Good afternoon, everyone. Welcome to the Crinetics Pharmaceuticals Fourth Quarter and Full-Year 2024 Financial Results Conference Call. Also, today's call is being recorded. With that, I'll turn things over to Gayathri Diwakar, Head of Investor Relations. Please go ahead, Ma'am.

Thank you, operator. Good afternoon, everyone, and thank you for joining us to discuss the fourth quarter and full-year 2024 results. Today on the call we have Dr. Scott Struthers, Founder and Chief Executive Officer, Isabel Kalofonos, Chief Commercial Officer; Dr. Dana Pizzuti, Chief Medical and Development Officer, Dr. Steve Betz, Founder and Chief Scientific Officer and Marc Wilson, Chief Financial Officer. Also, joining us to the Q&A is Dr. Alan Krasner, Chief Endocrinologist. Please note there is a slide deck for today's presentation, which is in the Events and Presentations section of the Investors page on the Crinetics website. In addition, a press release was issued earlier today and is also available on the 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 Form 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, February 27, 2025. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call.

Thank you, Gayathri, and good afternoon to everyone joining today's call. 2024 was a remarkable year for Crinetics. As you can see on Slide 3, we successfully executed on all of the key objectives we set out to accomplish. This sets the stage for what we believe will be a transformative 2025. On today's call, we'll review some of these accomplishments and outline our plans for 2025 and beyond. Since our last earnings call, the FDA accepted the NDA for our investigational drug, paltusotine for the treatment and long-term maintenance therapy of acromegaly. The PDUFA date is September 25 of this year. This is our first NDA filing, and I'm extremely proud of the team for its hard work in getting us to this point. We're continuing to prepare our organization for the anticipated launch of paltusotine later this year. As part of this, we are completing the build-out of our commercial and medical affairs teams as well as the underlying administrative infrastructure. A very important part of this was hiring Isabel Kalofonos this past December as Chief Commercial Officer. She successfully launched many rare disease products at both large and small biopharmaceutical companies. Isabel has all the skill sets and relevant experience to lead us through our upcoming transition into a commercial stage company. Given the strength of the clinical data for our lead programs and the deep pipeline behind them, we continue forward with our stepwise regional growth strategy in Europe. We anticipate filing the EMA for acromegaly shortly. We have incorporated a hub in Zug, Switzerland and brought a General Manager and leadership for EU Regulatory, Market Access and Medical Affairs. And we're beginning to extend this organization into Germany. As a leader in endocrine innovation, we plan on leveraging this infrastructure in the coming years as we evolve into a fully integrated global pharmaceutical company. Last year, we made significant progress on multiple clinical readouts, including for paltusotine's second indication, carcinoid. In a Phase II study, paltusotine treatment demonstrated rapid, sustained reductions in frequency and severity of flushing episodes and bowel movements. We have begun activating clinical trial sites for the Phase III trial and expect the first patient to enroll next quarter. We also shared extremely positive data for our second candidate, atumelnant, in both congenital adrenal hyperplasia, or CAH, and in Cushing's disease. In a Phase II study in adults with CAH, atumelnant achieved rapid, substantial, and sustained reductions of both biomarkers, A4 and 17-OHP. Importantly, significant clinical improvements in symptoms were also observed, which was impressive in a 12-week study. We believe that atumelnant can provide healthier hormone levels on both dimensions adrenal androgens and exogenous glucocorticoids. And this profile has the potential to differentiate atumelnant and provide meaningful improvements to people living with CAH. With this in mind, we're progressing towards initiation of late-stage CAH studies in both adults and in children. These studies are designed to take advantage of atumelnant's very potent mechanism of action to provide benefits for a broad spectrum of patients with CAH. Atumelnant also demonstrated initial positive results in Cushing's disease. All participants in this Phase Ia/Ib/IIa trial rapidly achieved normalization of urinary free cortisol. And that is the primary endpoint required for registrational studies in Cushing's disease. Lastly, we're making notable progress on our earlier-stage programs, including 9682, our first drug candidate from a novel nonpeptide drug conjugate or NDC platform. This year, we expect to submit 4 INDs in total, including 9682. Steve will discuss these in more detail towards the end of the call. With that, I'm pleased to introduce Isabel, who will tell you more about the progress in building our commercial capabilities.

