Welcome to the Crinetics Pharmaceuticals Third Quarter 2024 Financial Results Conference Call. At this time, all participants are in a listen-only mode. Following management's prepared remarks we will hold a question-and-answer session. I would now like to turn the call over to Gayathri Diwakar of Crinetics. Please go ahead.

Thank you operator. Hello everyone and welcome to Crinetics' earnings call. Joining me today are Dr. Scott Struthers, Founder and Chief Executive Officer; and Marc Wilson, Chief Financial Officer. Also joining us for the Q&A portion of the call are Dr. Dana Pizzuti, Chief Medical and Development Officer; and Dr. Alan Krasner, Chief Endocrinologist. A press release announced in the third quarter 2024 financial results was issued today and is also available on our corporate website. As a reminder, we'll be making forward-looking statements and I invite you to learn more about the risks and uncertainties associated with these statements as disclosed in our SEC filings. Such forward-looking statements are not a guarantee of performance, and the company's actual results could differ materially from those stated or implied in such statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release, the company's other news releases, and Crinetics SEC filings, including its annual report on Form 10-K and quarterly reports on 10-Q. I would also like to specify that the content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, November 12, 2024. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. With that, I'll turn the call over to Scott.

Thank you, Gayathri. Good afternoon everyone and thank you for joining us on our third quarter 2024 results call. We've had yet another incredibly productive quarter with advancements up and down the pipeline and we continue to strengthen our financial position. For today's call, I will summarize our recent accomplishments shown on Slide 3, preview some of our upcoming events and then hand the call over to Marc, Marc Wilson for a review of our financials. We'll end, as always, by taking your questions. As some of you may know, November 1st was Acromegaly Awareness Day. We commemorated this day by hosting acromegaly patients at our headquarters to bring life to the impact of our mission of improving patients' lives. That was the picture you saw on the first slide of our presentation today. It's especially timely for Crinetics as we recently submitted our first NDA for our investigational drug paltusotine for the treatment and long-term maintenance of acromegaly. We very much look forward to Acromegaly Awareness Day next November. We believe paltusotine will represent a next generation therapy for people living with acromegaly. We expect to receive the FDA filing notification later in December and expect a standard review period. In the meantime, we continue to focus on building our commercial capabilities and preparing for the anticipated launch of our first drug next fall. As part of these preparations, our national accounts team is meeting with payers to discuss formulary placement and product coverage. We believe that having these conversations early and often allows us to positively influence formulary placement and coverage decisions with the goal of broad access for patients living with acromegaly. In addition, our medical science liaisons are in the field speaking with academic KOLs and community endocrinologists to get their feedback from these clinicians on…

Thank you, Scott. Turning to Slide 8, Crinetics continues to be in a strong financial position, having ended the third quarter with approximately $863 million in cash and investments. As Scott mentioned, we completed a $575 million public offering that closed after the end of the third quarter. This further strengthened our financial position and our cash, cash equivalents and investment securities following the equity offering totaled approximately $1.4 billion on a pro forma basis. We project that with the proceeds from the recent offering we will be able to fund our current operating plan into 2029. That operating plan includes the commercialization of paltusotine for acromegaly if approved, as well as the initiation of multiple later stage clinical trials in carcinoid syndrome, in CAH and in Cushing's disease. In addition, we plan to continue investing in the product candidates that are emerging from our discovery pipeline, including the four development candidates that have been nominated this year. With respect to the financial results, there were no revenues for the quarter ended September 30, 2024 compared to $0.3 million for the same period in 2023. The third quarter 2023 revenues were derived from the paltusotine licensing arrangement with our Japanese partner SKK. Research and development expenses were $61.9 million for the quarter ended September 30, 2024, compared to $43.8 million for the same period in 2023. The increase was primarily driven by higher personnel costs, outside services and manufacturing activities, the majority of which were attributable to the advancement of the paltusotine and atumelnant development programs and the expansion of our preclinical portfolio. For the quarter ended September 30, 2024, general and administrative expenses were $25.9 million, compared to $15.5 million for the same period in 2023. These increases were primarily due to higher personnel costs and commercial planning activities.…

Thank you, Marc. I'm incredibly excited about the future of Crinetics. As we look to the end of 2024 and the start of 2025, we will continue to build on our strong progress. We've consistently delivered on our plans and we're committed to maintaining this level of execution. We look forward to sharing upcoming clinical and regulatory milestones from paltusotine and atumelnant and updates on the continued advancement of our deep pipeline of emerging candidates. Crinetics continues to be well positioned to become the premier fully integrated, endocrine focused global pharmaceutical company. Thank you all for your attention. Operator, we're ready to take your questions.

