Good morning, everyone. Welcome to our third day of our Piper Sandler Healthcare Conference. Really excited to be featuring the team from Crinetics Pharmaceuticals here with us. Alan, Scott, wonderful to have you. We have lots to cover in the next 25 minutes. Maybe makes sense to go sort of in chronological order of sort of upcoming catalysts. I think a lot of our investors listening to the fireside chat, they're very excited, looking forward to the open label carcinoid study, which you have noted will report out in December. For investors, you know, they probably wanna know how soon from now are you entering quiet period. Could you maybe talk about that? Yeah, thanks, thanks for having us. Mm-hmm. Yeah, it's always great to come back to New York in the holidays and see people in person and freeze a little bit. But it's, you know, I know overall the market's been tough this year, but I gotta say, for us, it's been a fabulous year. Mm. I can't think of one that's been better. Okay. Yeah, we have the carcinoid data coming up in December, so you know, here we are out talking to lots of friends before- Mm the end of the month, and we will probably be quiet starting- Mm-hmm -next week- Mm-hmm until we come out with some data for Santa to bring to your stockings. Okay. So given that you made the comment, bring the data for your stocking, I assume you would usually deliver gifts before Christmas and not after Christmas. There seemed to be quite a bit of concern about the precise timing and people planning their holiday season. That's exactly right, yeah. So I get it, and I too would not like to be on the phone answering a lot of questions between Christmas and New Year's. Got it. That's very helpful. We will do our best to make sure it comes out before the holidays so that we can all have lots of Christmas cheer. Yeah. Team, I think you guys have done a really nice job educating investors that as we go into this open label data set, it's not about figuring out whether it's gonna work or not, but rather figuring out what are the endpoints, and that you would move forward towards, well, what could you learn from this open label study that could inform your registrational path? So people understand that. People also understand that, you know, the symptomology of this disease is highly variable. So the question that's being posed is, as we go into this read out, how informative will it be to get color on the registrational path or path forward? Like- Yeah ... how, if you could maybe capture that, I think that would be really helpful. Well, I think it's, for context, it's important to remember- Mm-hmm -that this is a really severe disease that affects, you know, 30,000+ Mm-hmm patients in the U.S. But there hasn't been a, you know, a rigorous modern clinical trial in this space. Mm-hmm -in this type of population, essentially ever. Mm-hmm. It's a classic case of using phase II to really do some learning- Mm -and understanding. Mm-hmm. And then use that to refine a phase III. So Alan, maybe you wanna comment on some of the various specifics that we're trying to learn- Mm-hmm about guiding the phase III program? Yeah. So, primarily, the study is designed to assess- Mm-hmm -three major items: safety, toleration, of course, is number one- Mm-hmm -in every study. In this case, we're also going to be documenting PK to ensure that- Mm-hmm The drug is properly absorbed in these patients with a variety of GI issues. And thirdly, we're looking at, very carefully, information that would help- Mm-hmm -de-risk efficacy for phase III. And, that would be including daily- Mm-hmm measurements of patients' Mm-hmm of bowel movements Mm-hmm and flushing episodes, plus a variety of other Mm-hmm important patient-reported outcome material. I think on the third point, it will very much help us design phase III to know what doses seem to be- Mm-hmm affecting the symptoms. Mm-hmm. What other attributes of the symptoms we should really collect in phase III? Yeah. Okay, that's very helpful. Could you, as of the interim data, that will be about 15 patients, kind of remind us the distribution? Because there's a group that's washed out, there's a group that's naive, like, what's the distribution between the two? How variable is the symptomatology between these cohorts? Just some broad strokes. Sure. So, we have both patients who are naive- Mm-hmm to medical therapy Mm-hmm ... as well as patients who are on therapy- Mm-hmm who are willing to wash out of their therapy. Mm-hmm -during a screening period. The second population is more prevalent out there- Mm-hmm And so we are anticipating roughly two-thirds of our patients will be in the second group, the pre- Mm-hmm -previously treated group, and about a third in the naive group. It's important to understand the patient's background- Mm-hmm -when you interpret the data on drug. As you can imagine, those who have never started therapy yet, they are just- Mm-hmm Basically recently