Thank you, Scott. I'm pleased to have joined Crinetics to lead the commercial organization in this exciting new chapter for the company. Today, I will share more about how we are advancing our commercial capabilities and working diligently to be launch ready ahead of our first potential FDA approval. We are building a best-in-class commercial and medical affairs organization with strong leaders across all functions, operations, marketing, market access, medical affairs and sales. Separately, our medical affairs team has talented endocrinologists, leading their effort to liaise with health care professionals and KOLs. Our MSL team has already reached out to almost 100% of our core academic targets to solidify relationships and refine our understanding of the unmet needs in acromegaly treatment. We also have a strong partnership with the broader endocrinology community, which we believe will be instrumental for a successful launch. There is significant unmet need in the acromegaly market. Health care professionals and patients want therapies with a rapid onset of action, sustained effect, favorable adverse event profile and ease of use. We are building our commercial and medical organizations to drive educational efforts in a market that has not seen any meaningful innovation for a long time. And Slide 4 outlines the 4 imperatives of our commercial strategy: activate, adopt, access and adhere. First, we want to activate health care professionals and patients to demand more from their acromegaly therapy. For example, we wanted to realize that they can achieve better disease control and don't have to settle for frequent breakthrough symptoms. Across the Phase III program, paltusotine demonstrated rapid, reliable control of biochemical markers, decreased symptom severity and reduced the frequency of breakthrough symptoms. Second, after approval, we want to drive adoption of paltusotine by clearly articulating its differentiated efficacy and safety profile to patients and health care professionals. Our efforts will be focused on pituitary treatment centers as well as the community. Many patients see their doctors in the community setting whereas the introduction of new therapies tends to lag behind academic centers. And since these patient centers see their health care professionals only 1 or 2 times per year, we expect a more gradual adoption at the outset. We are actively developing strategies to motivate patients and health care professionals to accelerate this timeline. Over time, we are confident in the potential of paltusotine to become the new standard of care. Third, we want to ensure access to paltusotine. Our market access team has continued to engage with the top U.S. payers, and they have been very receptive to the value proposition of paltusotine. As with any new drug, there will be a standard formulary inclusion process that will need to be followed. But we are working towards having comprehensive coverage as soon as feasible after launch. We're extremely confident that we'll be able to provide optimal access for all acromegaly patients that could benefit from paltusotine. Lastly, we want patients to adhere to the paltusotine regimen. Patient support goes far beyond financial co-pay assistance. And our comprehensive patient support center will include a full suite of services to provide unparalleled support for patients at every step, starting at initiation of therapy and throughout the course of the long-term treatment regimen. In summary, the paltusotine profile we are sharing in market research is resonating with all key stakeholders, health care professionals, payers and multiple patients. We look forward to sharing more detail on our launch strategy in the coming months. Lastly, it is important to note that the work that we do today will serve as a solid foundation for anticipated future launches. We will leverage the infrastructure we are building today in the U.S. and Europe across additional indications for paltusotine as well as the other candidates in our pipeline. With that, I will hand the call to Dana to discuss our clinical development progress.

