Okay, welcome to this fireside chat with Crinetics Pharmaceuticals. I’m Joseph Schwartz from the equity research team at Leerink Partners, and it’s my pleasure to be joined by Alan Krasner, Chief Medical Officer, Gayathri Diwakar, Vice President of Investor Relations, and Omar Hamdy, Chief of Staff and Head of Portfolio Strategy. Thanks so much for joining me today. 2024 was a very exciting year for the company. To start, perhaps we could get a brief overview of the recent progress the company has made and how it positions Crinetics for 2025. Alan, do you want to start us off? We had a big year, with many major milestones and a lot of exciting developments ahead. I think Gayathri can take us through an itemized list of the company’s recent accomplishments. Sure. 2024, as Alan mentioned, was a great year in terms of data readouts. For Paltusotine, we submitted the NDA and it was accepted. We have a PDUFA date this year, September 25. We started site activation and activities for our carcinoid syndrome, which is our second indication for Paltusotine. That started at the end of last year, and we'll have our first patient enrolled in the first half of this year. Our second candidate, Atumelnant, had great data in our Phase 2 top-line readout in January in congenital adrenal hyperplasia, or CAH. We had Phase 2 data in a small number of patients in our second indication, Cushing's disease, and we presented at the end of last year. In both those indications, we showed really exciting data, and we'll be starting trials this year in adult CAH, pediatric CAH, and Cushing's. We also announced at the end of last year that we have four new molecules in IND-enabling studies. This year we plan to submit INDs for all of those. The first is 9682, which is the first candidate from our non-peptide drug conjugate, NDC, platform. We also have a molecule for a PTH antagonist for hyperparathyroidism. Not hypo, which is getting a little bit more press these days, but hyper, which we think is a bigger unmet market even. For a TSH antagonist as well for the treatment of Graves and/or TED. For all those three programs, we believe that in the Phase 1 studies, we can get some early reads on target engagement efficacy. We are really excited about that potential there. The last molecule is an SST3 agonist for the treatment of ADPKD. That has in the past been a little bit more outside of the traditional endocrinology indications. We think that the mechanism of action of SST3 agonism has a really clear driver in the ciliopathies, including ADPKD. We are really excited to pursue development of that ourselves and maintain more value for our company and our shareholders that way. Lots of new, exciting things. Great. Thank you so much. The GPCR space is very target-rich but has been a notoriously challenging place for drug development. Can you help us understand why Crinetics has been so successful so far? What sets your chemistry platform apart? What is the competitive advantage at the company that should allow it to continue pursuing even more targets going forward? Yeah, we have just a very talented group of discovery scientists at Crinetics that I have a great deal of admiration for. You know, it all started with Scott Struthers, who is our CEO and founder, and who has been working on the somatostatin receptor since age 18, and he hasn't stopped since. We have a team that is especially adept at efficiently cascading through a number of small-molecule candidates to final clinical candidates that are strategically tuned to interact therapeutically with various endocrine receptors, beginning with the somatostatin receptors. They go through a very extensive preclinical process of selecting molecules based on a variety of criteria. Some key ones are potency at the pharmacologic target and oral bioavailability. By the time we start Phase 1 studies in humans, we have a good idea this drug candidate will be effective via the oral route of delivery. So far, we have an excellent batting average with nominated candidates in clinic. Okay, that's helpful. A related question: to what extent are learnings from one program applicable to other parts of the pipeline, versus the extent to which individual programs are characterized by independent challenges? I'm just wondering which parts of the process are repeatable, which learnings are leverageable, and how similar the problems are that you have to solve for each of these compounds. Yeah, I mean, we try to develop a molecule for each specific target and indication and think about it in a unique way. To date, I think we've made something like 12,000–13,000 molecules that we've put through, and a few of those have been NDCs, as you can tell by the numbers. For example, NDC 9682 was the 9,682nd molecule we've made. We look at every side chain and every part of the molecule, including the core of the structure. We examine how those affect pharmacology and potency, and we tweak them along the way. There are learnings from program to program on how we develop these molecules. I think one way this plays out is with Paltusotine: it's targeted to SST2 but designed not to be internalized, instead remaining in circulation. In contrast, when we develop CRN09682, which will be evaluated for NETs and other SST2-driven tumors, we optimize the molecule to be internalized. We're very deliberate with each molecule—not just its target, but also its potency, specificity, and effect on the binding target. As Omar mentioned, it’s a thoughtful approach that builds on itself. Very helpful. Okay, now maybe we can dive into some of the specific programs, starting with the most advanced: Paltusotine and acromegaly. Can we talk a little about this market, which hasn’t seen a major advance in a long time, although some treatment options exist? What will it take for Paltusotine to evolve into the new standard of care? Can you discuss its attributes in the context of the