diagnosed. Mm-hmm they would be expected to have the highest baseline frequencies. Mm-hmm of both diarrhea Mm-hmm or flushing. Those who are treated, we do wash them out. Mm-hmm but we don't wash them out all the way, because- Yeah that would not be safe. Mm-hmm. They're gonna probably start with lower baseline frequencies. Mm-hmm. And we'll put both groups on paltusotine Mm-hmm -for eight weeks and, measure all those three things- Mm-hmm we talked about. Okay. If now, as we're getting a little closer to the data, do you, and this cohort is small, have you decided to show potentially-... patient per patient data across some of these, you know, bowel movements and, and flushing. Is, is that, is that an- No, I think that's a helpful way- Yeah to really realize that we're talking about individuals- Mm-hmm who are suffering Mm-hmm - who need medication. But it's also important for us then to begin to figure out how to aggregate that data- Mm-hmm and put it into ways that we can do statistical tests against. Okay. That's one of the things we need to learn as part of this phase II is, you know, you have a population who have flushing as their predominant problem, a population- Mm-hmm who have bowel movements as their problem, and some who have both. But you'd like to bring- Mm-hmm bring that into a single- Mm-hmm primary endpoint Mm-hmm of some type, and so testing that is one of the goals. Okay. Then, how soon post this data set, and we know that you're also waiting to get the additional 15 patients, can you start the interaction with the regulatory agency? I think a lot of investors are needing some kind of clarity on, like- Yeah How soon could you come back to us and tell us what you were doing? Well, so the process is that, you know, we're doing a lot of thinking and talking to KOLs- Mm-hmm ... and patients and things about what the phase III program should look like. But then we'll use the data coming out of this interim read- Mm-hmm to kind of narrow that down and make it a little more real. Mm-hmm. It's always a little abstract- Yeah - when you're talking about data- Yeah - until you actually have it. Mm-hmm. But I don't think we would talk to the FDA until after the full data set- Mm-hmm - comes in and we finalized a protocol. We wanted something very, very solid- Mm-hmm - for them to react to. Mm-hmm. Now, that being said, the rest of the patients are almost done enrolling. Mm-hmm. So the clock's ticking. Mm-hmm. Right? And so early in the next quarter, we'll be done with the rest of the treatment period- Mm-hmm for those patients. So it's just a question of how long- Yeah It takes to roll all that. Yeah together and get a smart submission in. Mm-hmm. Given that this is an open-label study, and even once you have your 30-patient data, you're gonna have to get ready to not only decide what are the right registrational endpoints and the intricacies around it, but you got to think about, like, sort of the powering assumptions of the size effect. How do you do that in the absence of a placebo, followed by, you know, a history of development that has been very not in alignment, right? Like, as measures were- Right collected differently. So how, how are you gonna model that or tackle this? Like, what do you think about that? Good start. Well, personally, we can do, even with small numbers of patients- Mm-hmm - as we did in our phase II trials- Mm-hmm - for acromegaly. Yeah. We can do dose and- Yeah - exposure response kind of modeling to help us- Mm-hmm - select doses for phase III. Mm-hmm. We can also look for the relationship between doses, exposures, and- Mm-hmm symptom relief Mm-hmm or safety. So I think it is very valuable data- Mm-hmm in many ways, to help us really pick the right endpoint- Yeah - including the primary endpoint for Phase III. Okay. We do have baseline data on these- Yeah patients that helps calibrate. Mm-hmm. You know, in the end, it's important to remember that when you go back in history and look at the initial approval of octreotide, it was based on a 25-patient Mm-hmm case series published Mm-hmm - in the New England Journal of Medicine in the late 1980s, and basically, the conclusion was, it just... it works. Mm-hmm. Right? Or at least it works for, I think it was 60%- Mm-hmm of the patients that had a- Mm-hmm - substantial impact. So in large part, we're looking for things that are relatively self-evident. Mm-hmm. We're not trying to tease out some- Mm - statistical parameters here. Mm-hmm. The other question that comes up is the last, fast forward, you meet with the agency, you get the design of the study, you start, you know, enrolling patients. You will get, you know, what do you think the time gap is between, I don't know, approval and acromegaly to potentially how soon you could also go into carcinoid? And then two, how much overlap is there between the physicians that treat carcinoid and acromegaly, that just allows sort of commercial efficiency? Yeah, the time overlap is