Thank you, Isabel. This is a very exciting time for Crinetics. Turning now to Slide 5. The NDA for paltusotine was accepted last quarter. We have a productive relationship with the endocrine division at the FDA and our NDA review is proceeding normally. In addition, we expect to file our MAA for acromegaly to the EMA in the first half of this year. Separately, the Committee on Orphan Medicinal Products of the EMA has issued a positive opinion on our applications for Orphan designation for acromegaly based on the committee's judgment that it has the potential to provide significant benefit over the currently available therapies. We are continuing to activate sites for the Phase III study of paltusotine in carcinoid syndrome. We are planning to run the study globally and expect to enroll our first patient in the second quarter. For atumelnant, in CAH, we are putting the finishing touches on our Phase III adult protocol after productive interactions on its design with the FDA and 2 European health authorities. I'll provide more detail on this in a moment. We have also had important and supportive discussions with FDA and EMA regarding our proposed Phase II/III pediatric study for CAH. We are completing protocol development and we'll provide more details on the design and plan to begin this study before the end of the year. We are continuing to pursue development of atumelnant in ACTH-dependent Cushing's syndrome or ADCS. We are finalizing a proposed seamless Phase II/III study design, which we developed after review of our NIH study data and in close collaboration with external experts and regulatory advisers. In the near future, we will provide our proposal to the FDA and European agencies for discussion. We will then finalize the protocol, and we'd expect to enroll our first patient late this year or early next year. Before I leave atumelnant, I realize there may still be some lingering discussion about the one case of elevated liver enzymes in the CAH Phase II study. As we have previously described, one patient in the 120-milligram dose cohort had liver enzyme elevations at the final study visit at 12 weeks. Those levels returned to near normal within 2 weeks. The patient did not show any elevation in bilirubin, nor any associated symptoms. It is also important to note that we have seen no concerning signals nor unexpected safety findings in the preclinical work or in the Phase I healthy volunteer studies. We have shared all preclinical and clinical data, including the details on this patient with the FDA and global health authorities as part of the consultation process for our proposed Phase III design. After reviewing all the data and the proposed Phase III protocol, the FDA has not recommended any changes to the safety monitoring in the ongoing open-label extension study nor any additional testing on top of routine hepatic safety monitoring in our proposed Phase III protocol. We remain very enthusiastic about the strength of the overall Phase II efficacy and safety results. And we believe this favorable benefit-risk profile will be confirmed in our Phase III trial. This enthusiasm is reflected in our Phase III protocol, which we will share in detail when final, but our intention is to use a novel endpoint. Based on the entirety of the clinical program and atumelnant's unique mechanism of action at the MC2R receptor, atumelnant should be capable of reducing androgens into a normal range and allow for lowering glucocorticoid doses to physiologic replacement levels. Our proposed endpoint would capture this differentiating aspect of atumelnant and will allow for broader Phase III inclusion criteria than was used for the currently approved CAH therapy. In particular, patients with normal glucocorticoid doses but high A4 levels could potentially benefit from atumelnant and will be included in our Phase III study. 2025 is an exciting year for paltusotine and atumelnant as we continue towards registrational studies for these candidates in multiple indications. We will soon have 4 late-stage clinical programs underway, which is a new high watermark for Crinetics. As we make progress on our preclinical pipeline, we look forward to potentially initiating additional early-stage trials. With that, I will hand it to Steve to describe our upcoming INDs.

Thank you, Dana. As highlighted on Slide 6, Crinetics has an innovative pipeline of drug candidates with intellectual property extending into the 2040s, currently featuring 10 wholly owned programs with more innovation from our discovery team. Our core expertise lies in targeting G protein-coupled receptors (GPCRs) using small molecules with specifically tailored pharmacology and properties. To capture the wide-ranging opportunities within the GPCR field, we've organized our discovery team into three main focus areas: endocrine disease, metabolism, and what we refer to as targeted therapeutics. Since our founding over 15 years ago, Crinetics has concentrated on developing innovative non-peptide drug candidates that target specific endocrine pathways to manage abnormal hormone secretion. Most of the candidates in our pipeline have emerged from our endocrine group, and we're continually investigating additional GPCR targets within the endocrine system, always focusing on critical areas of unmet need. Metabolic disorders, such as diabetes and obesity, affect the lives of millions globally, with significant and varied impacts on patients. We believe many of these disorders can be addressed by appropriately activating or inhibiting the receptors of key metabolic hormones like insulin, glucagon, GLP-1, and GIP. Our understanding of these hormonal pathways and the GPCRs governing them is driving us to create new molecules that could enhance patient lives. Lastly, in targeted therapeutics, our work started with developing non-peptide GPCR-targeted radioligands for imaging and treating a variety of endocrine receptor-driven cancers, ultimately leading to the formation of Oncology in 2021. We are further exploring the concept of using non-peptide ligands to target endocrine GPCRs that are relevant to oncology, but with non-radioactive payloads. This has resulted in a new modality we call non-peptide drug conjugates (NDCs), which are a novel therapeutic approach conceptually similar to antibody-drug conjugates (ADCs), but they utilize a non-peptide ligand to selectively target and deliver payloads to tumor cells expressing GPCRs. We believe NDCs offer several advantages, including straightforward production through standard synthetic methods and customized in vitro and in vivo properties that help us optimize half-life, tumor penetration, and payload. Currently, four early-stage programs from these discovery efforts are undergoing IND-enabling studies. The most advanced of these is CRN09682, our NDC for SST2-expressing neuroendocrine and solid tumors, for which we are on track to submit an IND early this year. Other candidates with INDs expected in 2025 include a PTH antagonist for hyperparathyroidism, a TSH antagonist for Graves hyperthyroidism and thyroid eye disease, and an SST3 agonist for autosomal dominant polycystic kidney disease (ADPKD). Similar to our experience with both paltusotine and atumelnant, a key advantage for many programs listed on this slide is that we can achieve early mechanistic proof of concept during Phase I trials. The first-in-human studies for 9682 will involve oncology patients to monitor disease progression. In cases of hyperparathyroidism and hyperthyroidism, there are hormonal biomarkers that should indicate whether we achieve our intended pharmacological effect. These early insights allow us to optimize our likelihood of success across all these programs, while maintaining an efficient capital and resource development strategy. We look forward to sharing initial results from these programs with you as they become available. With that, I will hand it over to Marc to discuss the 2024 financial results.