Thank you sir. [Operator Instructions] We will take our first question from Cory Jubinville with LifeSci Capital. Please go ahead.

Hi, congrats on the news and thanks for taking our questions. These NDCs in CRN09682 is pretty exciting. Anything more you could tell us about this program and kind of where you see it best fitting within the existing paradigm? And, I guess, what else are some of the key challenges that needed to be overcome to develop an NDC and what are some of the specific advantages you could point to of an NDC approach over say ADCs or radiotherapies?

Thanks, Cory. So for more details, I'd encourage folks to come to Chicago for the NANETS meeting where we'll be presenting some of the preclinical data on 9682 and data on paltusotine and carcinoid syndrome and can talk at some more length with data in hand. But broadly, the NDC platform is an extension of the types of ideas that led to the formation of radionetics a few years ago. We believe that these non-peptides small molecules provide a variety of different advantages when targeting GPCRs over antibodies in the typical NDC formats. For one thing, GPCRs are very difficult to make antibodies against, yet they're a whole class of selectively expressed cell surface targets. And unlike many of the targets of ADCs, binding of ligands to GPCRs can be tuned to selectively optimize internalization of these conjugates into the inside of the cell, which is something you want to do for selective intracellular cleavage. So I think it opens up new targets. It opens up simpler chemical synthesis. It opens up the ability to tune things in ways that you can't with antibodies, some as simple as most antibodies will stick around for weeks, whereas we can clear small molecules in a day or two. So I think it offers a number of different potential advantages. But with 9682, we're going to go learn about what these are in a real world setting and in the type of patients that we're already working with neuroendocrine tumors for those who have carcinoid syndrome. So it's highly synergistic with our ongoing efforts for paltusotine, the internal relationships we've developed with the investigators and the patient community, and it's pioneering this new idea about how we might branch out and use our core platform to expand into antitumor agents.

Excellent. Thanks for taking our questions. I'll hop back in the queue.

Thanks, Cory.

And thank you. We'll next go to Jessica Fye with J.P. Morgan. Please go ahead.

Thanks for taking my question. So with several products entering the clinic next year, what's the soonest that we can expect Phase 1 data from any of those and which will it be from? And then if I could sneak a couple in on 9682. Can you talk about how you chose the MMAE toxin for that product and how different or similar the ligand is to paltusotine?

Okay, there's a good bash. Thanks, Jess, and look forward to seeing you later this week. In terms of the timeline on the different programs, I think, we'll probably stick away from providing precise guidelines on each of those. Just have to stay tuned throughout the year and see how they come. In part it's because you also don't know how far you need to go up in dose response curves to know when you're starting to get meaningful results. It's a little difficult to predict when they'll each complete, but I think you can expect a nice flow of new information from those and some other compounds that are getting close over the next year and little into 2026. And then in terms of 9682, it's not paltusotine. It's not a direct homolog of paltusotine. It's another SST2 agonist that was selectively optimized to be the best ligand we could get for the purpose at hand, which is to bind selectively and internalize receptors and get the right biodistribution, so it spends very little time in the periphery. And all those various factors were considered as we built that conjugate both the ligand and the linker group. And MMAE was chosen simply because it's a very well established payload in the ADC world, but we have ongoing activities to explore alternative payloads as well, and that may be seen in some of our backup or follow on compounds.

Thank you.

Thank you. Next we're going to go to Jeff Hung with Morgan Stanley. Please go ahead.

Thanks for taking my question. From your early stage pipeline how are you thinking about the obesity indications for candidate selection in 2025? What would you need to see with your GLP-1 or GIP programs in order to have confidence [indiscernible] given the increasingly competitive landscape? Thanks.

Thank you. And what I think we're seeing in the competitive landscape is some of the limitations that arise if you're not super careful about how you select candidates. These are things as simple as getting to easily manufactured dose levels. Clearly, there is questions around tolerability in some molecules and the doses needed for good weight loss versus good tolerability. And we have a variety of different hypotheses we're testing as we tune these molecules to be what we think can be the best-in-class profile for an easy to synthesize small molecule GLP-1 agonist. And basically, the course limiting step is we want a really, really good molecule and we're not going to settle for anything less than what we think is as close as reasonably expected to perfection.

Okay, thank you.

Thank you. Next we're going to go to Brian Skorney with Baird. Please go ahead.