a little hard to estimate at this point. Mm-hmm. We're working on those plans. Mm-hmm. But, you know, we've been building an organization that's pretty darn good at doing global clinical trials. Mm-hmm. We'll be going back to many of the same institutions as- Mm-hmm - this phase II, but also as the phase III that we did in acromegaly. Mm-hmm. That means you can streamline your contracting- Mm-hmm process, your logistics. You're working with the same staff. Yeah. I think things should be getting easier and easier- Mm-hmm - each trial we do. And then it's a matter of just, you know, getting excitement- Yeah - and getting people into the trial. And the history now of paltusotine in acromegaly, and then presumably with- Mm-hmm - some good data out of this phase II- Mm-hmm - all builds momentum. Mm-hmm. I think the other thing is, while it's hard to predict, it's really important to us. Mm-hmm. So we're gonna make it a real priority- Mm-hmm to make this happen as fast as we can. Okay, great. So maybe we'll now switch sort of to the next capital, and switch to PATHFNDR-2, which is expected in 2Q. A lot of clients have asked us, and just want to drill down in regards to... Given that the 30-patient open label data and the PATHFNDR-2 data kind of potentially could come in around the same time, lots of clients are asking: Do you envision this as reporting at the same time, or maybe given the depth of the data, have it at two different disclosures? Well, we're still a growing organization- Mm-hmm - and any data release is a ton of work. I mean, you gotta- Yeah go out and validate all- Yeah - the raw data, you know, the whole data management crew works. You gotta crunch it, you gotta put it into- Mm-hmm. -slides that are meaningful. And doing two of those- Mm-hmm. in parallel is unlikely. Okay. So they, they'll get staggered somehow, and little bit is luck of the draw as to- Okay. which comes out first. Good. And then, you guys have done a phenomenal job on PATHFNDR-1, and now as we're going into PATHFNDR-2, you've also said there's quite a bit of site overlap. Could you quantify how much overlap exists from an execution perspective across the studies? Do you remember? I can't give you a number- Okay. But, I would say, nearly half are probably doing both studies, both, both of our, of our sites, but not all. Mm-hmm. A number of sites are only able to do one study at a time for us. I think one difference between the two is we brought in, China and India in the PATHFNDR-2. Okay. In part to explore new regions where we might find- Yeah ... more naive patients, and in part to support long-term commercial aspirations in China. Okay. So we did get enough patients in the Chinese sites to that we believe supports the filing directly off of PATHFNDR-2. Mm-hmm. -for China marketing authorization. Okay. Do you have any, and I didn't look, any patients in Japan by chance? Because now the regulatory, you know, requirements have changed. You could actually, without doing a bridging study, go into Japan. Do you have any in Japan? Well, you still have to do bridging studies, and we did a Japanese- Okay. bridging study. Mm-hmm. We're working with a group at SKK- Mm-hmm ... to develop the molecule for both- Mm-hmm ... both acromegaly and NETs- Mm-hmm ... in Japan. It's proceeding well. I don't know exactly the state of that study. I didn't make the steering committee meeting last week. It's coming up soon. Okay ... the Japanese study. Okay. Is there, I think a lot of the next questions are, you know, a lot of clients are, they're getting ready for the study. You have stratum one and stratum two. If you could just remind us across the two, stratum one and stratum two, what do you hope to see, you know, on the treatment arm and on a placebo? Right. So the population eligible for enrollment in PATHFNDR-2 is based on lanreotide's registrational trial- Mm ... for acromegaly. They enrolled the same sort of mix of patients. We stratified the study because we know that expected responder rates, or I should say IGF-1 normalization rates, are expected to be lower- Mm ... in the naive stratum, stratum one- Mm-hmm ... which also includes patients who haven't recently been treated- Mm ... with drug for any number of reasons. Mm-hmm. They could start out with very high IGF-1 levels. Mm-hmm ... and that group is expected to have a bit lower responder rates- Mm-hmm ... than stratum two. Mm-hmm. Stratum two are those who are already controlled on treatment- Mm-hmm ... and are willing to wash out of their- Yes ... treatment during a screening period. That responder rate is expected to be higher. The study as a whole, though, is well powered- Mm-hmm ... to show statistically significantly greater responders, Mm-hmm ... on drug versus placebo. So it turns out to be, it will be a blended- Mm-hmm ... responder rate- Yeah ... at the end of the day, but it should be greater than placebo. It's well powered to show that difference. Could you remind us of the powering across these two strata? Yeah. The overall power of the study is over 90%. Yeah. We make assumptions in terms of- Yeah ... responder rates at the beginning when we do these- Yeah ... sample size calculations. And, you know, overall, in stratum one, that rate overall is expected to be roughly between 20 and 30- Mm-hmm ... 