Thank you, Steve. Turning to Slide 7. 2024 was an outstanding year that demonstrated the strength of our strategy and our team's execution capabilities. Crinetics entered 2025 with strong momentum across all programs. And the company remains focused on discovering and developing novel therapies for patients as well as generating value for its co-owners. The tremendous progress made over the course of last year has enabled the company to continue investing in the pipeline as we prepare to launch the first drug candidate emerging from our own R&D efforts. Now, I will walk through the financial results for the fourth quarter and year. Revenues were $1 million for the full year ended December 31, 2024, compared to $4 million for the same period in 2023. There were no revenues in the 3 months ended December 31, 2024, or the 3 months ended December 31, 2023. Revenues in both years consisted of the amortization of payments we received in connection with our paltusotine licensing arrangement with our Japanese partner, SKK. Revenue in 2023 also included approximately $2 million associated with the development candidate that we licensed to Loyal to explore extension of lifespan in large and giant breed dogs. Research and development expenses were $66.6 million and $240.2 million for the 3 months and full year ended December 31, 2024, compared to $45.6 million and $168.5 million for the same periods in 2023. The increases were primarily attributable to higher personnel costs and increased development activities associated with the expansion of our pipeline. G&A expenses were $28.2 million and $99.7 million for the 3 months and full year ended December 31, 2024, compared to $17.1 million and $58.1 million for the same period in 2023. These increases were primarily driven by increased personnel costs and commercial planning activities. Our net loss for the 3 months ended December 31, 2024 was $80.6 million compared to a net loss of $60.1 million for the same period in 2023. For the year ended December 31, 2024, the company's net loss was $298.4 million compared to a net loss of $214.5 million for the prior year. For 2025, we anticipate our cash burn to be between $340 million and $380 million. This increase reflects our plans to initiate 4 late-stage trials in 2025. So we expect our R&D spend to grow in 2025 as those trials start to ramp up. SG&A will also increase this year as we continue to build our commercial infrastructure and prepare for the potential launch of paltusotine in the fourth quarter. We ended 2024 on strong financial footing with approximately $1.4 billion in cash and investments, which is expected to fund our operating plan into 2029. Before I turn it back to Scott, I'd like to take a moment to thank my fellow Crinetics for their support during my tenure, particularly since I announced my plan to transition out of the CFO role a number of months ago. I would also like to thank those of you in the investment community who have been outstanding colleagues over the years. I truly believe in the work that is being done at Crinetics. It is a genuinely unique company. And I'm honored to have been a small part of what the organization has accomplished. I am optimistic about the future and I'm confident that Tobin will be an exceptional steward of the company's resources through its next phases of growth. I'll now turn it over to Scott for closing remarks.

Thank you, Marc, and thank you for your leadership over the past 7 years. You've been instrumental through these years of incredible growth. With your help, we have grown from a pre-series B private company to the public company we are today with operations around the world and on the verge of our first PDUFA date. I speak for everyone here when I say that we are deeply grateful for your dedication and contributions. We're also very excited to welcome Tobin Schilke, who will succeed Marc as Crinetics CFO. Tobin brings over 25 years of global pharmaceutical experience and has led several biotech companies through the transition to fully integrated commercial enterprises. He brings a wealth of experience and a unique perspective, and we're excited to have him on board as we prepare for our first commercial launch. Turning to Slide 8. I'm very bullish on the bright future before Crinetics. The array of opportunities for us to help patients with endocrine-related diseases with the pipeline we've created from scratch is breathtaking. With the progress I have described today, we have made great strides on our path to becoming a premier fully integrated global pharmaceutical company. The combination of our best-in-class in-house discovery capabilities, proven clinical development and our ongoing build of commercial capabilities strongly positions us to execute on a number of key milestones in 2025. We plan to leverage our growing infrastructure across multiple programs and therapeutic areas while recognizing economies of scale along the way. I believe this strategy will propel us to maximize patient reach and drive long-term value growth for all our stakeholders. With that, I'll hand the call back to the operator to begin Q&A. Please limit yourself to one question each in the interest of time.