disease and the unmet need? Is there potential for market expansion as well as a switch opportunity for Paltusotine? Sure. Alan, if you're happy to start, you can jump in. For acromegaly, the current standard of care is injectable SRLs or somatostatin receptor ligands. Things like octreotide and lanreotide are given via deep subcutaneous or intramuscular injections monthly. They're obviously very painful for the patient and for the HCPs. It's often administered in the office, which can take away staff time from other tasks. There's also a lot of patients who have breakthrough symptoms. In the month that they're given the injection, for the first couple of weeks, they might have good control of the symptoms. As they approach the next injection, they may have symptoms start to reappear, and we refer to those as breakthrough symptoms. We think that for Paltusotine, both because of its better ability to control breakthrough symptoms, its efficacy, and the superior tolerability profile in terms of the route of administration, it is a natural choice for many patients with acromegaly. There are the naïve patients, for whom this could be an easy first-line therapy. With monthly injections, it could take six to nine months for patients to be titrated to the right dose, whereas with Paltusotine daily dosing, the correct dose can be reached in two to four weeks. Another segment of patients currently receiving injectable SRLs could see similar or better control of biomarkers with improved symptom control. This also includes untreated and undertreated patients. We don't think that all untreated patients are cured. Some undertreated patients are not receiving standard of care today. We are doing more work in these two segments to understand what messaging is needed to communicate the value of Paltusotine. In the longer term, we could also grow the market by potentially accelerating the diagnosis of acromegaly. Alan, if you have anything to add to that. No, I think that’s a very good summary. I believe the current first-line medical treatments for acromegaly are not very precise or reliable, relying on month-to-month painful injections. It’s not a great experience for patients. Even when biochemical targets are met, many patients still report breakthrough symptoms. I see an opportunity for a well-absorbed oral alternative. With once-daily dosing, patients can be confident they’re receiving the necessary drug exposure to control symptoms. Our data so far support this approach. Yeah, and that includes clinical data as well. You’ve put a lot of emphasis on capturing the patient experience beyond biomarkers. Can you elaborate on that? Is this something you hope to include on the label and promote in the marketplace? Yeah, we developed from scratch what we call the Acromegaly Symptom Diary at the beginning of the development program for Paltusotine. No validated symptom instrument or PRO instrument existed in this patient population. We took that through Phase 2 and then incorporated it into the Phase 3 trials as statistically pre-specified secondary endpoints. In both Phase 3 trials, we showed superiority of symptom control using that tool versus placebo in a broad spectrum of acromegaly patients. We believe we have followed regulatory guidance for patient-reported outcome development and usage in clinical trials. We hope to potentially see that information included in an approved label someday. Okay, I know that with the PDUFA in the second half of the year, 2026 might be a more important year to gauge the launch trajectory. Are there any potential analogs, or anything you can think of, that we could use as benchmarks to imagine how a product like this might be adopted in the marketplace? We haven't shared specific analogs, but we could probably guide you to disease launches where there's an oral option with superior or equivalent efficacy. In terms of launch dynamics, naive patients, as I mentioned, are probably a more obvious place for physicians to prescribe initially. For switch patients, there is clearly demand from HCPs and patients to move to something like Paltusotine. Patients will see their HCPs a couple of times a year, which might naturally limit how quickly they can start the drug. From a macro perspective, we see a lot of potential in the market in the medium and long term; it's mainly the short-term dynamics that differ. Okay. Of course, there's carcinoid syndrome as the second indication. You've also generated some exciting clinical data there. Can you talk about what you hope to demonstrate in Phase 3 and what kind of a timeline we can look forward to for that program to mature? Yeah, we are getting underway with Phase 3 as we speak, and we hope to have the first patients enrolling very soon. In Phase 2, we showed very impressive reductions in bowel movement frequency as well as flushing episode frequency, both of which are hallmark symptoms of carcinoid syndrome. In Phase 3, our goal is to demonstrate that again in Paltusotine-treated patients, this time showing statistical superiority to placebo. It will be a modern, placebo-controlled trial designed in consultation with the FDA. I would say this could be a very exciting trial, not only to look at the frequency of these symptoms, but also the severity is very important, particularly when you think about the urgency of bowel movements, for example, when you have uncontrollable diarrhea, and this syndrome can be very, very problematic from the patient perspective. We would expect, as we did in Phase 2, to show data with regard to severity as well as frequency of these critical symptoms. Okay, great. Let's switch gears to Atumelnant. There's obviously been a lot of focus on this program. You've seen some great efficacy. We have another treatment option now that Neurocrine's Crinecerfont has been approved. I'd love to hear for the first question on this program. I know it's really early and the