40% range- Placebo adjusted ... based on literature. Yeah. Sorry? Placebo adjusted. No, the overall responder rate. Oh, overall response. Okay. But with a relatively low placebo rate. I see. Got it. In that group, but when you start out that high, we don't expect many placebo- Okay ... responders at all. Okay. Stratum two is more like the PATHFNDR-1 population. Yeah. The same assumptions apply for that stratum. Yeah. The overall power, though, is very strong, I would say. Okay. Is there a scenario by which... Let's say, is the expectation in stratum one, as long as you have any statistical separation, even if it doesn't get to that 20%-30%, could you still be eligible for applying, for getting, you know, for the treatment of acromegaly rather than for the maintenance of acromegaly? I think the whole study is designed for that- Mm-hmm ... not just stratum 1. Yeah. Right? So, you know, I think the whole study is super well powered. Mm-hmm. Remember, we over-enrolled it- Mm-hmm ... well, we upscaled it- Mm ... and then we over-enrolled it some more. So I think it's in pretty good shape. Okay ... to demonstrate what we hope to demonstrate. Okay. I know you noted that speaking, but sometimes investors get worried. "Well, what happens if stratum one is not that sick?" Is that on the bar of risks that you think about where PATHFNDR-1 could go wrong, PATHFNDR-2 could go wrong, where does that stack up in your worries at nighttime? It is not in the things that keep- Okay ... me up at night. Got it. Okay. What are the things that keep you up at night? Well, things that most of our investor friends find boring. Yeah. You know, recruiting top talent. Yeah. Even though the Yeah ... recruiting market has gotten much better- Yeah ... it's still hard to find good people. Mm-hmm. Managing our budget. We have $550- Mm-hmm ... million in the bank, which is great. Takes us into 2026. Yeah. We're better than many, many other companies, but I don't wanna let that slip, right? Yeah. We're working really hard, and it's... you know, we all have our cycles in business. Mm-hmm ... and this is our annual budgeting cycle. Yeah. So we got a lot of work to do on that. So those are the things I worry about, but then I get excited about seeing the new things coming out of discovery. Yeah. It's like: "Oh, really? That worked? Yeah. Yeah. That's great, and that'll keep you up in a good way. Mm-hmm. How do you... So obviously after the data, your team will be working really diligently on the filing. Do you envision the U.S. and Europe filing are gonna be processed at the same time, or do you think the strategy will be like, "Let's focus on, FDA submission and then move on to EMA? Well, clearly, the bulk of the commercial opportunity is in the U.S. Mm-hmm. Absolutely, we focus on doing that right- Mm-hmm And not getting in any way compromised by trying to do everything at once. Mm-hmm. That being said, we're working now also on our plan for the European authorization- Mm-hmm And when do we submit it? And we haven't finalized that. Mm-hmm. It's a mix of commercial and Mm-hmm -just logistical- Mm-hmm Questions. So we should know more about that as we get into next year. Okay. But don't expect it super tight together- Okay -because- And if- We've got a lot of things to lift right now. Is it fair that historic... Like, when we look at other company biotechs, usually post a phase III study, it may take them about four to six months, you know, to process the NDA. Is that a reasonable timeframe that- Yeah, that- you and your team could achieve Yeah, that's about right. ... that standard. Yeah. We're working now on, you know, doing all the stuff we can- Mm-hmm ahead of the final data. Yeah. There's more than 2,000 documents that go into- Yeah -this filing- Mm-hmm plus all the pieces that thread it together, and so a lot of that are freestanding. Yeah. You can get them done, but you really need that last bit of clinical data to be able to tie the whole story together- Mm-hmm -especially the safety database. Yeah. It's, it's a big lift. To bring it to the finish line. And then... have you... As obviously you're doing the filing, you also have to kind of get ready to get the company commercially ready. So at what wave is that sort of starting in 2024, and how do you visualize the- Well, that started in 2022. Okay. And there's been a lift this year, and there'll be a lift next year, but it's things as simple as getting all the various- Mm-hmm Policies and compliance aspects in place. Mm-hmm. Getting your IT systems up to snuff- Mm-hmm getting your accounting systems Mm-hmm up to snuff. There's a lot