We'll go first this afternoon to Tyler Van Buren of TD Cowen.

It's great to be back in coverage of Crinetics here again and congratulations on all of your achievements. Marc, I wish you the best. I want to ask about paltusotine. The data with paltusotine and acromegaly are clearly strong and the likelihood of approval in September is very high, but expectations for the launch seem conservative or even modest from some of your investors. So can you elaborate on the ongoing launch preparations for paltusotine? What might surprise people and your global strategy in particular?

Thanks, Tyler. I totally agree with you regarding how strong the data has been for acromegaly. And as we talk to the KOL community, I think there's an emerging consensus that this really is the next level of care. And we're super pleased with the announcement from the EMA that we've been granted orphan drug designation, which in part recognizes that because they felt that paltusotine constitutes a clinically relevant advantage over currently approved therapies. And that's part of their process in making orphan designation. So I think we've built something that is going to give Isabel and the rest of the team something very strong to work with. And let me let her talk to you about the ongoing preparations.

Yes. Thank you, Scott. Yes, we are in a really good place in preparing the organization, the market and the product. In terms of the organization, we hired a very talented team. And we're very pleased to welcome our VP of Sales as we continue to build our customer engagement model, including not only the sales team but field reimbursement managers to facilitate the onboarding of the patients. In addition to that, we are preparing the market. And that involves very successful engagement right now with the payers that are responding very well to the value proposition of the drug. As Scott has stated, we have a treatment that has a fast onset of action, sustainable effect, less breakthrough symptoms, and has a very good tolerability profile. And of course, it's a once daily, which really resonates not only with the payers but also with the physicians and the health care professionals. We continue to drive educational activities to engage with the doctors in disease awareness as well as with the patients. In terms of the product, we are in a very good place when it comes to our supply chains and distribution. And we continue to develop our training modules and launch materials consistent with the expected label. So we are in a very good place, and the product really offers the opportunity to really change the standard of care. In terms of the international organization, we think it's very important that this product is not only for U.S. patients but it starts really making a difference internationally as well. So we're starting in Europe, where we have hired a very talented team that, as in the U.S., has significant experience in product launches and in rare diseases. We have a general manager, market access, medical affairs and regulatory in place. And it's our goal to now focus on building Germany. Similar to the U.S., the model is very fit for purpose, really with a significant value concentrated in centers of excellence. And we are preparing and advancing that as well, so really exciting times and the commercial organization is fully engaged and making sure that we advance towards a successful launch.

We'll go next now to Yasmeen Rahimi at Piper Sandler.

This is Dominic on for Yas and congrats on continued strong execution. Our question is just how do you envision your disclosures as you continue your dialogue with the FDA between now and September '25? And are there certain topics of interest that could come up at your mid-cycle review? And also, have you had your mid-cycle review yet? And what was the outcome if you had?

Let me let Dana answer that. But just in general, I'm pleased with the overall cadence of our communications. From a communications point of view, I think that will be simply on an as-needed basis. But let Dana just say a little bit more.

Yes. Well, we haven't had the mid-cycle yet, but we are scheduled to do that. And we're awaiting further interactions with the FDA as we go along. But as I mentioned in my initial remarks, everything is proceeding normally. And there's a very productive relationship with the agency.

We'll go next now to Joe Schwartz of Leerink Partners.

And congrats on all the progress. I was wondering if you could talk about the strategies you're working on to motivate acromegaly patients to see their health care providers, such as those in the community, we heard you say often lag in the uptake of new treatments. And in a related sense, how long do you think Phase III enrollment for atumelnant in CAH may take, recognizing that there's a new treatment option for the first time in a long time and could be a bit competitive. But also, I think you've already had a lot of experience with clinical development now for paltusotine. So I'm just wondering relative to that Phase III enrollment timeline. How should we think about how long it might take for atumelnant in Phase III?

Nice working in a compound question, Joe. So let me answer the latter and then I'll hand it off to Isabel. But CAH, look, we've got quite a bit of experience now in that community. In many cases, it's the same institutions as we did with acromegaly. The fact that now there's an approved drug on the market in chronicity is fabulous for these patients. But I don't think it's going to significantly impact our enrollment, especially since we're in a global clinical trial. In fact, it has been our past experience, and I think the past experience of most other companies. Recruitment tends to be higher outside the U.S. than inside the U.S. And so I see no effect. Compared to prior trials of CAH that were underway during the pandemic where people were late to the international markets, I expect us to do significantly better than previous experience. But Isabel, maybe talk a little bit about activating patients. I think they're highly motivated already. But we want to make sure they're empowered, not just motivated.

