atumelnant is doing things that people had never seen before in these indications. As we then started thinking about the CAH phase three trials, so an adult phase three and then a pediatric phase two-three trial that are spinning up now, we really wanted to rethink the treatment paradigm for CAH. From its original description, the only treatment has been glucocorticoids. Glucocorticoids are needed for replacement because they're missing in CAH patients, but they're also being used to suppress the excess ACTH. That means you're giving too much glucocorticoids, which causes its own set of problems, essentially iatrogenic Cushing's disease. With atumelnant and what it can do pharmacologically, it's time to rethink. Our vision for atumelnant is it treats the adrenal. It lowers and reduces and normalizes all those excess precursors that are being made by the adrenal. That allows the glucocorticoids to be used only for the replacement that they're needed. In thinking about that paradigm, we designed a trial that emphasized it where the primary endpoint is the% of patients or proportion of patients compared to placebo who achieve normal levels of adrenal androgens as measured by A4 and at normal levels or physiologic levels of glucocorticoid replacement. That's a very high bar, but it's exactly what the treatment goals are for these patients. In the cascade of secondary endpoints and exploratory endpoints for measuring all the other things that are important, like what's happening to percentages or reductions of some of these markers, what's happening to the testosterone levels in women, what's happening to the symptoms like menstrual irregularities or the TARTs that are the testicular adrenal rest tumors. We have already seen in the phase two program improvements in signs and symptoms in addition to great reductions in adrenal androgens. Super excited to get that going. We are launching it around the world. We are using many of the same sites as we have done in our acromegaly program and many of our friends around the world because, as I mentioned in the intro, we are part of the endocrinology community. It is not like we just have one program. We may be going back to the same sites for four different clinical trials, five different clinical trials. That gives us a differentiation at a company level that is, I think, unique. Great, and Scott, I'm going to have to ask about the LFT in the phase two. Just your thoughts around that and why you may or may not be concerned going to phase three. Is that just a normal course of drug development? Is there anything specific with atumelnant? Just some comments there. Yeah, so what Dennis is referring to is in one of our phase two trials, we had one patient at their last visit who had a significantly elevated LFT that could not be explained by something else. And we are super transparent about all our data, and you will look back on our data releases, and we almost always give patient-by-patient data. And that one LFT drew quite a bit of attention primarily from the investor community. That is part of all the packages we have been submitting to regulators in the U.S. and in Europe. It is part of the packages we have been submitting to the IRBs at the various sites. And nobody is asking any special questions about it. It is just part of normal drug development. We are confident in the safety profile of this compound, or we would not be launching global phase threes in multiple indications. I realize people have been burned by drugs blowing up. The only thing that's probably going to let you have confidence is as these progress, we'll have more and more patients for longer and longer, and the safety will reveal itself. We're actively continuing to expand the phase two with a fourth cohort and now an open-label extension. Soon we'll start enrolling patients in the phase threes, and that comfort will come with time. When does the company expect to provide an update to investors on the open-label extension trial and some of the patients that have rolled over into there, as well as the cohort four? Yeah, so the cohorts are now, cohort four is fully enrolled, and we are moving forward with getting the OLE going at all the various sites. I realize there's some interest in how things are progressing. I don't want to come out and talk about efficacy data and things until we really have a complete picture. I'm not exactly sure when that'll be. I think maybe we should provide a little bit of guidance that when we get a certain number of patients at a certain number of time points, things are still progressing smoothly. Maybe that'll help just with the safety aspects. Look for that in our quarterly earnings maybe, but don't expect us to always start providing quarterly blow-by-blow updates on all our trials because that doesn't help anybody. Okay, I think we are out of time, and unfortunately, we could not talk about the other five or six other programs that you guys have. Quite a broad pipeline, and you guys have more than $1 billion of cash to interrogate all of them. Unfortunately, that is all the time we have, but it is great to see you guys. Thank you for coming, and excited about the outlook this year. Thanks, Dennis. Thanks all for coming, and happy to talk to you on a one-on-one basis. R&D Day. Yes, and the R&D Day. Yeah, R&D day on the 26th here in New York, right? Perfect, thank you. Thank you.