of- Mm-hmm I don't want to say boring infrastructure. Yeah You know, because people at the company listen to it. Mm-hmm. But a lot of kind of relatively- Yeah things that you don't pay much attention Yeah -to, right? And then, as we start into next year, we start fleshing out the layers of management that are gonna- Mm-hmm be doing the training of the sales force, the medical affairs leadership Mm-hmm you know, that, those anchor pieces. And then the last piece, just as we're approaching the PDUFA date, is the actual sales force- Mm-hmm and getting them trained. Okay, that's great. Do you... have you guys started engaging with payers and, and- Absolutely. We've got a- What's the feedback been on that product profile or even also from patients and physicians? Well, so, we've got a crackerjack head of- Mm-hmm market access Mm-hmm who is out there. She's been previously on the PBM side. Mm-hmm Previously on the sponsor side, and she's out there doing a lot of work. Mm-hmm. You know, we now have the PATHFNDR-1 data for her- Mm-hmm and her team to work with Mm-hmm So that's gonna help, but it's fairly fresh. Mm-hmm. You know, we've presented it now at a couple medical conferences, Mm-hmm in addition to our investigators, and Mm-hmm the responses are from, "That's really good," to- Yeah Wow, that's really good! Good, yeah. So we're very pleased with that. And, you know, the patient advocacy group is out talking to patients, and- Mm-hmm. Yep They're pretty excited to see a company pay attention to them and start looking at things beyond just IGF-1 numbers. Mm-hmm. This Acromegaly Symptom Diary that Alan- Mm-hmm put together is, really resonating with them. Is there an opportunity, given that this was a designed PRO, signed off by the agency, how could that be captured in the label to really allow you commercially, you know, to not just say, for the treatment of acromegaly, acromegaly, but also for the symptomology? And so, like, how could that be? Could it be in the indication statement? Could it be in the actual data? Well, you know, so this patient-reported outcome, the Acromegaly Symptom Diary, was designed based on FDA guidance- Mm-hmm from the outset. Mm-hmm. The goal is to be able to include data from- Mm-hmm the patient-reported outcome Mm-hmm in the approved label someday. Yeah. I don't know exactly where in the label it would be- Yeah This would be the first SRL approved. Yeah for the treatment of acromegaly with that kind of data in the label. Mm-hmm. So we look at this as a potential major differentiator. Yeah. So it's not a guarantee it'll make it in the label. Yeah. This type of stuff- Yeah You know, you've really got to work at it. But we've done a good job on it. Mm-hmm. Minimally, it's gonna be some interesting publications about what it really means- Mm-hmm to be a patient taking our drug Yep and suffering from acromegaly. Then, team, I know it doesn't do justice for a minute and a half to discuss the pipeline, but as we look into 2024, what are some key inflection points of the rest of the pipeline that we didn't talk about, that you think investors should be paying attention to? Well, the obvious one is 4894- Mm-hmm ACTH antagonist will be reading out, and I will predict it's gonna really do well. Mm-hmm. Very excited about that molecule. It's a whole breakthrough in the field of endocrinology. Mm-hmm. We've known about ACTH as the central stress hormone- Mm-hmm for 100+ years, and nobody's ever had an antagonist. Mm-hmm. So we're really excited to see that. But as I said, I'm also really excited to see new things enter the clinic. I think we'll be in the clinic with a PTH antagonist- Mm-hmm or at least late development. Yeah. There's a few other things cooking around. You know, don't want to- Okay Put it all out there. Okay Just yet. Maybe something else will come in. Is that something else, something obesity-related that you're contemplating? Well, hey, we have efforts in obesity that are pretty exciting. Mm-hmm. Graves' disease- Mm-hmm which affects 1%-2% of the population Mm-hmm Mostly women. And there's a few things just kind of cooking down there. Yeah that we don't necessarily put on our chart. These are all potentially 2024 opportunities, or that could- Well, these are things that will enter- -more later ... development 2024. Okay. Then it usually takes us 9-12, 14 months to get it from- Okay Entering development into a trial. Okay, wonderful. Well, team, you have done a very nice job efficiently covering a lot of topics in 25 minutes. Just want to say thank you on behalf of all of us at Piper Sandler, and it's been a pleasure working with you and seeing the incredible journey and the path that you've built. So thank you. Thanks, Yas, and thanks to your hardworking posse. We appreciate you, you know, all the work you've done. Great To help us get the word out and help clarify what we're trying to do. It's our pleasure, absolutely. Let's thank the team for an awesome presentation.