Yes, Scott. Indeed, we are engaging with the patients through different venues, including our disease awareness campaign. Really to highlight the significant unmet need that is happening in the marketplace. Today, the data we show that only 35% of the patients are uncontrolled. So many of the patients have significant unmet needs and the majority of the patients have breakthrough symptoms. So even though the IGF-1 level might look like normal, they continue to experience significant effects from fatigue, sweating and other symptoms as well that are impairing their quality of life. So we are making them aware of that. And there are different educational events and a disease awareness campaign as well as our media outreach that is starting right now throughout the country. In addition to that, we have a patient hub that we believe is going to really help patients reach out. And we will support them not only through co-payments and additional activities, but also helping with their mental health and other things that will provide support to them. So overall, we are in the process of activating not only the patients but the health care community.

We'll go next now to Jessica Fye of JPMorgan.

I was curious if there's any update on where things stand with the open-label extension for the CAH Phase II trial. I'm just trying to think about if that's something we could see data from prior to getting those Phase III results.

Thanks, Jess. Yes, the sites are activating. And patients are switching into the open-label extension and eager to see how they do. It's a little bit of a second bite at the apple since we had a bit of a delay in starting the OLE to finish up the long-term tox. So all the patients had come off of drug and now they're coming back on under physician care. And yes, I look forward to seeing how that plays out. And I think it will be a valuable source of information.

We'll go next now to Cory Jubinville of LifeSci Capital.

This is Kate on for Cory. Congratulations on the amazing progress this year. Just one from us related to the CAH program. It's, of course, still early days. But it seems like the carcinoid launch in CAH has gotten some early momentum. And we're just curious what were the learning you've taken from the launch thus far and how you might be considering that for atumelnant in the future? And is there anything thus far that surprised you?

Thanks, Kate. I think it's really a little early for us to draw any conclusions. But our friends and neighbors down the street have proven themselves as very good commercial pharmaceutical companies. So I expect they'll do a good job. And we're watching closely to learn from them and wish them well.

We'll go next now to Gavin Clark-Gartner at Evercore ISI.

Congrats on the progress. For atumelnant, can you share any additional details on Cohort 4 in the TouCAHn study? And when we may be able to possibly see that data?

Yes. Thanks, Gavin. We haven't really started talking about Cohort 4. Remember, it's just one cohort in a large overall program. But I think one thing we will be telling you about in the not-too-distant future is the overall study design details for the Phase III program. And maybe at that time, it's relevant to talk about Cohort 4. But I'll try and get that out as soon as we have the final pieces in. I just don't want to tell you something that might have slight revisions. So we're very close to finalizing that and starting to activate sites and things like that. So I think we'll be able to provide clarity by our next earnings call at the latest.

We'll go next now to John Wobel at Citizens.

This is Catherine on for John. I have kind of a follow-up question on CAH as well. I know that you just mentioned that you're going to be discussing the design details of the Phase III program going forward. But just kind of a general question on the endpoint and a differentiated endpoint from the one that was previously used. So what is the rationale from a regulatory standpoint as well as a commercial standpoint on changing up the endpoint, if you could give a little bit more color on that?

Yes. Thanks. I think the thing to recognize is that this is a completely different mechanism of action with a different pharmacologic profile. And we've shown in both the Phase II and CAH patients, deep suppression of A4. We've shown in healthy volunteers that even under conditions of very low glucocorticoids and extremely high levels of ACTH that we can maintain suppression of the adrenal gland and keep those patients even to the point where they still need glucocorticoid add-back. And so our vision for the drug is not one, which is just helping glucocorticoids manage the adrenal. We think that atumelnant should be the treatment for CAH. And then glucocorticoids are not used for treatment; they're simply used for replacement. And so maybe Dana can elaborate a little bit more. We're trying to be not completely specific because there are still a few things to work out. But let me let her talk about principles.