Crinecerfont, there's very limited Crinecerfont uptake numbers, but if you have any thoughts on where Crinecerfont and Atumelnant will fit into the treatment paradigm and what you are doing in order to differentiate your molecule, which it looks like might be much more potent. These patients have a congenital condition and for life require glucocorticoids like prednisone or hydrocortisone to replace missing cortisol. These patients cannot normally manufacture the most important glucocorticoid from the adrenal glands, cortisol. What happens over time is that because of the inability to synthesize cortisol, the patient's pituitary gland secretes too much ACTH, and this is true for the lifetime of these patients. The only treatment that's been available for decades is using the glucocorticoids that are supposed to be used only to replace the missing cortisol, but at higher doses can also help to suppress the elevated ACTH and thereby reduce excess adrenal output of androgens. The problem is it's very difficult to find a dose of glucocorticoid that suppresses androgens, but doesn't cause what we call iatrogenic Cushing's syndrome or too much cortisol—the symptoms and signs that we're all very familiar with: obesity, hypertension, diabetes, et cetera. Crinecerfont is the first new agent approved for these patients that actually helps reduce the dose of glucocorticoid necessary for long-term use in these patients. That's a great step forward. The problem is that mechanism of action, CRF1 antagonism, has really only demonstrated a pure steroid-sparing effect so far. In other words, they were able to reduce the glucocorticoid dose, but these patients were left with very significant hyperandrogenism, or high androgen levels. n reality, the therapeutic goals here are not just to reduce glucocorticoid doses, but also to correct androgens, which themselves can cause many symptoms and signs that need attention. Atumelnant is an ACTH receptor antagonist, which has a more profound effect on androgen output from the adrenals. Although we have not yet studied glucocorticoid dose lowering, which we will need to do in Phase 3, I expect based on the unprecedented magnitude of androstenedione reductions that Atumelnant will have a more impressive effect not only on steroid-sparing but also on androgen correction. By correcting androgens in our short Phase 2 studies, three months in duration, we have already shown many clinical outcome improvements related to androgen reduction, which is a very impressive sign. Atumelnant is an ACTH receptor antagonist, which has a more profound effect on androgen output from the adrenals. Although we have not yet studied glucocorticoid dose lowering, which we will need to do in Phase 3, I expect based on the unprecedented magnitude of androstenedione reductions that Atumelnant will have a more impressive effect not only on steroid-sparing but also on androgen correction. By correcting androgens in our short Phase 2 studies, three months in duration, we have already shown many clinical outcome improvements related to androgen reduction, which is a very impressive sign. One of these findings is the documented shrinkage of overgrown hyperplastic adrenal glands in CAH patients, occurring far faster and more extensively than expected in this timeframe. This indicates that ACTH receptors are being effectively blocked and that we are already observing associated clinical outcome benefits. Yeah, it's exciting. How do you see this market segmenting in terms of the patient population, and which patients might Atumelnant address better than Crinecerfont? Yeah, I mean, when you think about the patient population for CAH, you have patients with high androgens and high glucocorticoids GCs, and those are probably the most severe. You have patients with low androgens and high GCs, where you want to bring those levels down. You also have patients with low GCs and high androgens. These are three different segments that we think Atumelnant could address based on the reductions we’re seeing in androstenedione A4 so far in Phase 2. I think only one of those segments was studied in other agents’ Phase 3 trials. We will share more about our Phase 3 trial design soon, and we are not looking to exclude any patient segments. That is how we're thinking about the program and hopefully a broad set of patients that we can treat with Atumelnant to both reduce A4 to normal levels and reduce GC to physiological levels. You gave me a good segue. For Phase 3, you're thinking about a novel endpoint. What do you hope to capture? Do you hope to capture both A4 reduction and GC lowering in the same endpoint? Is this like a composite endpoint? Any insight into how you're thinking about and what you want to accomplish with that? We have not finalized the design yet, but we will share that soon. We’ve had very productive discussions with the FDA on this. As you can imagine, they, like us, are interested in showing more than just the steroid-sparing effect. It is reasonable to consider a composite endpoint that accounts for both therapeutic goals in this disease. Whether it ends up as a single composite endpoint or one primary endpoint with a powered key secondary endpoint remains to be finalized. Either way, we believe we can demonstrate Atumelnant’s potential in this disease. Makes sense. Sticking with Atumelnant, can you talk a little bit more about the OLE trial and what are the differences between the OLE study and the main trial that you already completed? What do you hope to accomplish with the OLE? Yeah, the open-label extension (OLE) study for our Phase 2 parent study that I described earlier, the three-month parent study, is going to begin enrolling soon. Like every OLE, this is mainly about long-term safety and also showing duration of efficacy over time. One big difference in an OLE, which is also the case here, is that these studies are designed more to simulate a real-world