Hi, guys. This is Charlie on for Brian. Just kind of piggybacking off the last question, noting that your GLP-1 and GIP assets are non-peptides. How are you guys thinking about the potential advantage of a non-peptide compound here relative to other assets in the space? Thanks.

Well, I think, the whole field in the obesity space is moving towards alternative modes for delivery of the activity and the main challenge on the peptides is twofold. One is manufacturing that I think everybody and their brother has been hearing about. But also peptides just limit you in the physical, chemical space that you can explore and the delivery methods that you can utilize. And with small molecules, you don't have those limitations. You can tune every dimension of chemical space to get the types of physiologic or pharmacologic activities, pharmacokinetic activities, and test different types of hypotheses to get the right clinical profile. And so I think what this today's talk about 9682 and paltusotine gives you a sense of some of the depth of types of things we try and optimize when we're making small molecule drugs. And you'll see us employ all these different type of techniques as we're applying it to the obesity space and in molecules that can be made at scale because this is one of the biggest public health problems in the world or at least in most Western societies.

Got it. Thank you.

And Dennis [Jefferies], your line is open.

Hi. Thanks for taking our questions? I had one on the non-peptide drug conjugate. Can you remind us of the common toxicities associated with MMAE ADCs like POLIVY, PADCEV and TIVDAK? And just curious around your confidence in your ability to thread the needle on efficacy and tolerability. Thank you.

Yes, thank you. That's a great question and certainly something we explored carefully in our preclinical program. Now, we need to see it in a clinical setting, but we obviously were aware of the types of common toxicities for MMAE and looked carefully for that in the preclinical packages. And we think we've got very, very good margins. And in part, that's because we tuned the molecules so there's very little circulating free MMAE. The conjugates are cleared rapidly from systemic accumulation, but cleaved MMAE is accumulated both rapidly and persistently in tumor cells. And we'll show this data at NANET.

Perfect. Thank you.

Thanks.

Thank you. And next we'll go to Joe Schwartz with Leerink Partners. Please go ahead.

Thank you. It's great to see you select the TSH antagonist development candidates. So I was wondering if you could talk about what your criteria has been for the characteristics you need to reach in order to be satisfied that the candidate meets your criteria. And how high is the hurdle here compared to what you needed to clear for other programs such as paltusotine and atumelnant? And then from a biological standpoint, how should we think about the relative degree of efficacy which an IGF-1 or a TSH antagonist can inherently offer all us equal based on crosstalk or any other factors? So just the chemistry and the biology, if you could address those, that would be great. Thank you.

Yes, great question, Joe. Philosophically, we try and make every molecule as high a quality of a drug candidate as we can. Frankly, I'll tell you that when we advanced paltusotine into the clinic, we took a couple risks. One is there was a slight risk of drug-drug interactions, which we disproved later in the clinic. And there was a slight risk of lower than hoped oral bioavailability, which we disproved later in the clinic. So we did very well with paltusotine, I think you'll agree. But as we get into some of these more prevalent indications like Graves’ disease or obesity, we're adding extra layers of carefulness, including broad testing against any other potential liability, making sure the physical chemical properties are good, making sure it's scalable at high levels of production, because you're going to have a lot more patients in Graves’ disease than you would in acromegaly, for example. So I don't think we've changed our goals that much, but we're just looking with even closer eye at the quality of these candidates as you get into the very, very large indications. And then I'm sorry, I missed this -- what was the second part about that?

It just seems like your TSH antagonist has a different approach in IGF-1.

Yes, yes, yes.

Yes.

So remember, in Graves’ disease, the root cause of the disease is autoantibodies which bind to the TSH receptor and activate cell signaling. And our candidates that are TSH receptor antagonists block the activity of those antibodies at the level of the receptor. Now, in Graves’ eye disease, what happens in the cells at the back of the eye is those antibodies bind to the TSH receptor. That activates the TSH receptor, which then signals down its main pathway of cyclic AMP. But it also cross activates the IGF-1 receptor. And that IGF receptor also starts signaling into the back of the eye. And TEPEZZA and the other drugs are aimed at IGF signaling or acting downstream of TSH. So if you block the activity of the TSH receptor, and we've shown this in preclinical studies that I believe we published at ENDO last year, you also block the signaling of IGF in the cells from the back of the eye. So generally, we expect this to be more efficacious or at least equally efficacious as the IGF approaches and it can be used to treat the underlying Graves’ at the level of the thyroid. And if we had the right drug for the treatment of Graves’ disease itself, we wouldn't be having thyroid eye disease. So one of the challenges for this program is to figure out the sequence of indications that we address in later stage trials.