Yes, I agree. As Scott pointed out, and as I mentioned earlier, we believe that the drug can do more than just help manage the disease with glucocorticoids. We think, as Scott indicated, that it should be able to accomplish both objectives. Therefore, when we develop an endpoint, it needs to encompass both aspects. We haven't yet finalized how this will work from a statistical perspective, but we believe that the evidence supporting our understanding of the mechanism of action could open the door to a new potential indication for the drug. We see this as the primary treatment for the disease, while glucocorticoids serve merely as a safety measure to avoid adrenal insufficiency.

We'll go next now to Dennis Ding of Jefferies.

We recently had a discussion on atumelnant. Can you commit to sharing additional data this year, whether it's from CAH 14 or longer-term extension data or related to Cushing's? Additionally, for the long-term extension, how do you anticipate the efficacy will change with extended treatment?

I prefer not to commit to any timelines until we are completely sure. So please stay tuned. Apologies for the suspense. Regarding the second part of your question...

Just around the long-term extension and how do you think efficacy could evolve if patients are on.

Yes. So I think that the most relevant data there is what we saw with the adrenal sizes in a very short 12-week study. So ACTH is trophic for the gland. In CAH, when these patients are experiencing high ACTH levels from birth, they end up getting larger adrenal glands, as my friend, Dr. Krasner says they become angry. Certainly, they're very active. And we're showing shrinkage of those glands in only 12 weeks. So I would expect that to continue with time. And if anything, then the ability to suppress the adrenal should increase or remain with time. There's no mechanistic reason to believe that any sort of tachyphylaxis should develop.

We'll go next now to Catherine Novack of JonesTrading.

My question is around how are you prioritizing the 3 non-oncology assets that you're moving forward into IND filing this year? If you had to pick, which indication is most exciting to you at this time?

Catherine, I'll answer that the same way I often do, which is I'm now up to 4 grandkids. And they each have their wonderful traits and I love them all. But the prioritization, we're in a fortunate position, where because of our strong balance sheet and our build of the company that we're not at a position where we have to prioritize them. We are able to move all of those forward at their natural pace. And at the moment, while clearly 9682 is in the lead, we'll be filing that IND very shortly. There's a bit of a race between the PTH antagonist and the TSH antagonist, and it looks like TSH is catching up a bit. And then ADPKD is working in the background. I just saw you wrote a note about ADPKD. And it hit my inbox as this was starting. So I'm looking forward to reading it. Thank you.

We'll go next now to David Lebowitz at Citi.

John on for David. For the atumelnant and Phase II data, just curious, what is the current thinking behind the lack of observed dose response in the 17OHP decrease across all the doses? I understand that A4 was the primary endpoint. But just given the fact that 17OHP plays an important role as an intermediate hormone, just interested to hear what the latest thinking is on that data point.

Thanks very much for the question. 17 hydroxyl is a very variable biomarker even in the clinical care of these patients and particularly when you use it to try and assess adequacy of care in clinical practice. I feel like both biomarker responses, including the more variable 17-hydroxyprogesterone are pretty impressive. And I take a lot of learnings from the fact that we actually in this very short study see clinical outcome benefits. And in that kind of situation, we no longer need to rely on the exact amount of surrogate biomarker reduction. We know it's unprecedented magnitude compared to other therapies in the past. And it's very difficult to achieve those kinds of reductions with glucocorticoids alone, which is why we'd like to think of atumelnant as ultimately, hopefully, the treatment for CAH, whereas glucocorticoids just used at low doses for replacement.

But I will say I was looking earlier this week with the group at some of the exposure response modeling. And I don't think I agree with you. I think there is a nice exposure response with both 17-OHP and A4. So although, as Alan said, 17-OHP is a bit more variable.

We'll go next now to Rohan Mathur at Oppenheimer.

This is Rohan on for Leland Gershell. Just one for me on paltusotine. Just given the use of adrenal steroidogenesis and acromegaly in patients with neuroendocrine tumors. How do you think about carcinoid from a commercial standpoint as there may be some overlapping call points and complementary dynamics once it's potentially made available in both indications?

Yes. Thank you. I think there are a couple of areas of synergy there. One, from a geographic point of view, the oncology centers of excellence and the pituitary centers of excellence are geographically overlapping. And so, there are some efficiencies there. I also think that our growing experience in acromegaly provides additional safety confidence for the patients with neuroendocrine tumors, which I'll remind folks are things that are really becoming a chronic disease in many ways, so long-term safety is, of course, important. There's an interesting dynamic to note outside the U.S., which is in many of the countries in Europe, unlike the U.S., the prescribers who manage the acromegaly patients overlap more frequently with those that are managing neuroendocrine tumors. So for example, investigators of ours in the U.K. and some in Germany have many more neuroendocrine tumor patients than they do acromegaly patients, but they see both. So the beginning experience in one population helps them understand how they might use it in another later. So I think overall that people are used to using somatostatin analogs for both, and paltusotine is a next-generation somatostatin analog or ligand, excuse me.