practice kind of setting. In the parent study, we fixed the glucocorticoid dose and assigned each patient a particular dose of Atumelnant. In the OLE, we give the investigators doctors for each patient more leeway and flexibility in dosing both. They’ll be able to adjust doses of both glucocorticoid and Atumelnant to achieve the targets of therapy, like biomarker control and symptom control. Okay, great. A similar question with cohort four. What's the purpose of that recent addition to the study? When will we get some data out of that? Cohort four is another cohort in the parent Phase 2 study, six to twelve patients, just like in the other arms of that study. We'll be disclosing the details of that cohort along with more information about the Phase 3 program in our next earnings call. It's all part of the overall strategy to show long-term safety and efficacy. Okay, great. You have a lot going on in the earlier-stage pipeline, so I want to make sure we can touch on all that or part of it at least. For CRN09682, which is the first program coming out of the non-peptide drug conjugate platform, what are you trying to accomplish here? How is this approach differentiated from ADCs? Yeah, maybe we'll start with that question. Yeah, so 9682 is an SST2-positive targeted non-peptide drug conjugate. It is a small molecule ligand for SST2 that is designed to be internalized, and that is conjugated to an MMAE, similar to ADCs for a targeted therapy. However, it is a small molecule ligand, which we think provides more tumor penetration and a differentiated distribution profile for this molecule. What we have seen in some of the preclinical data is that we are able to get MMAE into the tumor, and it lasts for up to 10 days and in circulation, it is gone within 24 hours, which gives us a larger, hopefully, therapeutic window in the clinic, and we are able to dose and see what the effect of this treatment has in patients that are SST2 positive in the clinic. I think it has differentiation from ADCs with regards to that. t. There's some manufacturing as well, advantages to doing small molecule synthetic chemical manufacturing versus antibody engineering, et cetera. That's how we're thinking about the non-peptide drug conjugate. We're starting in the NETs patients that are SST2 positive, but we also understand that SST2 is expressed in many other tumors. It's highly expressed in head and neck, breast, some other ones as well. Those are going to be expansion opportunities for this program as well as it progresses through the clinic. Okay, and with an IND? The IND very soon. When should we think about when data might start to emerge from that program? What's your strategy for reporting data from that? Yeah, we haven't defined that yet, but it is an oncology trial. You get oncology patient data, patient by patient as we're going through the escalation Phase. We'll be reviewing that and determining when the right time is to share that package. Okay, great. Maybe we'll move to the hyperparathyroidism program. Would love to hear how you foresee this fitting into the treatment paradigm. Obviously, surgery is frontline. I'm just wondering for those patients that aren't candidates for that, what is the bar for success that you'd like this agent to be able to clear in order to be a meaningful treatment advance for those patients? Yeah, primary hyperparathyroidism is a fairly common condition. It is characterized by elevated serum calcium levels. This is often how it is discovered, based on routine serum calcium blood testing results that your physicians order. However, hypercalcemia is only part of the picture in this condition. Patients with this also suffer different degrees of bone loss and bone thinning and increased fracture risk. There is also excess calcium spilling into the urine in this condition, and they are left at risk for kidney stone formation and nephrocalcinosis and long-term renal dysfunction. There really is not a good medical option other than surgery to treat this condition at this time. A lot of patients do have surgery and can be cured in the best of hands in this condition. However, many patients who need surgery for this are not getting it for a lot of reasons. A nice medical option to surgery would be, I think, a welcome addition to this field. In order to be effective, you need to treat the fundamental problem of hyperparathyroidism, which is excess exposure to PTH and blocking that excess PTH exposure, which thins the bones and causes kidney stones. I think when you ask how do you define success, to me, it's reducing hypercalcemia and also reducing hypercalciuria and reducing the risk of kidney stones and also helping to improve bone health by improving bone density and reduced fracture risk. I think there's a great need here. There really is not a great alternative to surgery here. Not everybody has access to these expert surgeons to get cured. Are both this program and the TED/Graves’ disease program expected to include healthy volunteer challenge studies to assess target engagement and dose response in that kind of assay setting? Will we see more work similar to what we did with Paltusotine and Atumelnant? Does this approach continue across the earlier-stage pipeline? Absolutely. With the TSH receptor antagonist, which we have in mind for thyroid eye disease and Graves hyperthyroidism, or with the PTH receptor antagonist, there are easy-to-measure blood-based biomarkers. For the PTH antagonist, I would expect serum calcium and PTH responses to indicate target engagement. Similarly, routinely available thyroid hormone levels can be measured for the TSH antagonist. As we’ve done multiple times in the past, we hope to de-risk efficacy in patients by conducting our Phase 1 study in healthy volunteers. Excellent. We look forward to continued progress on all of these fronts. I appreciate the update. Thank you. Of course. Thanks, Joe. Thank you.