Very helpful. Thank you.

Thank you. Next we'll go to Douglas Tsao with H.C. Wainwright. Please go ahead.

Hi, good afternoon and thanks for taking the questions and congrats on the progress. I guess, Scott, maybe as a follow up to that, I mean, historically you as a company have been very innovative in terms of using sort of Phase 1 studies to provide very compelling proof of mechanism data that has really sort of given confidence in de-risk programs as they enter Phase 2 and ultimately Phase 3. When you think about the TSH program and Graves’ as well as TED, from your sort of initial sense, will you be able to accomplish that in sort of a Phase 1, Phase 1b study? And will that necessarily inform the initial direction you take with that program in terms of the sort of time at which you sort of intervene with Graves’ and if patients are already starting to show manifestations of eye disease. Thank you.

Thanks. Why don't I let Alan answer that question.

Thanks, Doug. Yes, I think actually a TSH antagonist is very, very -- it would be a nice model in Phase 1 to evaluate in the sense that we do have biomarkers that we can evaluate in real-time as we've done in our previous Phase 1 studies before. In particular, thyroid hormone levels, TSH and T4 responses to a TSH antagonist could tell us, I think in theory at least very quickly, whether we're hitting the intended pharmacologic target as we've done in other studies before. So now it's a typical Phase 1 study. That time course is a little short to measure or efficacy in thyroid eye disease. But certainly this is still, I think, a good candidate for pharmacologic proof of concept even in Phase 1.

Okay, great. Thank you.

Perfect. And next, we're going to go to Jon Wolleben with Citizens JMP. Please go ahead.

Hi, this is Katherine on for Jon. I have a question about the carcinoid syndrome program and if you can give any additional color on kind of the feedback from the FDA and how you kind of foresee the Phase 3 program looking relative to kind of what's been guided before anything that the FDA is kind of required, that's sort of been unexpected?

Yes, why don't I let Dana answer that question?

Yes, well, thanks for the question. Yes, the interaction with the FDA on carcinoid went very well. I think that there were many areas that we had agreement on and then needed their perspective on issues like the endpoints and duration of the trial. But we had anticipated a lot of those potential perspectives and it wasn't very challenging to be able to accommodate those changes into our proposed plan. So we're just finalizing that right now and we are continuing to be on track to get that started in the same timeframe that we've always been saying.

Thank you so much.

And next, we're going to go to Leland Gershell with Oppenheimer. Please go ahead.

Hey, thanks for taking my questions and for unveiling this new program in NDC. Scott, just wanted to ask sort of a forward-looking question with respect to the opportunities here with this new approach. As we think about ways in which you can tune ligands to successfully cause the internalization of GPCRs versus not having them be internalized i.e. with paltusotine, are you able to identify others that you could approach following the first compound for perhaps other tumor types with GPCRs? Thanks.

Yes, thanks, Leland. I think there's lots of other opportunities but at this point, we really want to learn from 9682 about what it's really going to take to be successful in the clinic. And I think those lessons that we'll learn there, both in pharmacokinetics and tumor responses and lines of therapy and things like that, will be very informative for us. So in the meantime, the discovery group is exploring new ideas, new payloads, new targets, things like that. But before we advance the next one, we really want to see how this does.

Got it. And then just a question on the TSH antagonist, good to see that be nominated. So will you be planning to study that in Graves’ and TED as separate kind of campaigns, or will you be looking at kind of an overarching Graves’ development program with TED as constituting a sort of a subset of those patients? Thanks.

Well, I think it's maybe a little early to discuss the overall strategy there. You might imagine there's both some questions we need to ask ourselves around the economics of the two different indications and the feasibility of recruiting in the different indications and the competitive environments. But honestly, I think this is the absolutely best approach for both Graves’ hyperthyroidism and Graves’ associated ophthalmopathy, or TED. We just have to figure out how to stage those investments.

Great. Thanks very much.

Thank you. And we'll take our next question from Catherine Novack with Jones Trading. Please go ahead.

Hi. Afternoon, guys. Thank you so much for taking my questions. Just one on CAH, given that this is an area that has not really seen any new approvals in recent years, as what learnings were you able to take from Neurocrine's pivotal programs when you go to design your own, maybe you can learn from anything or have better designs. And then what do you anticipate the standard of care would be following potential crinecerfont approval next year?