We'll go next now to Andy Chen of Wolfe Research.

I think it was Isabel during the prepared remarks that mentioned that payers are very supportive of the value proposition of paltusotine. Can you discuss which features of the product they are the most excited about? So especially now that we know that Cipla will be back to the U.S. market against Ipsen in this quarter? And then I hear that generics will launch in Europe in the second quarter. Wouldn't payers be more excited about those generics a lot more? Or do you think those are just basically non-factors in the grand scheme of things?

Yes. I do think that in general, the generics or 501 equivalents are really just the next generation. And the long-term small changes to the injectables. And I don't think that that provides the next generation of care that paltusotine provides. So let me let Isabel answer in a little more detail, though.

Yes, Scott, that's right. Currently, with the injectables, you see a significant discontinuation rate and lack of adherence to treatment, which many of the payers consider almost wastage, because in theory, you are reimbursing for those treatments but you are not getting the efficacy you are expecting to get. Also, the coverage, whether it's a generic or a branded product, the injectables tend to lag towards the last week of the 4 weeks of treatment, and many of the patients continue to have breakthrough symptoms. We have done some economic analysis that shows that many of those patients end up having to have surveys and continue to have pain. So overall, the payers see this as an improvement on the standard of care. They are very positive about the sustainability of effect, the rapid action because we also see an injectable that sometimes it takes a long time to find the right dosage, which is not the case here. And this is really transforming the standard of care. So we are very pleased with how they are appreciating the value proposition of the drug.

We'll go next now to Brian Skorney of Baird.

This is Charlie on for Brian. Just touching on the PTH antagonist, it would be great if you could tell us more about the landscape there in terms of how patients are usually treated as well as what you believe the antagonist could offer over that as well as when you think about the 200,000 incident cases. How many of those would you expect to be addressable with this compound?

Thanks very much. Yes, a PTH antagonist for clinical use would be a very novel opportunity for patients with primary hyperparathyroidism. Right now, the major treatment option is surgical removal of the overgrown parathyroid adenoma, which usually causes this disease. That is curative much of the time. However, unfortunately, there are a lot of patients with this disease, as you mentioned, and many of them do not get surgery. There is no true medical option for the treatment of hyperparathyroidism. There is Cinacalcet which is approved. Cinacalcet, however, has only been shown to resolve or improve one aspect of this condition, that's the hypercalcemia or elevated calcium levels. But hyperparathyroidism is a multi-organ disease that affects the bones and the kidneys adversely. Cinacalcet, although approved, has never been shown to help the kidneys or the bones. We really need a medical option for the treatment of this disease. And in theory, a PTH antagonist could help all of the end organ damage that we see in this condition.

Yes. And I think this is the case also as we start thinking more about PTH, where I want to spend some time talking to the community in more detail about these programs so that people can begin to appreciate it. I know most of our conversations with various investors and analysts have to typically stop at the phase. But we are planning on putting together an R&D Day this spring or early summer to try and provide more clarity. And I think the other thing about PTH is that it's one of those that together with neuroendocrine tumors has started to become more personal. So as we address more and more of these diseases, I'm meeting employees or family members that are suffering from these. And we're starting to hear some of the first-hand experiences and challenges that they're facing, which always brings this home. And so as we think about PTH, I think it's a great example where you got to think of us as trying to really transform the treatment paradigm for the disease. And maybe there's a better way to manage patients while they're either waiting for surgery or maybe they're not the best surgical candidate or maybe there's just not a good surgeon nearby. So I think we can do something special with PTH.

And ladies and gentlemen, that's all the questions we have today. Dr. Struthers, I'd like to turn things back to you, sir, for any closing comments.

No. Thank you, everybody, for your questions and your hard work. We appreciate all of you and look forward to talking to folks in the coming hours and days. Take care.

Thank you, Dr. Struthers. Again, ladies and gentlemen, that will conclude Crinetics Pharmaceuticals fourth quarter and full year 2024 financial results call. Again, thanks so much for joining us, everyone, and we wish you all a great remainder of your day. Goodbye.