Well, I think crinecerfont is -- if it's approved, it'll be the first drug specifically for CAH ever. We've used glucocorticoids to treat these patients, but I'm excited to see the potential approval there and the type of labeling that is awarded by the FDA, assuming all goes well, and I think it will be incorporated into the standard of care for some patients. What we've learned is about the role of different hormones in this pathway, and we've speculated for years about how much of the HPA axis is controlled by CRF or vasopressin or ACTH. And I think it's pretty clear now with our early data and Neurocrine's Phase 3 data that CRF contributes to the activation of the adrenal, but it's not -- the stimulation of adrenal is not completely dependent on CRF, whereas it does appear to be nearly completely dependent upon ACTH as we expect. So I think we've chosen the ideal target in the pathway and be looking forward to talking more about the rest of the data we have in the not too very distant future. At that time, we should be able to clarify more about our Phase 3 plans, too.

Great. Well, looking forward to the rest of the data. Thanks very much for taking my questions.

Thanks, Catherine.

We'll take our next question from Yasmeen Rahimi from Piper Sandler. Please go ahead.

Good afternoon, team. Thank you so much for that really nice surprise. Definitely caught many of us for this really wonderful update and I'm sure a ton of work went into this. So I guess, the question to ask is in terms of development for NETs like, what would a path look like? I mean, I think many of us may think of these tumors more slow growing. Takes a long time to show a separation, could you maybe educate us what a path would look like? And next, if you decided to pursue that, that would be really important and how big that market would be, if you've done any work in that regard?

Yes, thanks, Yas. I hope we're able to provide a few surprises every now and then. And we've got a very active discovery group that is working really hard. We just want to make sure we got things ready for prime time before we start talking about them. But, Alan, maybe you want to comment on some of our ideas on development for this.

Yes. So we would -- we are planning on starting with an oncology style Phase 1 study, which is a little bit different than our Phase 1 endocrine trials. The first step, of course, is to escalate doses from a safe starting dose in volunteers with tumors and increasing that dose in subsequent cohorts till we get close to a maximally tolerated dose. The kinds of tumors we're talking about that would be included in such a trial would be patients who have SST2 receptor expressing tumors. Those are largely patients with neuroendocrine tumors, although I will point out that there are variants of neuroendocrine tumors and even tumors which are not technically neuroendocrine tumors which can express these receptors. And we're going to be pretty agnostic as to which patients we study because these are patients often who have a great deal of medical need. These are patients who would have progressing disease. And we'll first define the right dose and then proceed to dose expansion cohorts. Once we have sort of a dose which we expect to be well tolerated and potentially therapeutic, we would explore a variety of different kinds of tumor types based on the origin of the neuroendocrine tumor. Assuming that's all successful, then we would look at this kind of novel, potentially therapeutic compound in patients who have progressive disease and need adjunctive therapy to improve outcomes in Phase 2 and potentially Phase 3 as well. So this is a very novel approach, it's a very exciting approach. And this is, I would say, a fairly underserved patient population. There's a lot of research going on in the neuroendocrine tumor and related tumors now, but not a lot of great options, particularly beyond PRRT, which is a radioactive therapy. This is a non-radioactive therapy, which we hope would be similarly effective or better. And you could imagine a lot of advantages to using a small molecule as opposed to a very discreet treatment with a radioactive therapy in the long run. So we're very excited we would follow this kind of oncology path to approval, hopefully someday.

And just to follow up on your population size, we're still working on some of that. But you'll recall we've said that the carcinoid syndrome patients are roughly 20% of the total population of the neuroendocrine tumor patients. And the vast majority of neuroendocrine tumors do express SST2. So we expect this just in the NET space to be quite a bit larger population than just than carcinoid. And then you'll see if you look in the radiopharmaceutical space where there's a lot of entrance in the SST2 targeted radiopharmaceuticals, that they're starting to expand out into some of the other tumor types. In particular, there's certain types of breast cancer that express SST2. Many head and neck cancers express SST2 and some of the pheochromocytoma, other types of more rare cancers. So that's something we're working on, making sure we understand the full potential, but it's not small.

Thank you so much. Congrats again. Great surprise.

Thank you. I'd now like to turn the call back over to Scott Struthers for any closing or additional remarks.

No, thank you everybody. Thank you for your attention to our story and your support in our financing and participating with the success and growth of the company. We appreciate it and look forward to talking to many of you in the coming days and weeks.

Thank you. And this does conclude today's program. Thank you for your participation. You may disconnect at any time.