Crinetics Pharmaceuticals, Inc. Q4 FY2025 Earnings Call

Welcome to Crinetics Pharmaceuticals Fourth Quarter and Full Year 2025 Financial Results Conference Call. I would now like to turn the call over to Gayathri Diwakar, Head of Investor Relations. Please go ahead.

Thank you, operator. Good afternoon, everyone, and thank you for joining us to discuss the fourth quarter and full year 2025 results. Today on the call, we have Dr. Scott Struthers, Founder and Chief Executive Officer; Dr. Alan Krasner, Chief Endocrinologist; and Tobin Schilke, Chief Financial Officer. Also joining for the Q&A portion will be Isabel Kalofonos, Chief Commercial Officer. Please note, there's 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. In particular, today, we will be reviewing launch progress to date, our commercialization plans as well as estimates relating to market size, future performance and other data about the acromegaly market, which are all necessarily subject to a high degree of uncertainty and risk. 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's accurate only as of this live broadcast. 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 hand the call over to Scott.

Thank you, Gayathri, and thank you all for joining us today. 2025 was a breakout year for Crinetics. We're transitioning from building a pipeline to building a business. In 2025, we successfully launched our first commercial product with a label that reflects its ability to become the preferred medical treatment for acromegaly. PALSONIFY uptake continues to grow. We presented compelling Phase II data on our second late-stage candidate that illustrates its potential to be the preferred medical treatment for congenital adrenal hyperplasia or CAH and in Cushing's disease. Atumelnant Phase III studies in both adult and pediatric participants with CAH are underway. And today, we will tell you about its Phase II/III study in Cushing's disease. Finally, the first candidate from our new non-peptide drug conjugate program, CRN09682, has begun the dose escalation phase of a Phase I/II study in a broad basket of people with SST2-expressing tumors. With this growing pipeline and the support of our strong balance sheet, we are now focusing on building a successful commercial business that will grow into the leading endocrinology company. Turning to Slide 5. Before I turn the call over to Alan to talk about the atumelnant development program in Cushing's disease, let me take a few minutes to review results from the PALSONIFY launch. As we previously shared, in Q4, we received more than 200 enrollment forms. As a reminder, this included all 22 U.S. participants in the open-label extension studies of the clinical program. We're effectively getting the word out about PALSONIFY. More than 125 unique prescribers in both community and pituitary treatment center practices have entrusted the treatment of their patients to PALSONIFY. Finally, we're making significant progress with payers. As we announced in January, we are seeing early and encouraging formulary momentum. Payers recognize the transformative value we're bringing to the acromegaly community. We are already securing wins with some of the top plans in the country adding PALSONIFY to their formulary with straightforward prior authorization written directly to our label and no step edits. In the interim, we expect to continue seeing reimbursement through the medical exceptions process for patients from all payer types, including all government payers. Turning to Slide 6. With the launch of PALSONIFY in the U.S., we have built a fully integrated and highly capable commercial enterprise. Our sales professionals are in physician practices educating about PALSONIFY and the services Crinetics provides to patients and offices, including help from our nurse educators and field reimbursement specialists. Our efficacy-first messaging shown on our HCP site on the left side of this slide is resonating with health care providers, and they understand the importance of symptom control as well as biochemical control. Our medical affairs team is there to help with deeper scientific and medical support for providers. We're presenting data on PALSONIFY in the rest of our pipeline at regional and international endocrinology conferences every month. CrinetiCARE is online and staffed by nurses to help patients navigate their acromegaly health care. Our first patient ambassadors, 2 of whom are shown on the right side of this slide, have been deployed to provide patient-to-patient conversations and testimonials. Our market access team is ensuring that all patients can get access to PALSONIFY. I'm very proud of the great team we've built and their passionate dedication to serving our patients. Every day, they're working hard, spreading the word and helping people with acromegaly get access to PALSONIFY. Our goal for PALSONIFY is to become the new standard of care for people with acromegaly, and we are well on our way. But this is about more than just the launch of PALSONIFY. This is about building, testing, refining and honing an enterprise to launch many new innovative pharmaceuticals to come from our pipeline. This is the core of the team that will launch paltusotine for the treatment of carcinoid syndrome, atumelnant for CAH and Cushing's and our other pipeline candidates pending their own approvals. As I said, we're now in the stage of building a sustainable business to create, develop and deliver novel therapeutics using the tools of endocrinology. With that, I'll hand it over to our Chief Endocrinologist, Alan Krasner, to talk about the pipeline and the upcoming Cushing's study in particular. Alan?

Thank you, Scott. As seen on Slide 8, our late-stage pipeline is guided by compelling science and the ability to develop innovative candidates in-house. My very talented colleagues at Crinetics design novel molecules, which are rationally aimed at the key targets of endocrine disease. These drug candidates have consistently demonstrated the intended pharmacology in healthy human volunteers and in patients. Paltusotine is already approved in the U.S. for the treatment of acromegaly, and we are in Phase III evaluating paltusotine for the control of carcinoid syndrome. We are also actively enrolling patients in both the later-stage studies of atumelnant in adult and pediatric patients with congenital adrenal hyperplasia, or CAH, and in the Phase I study of our novel non-peptide drug conjugate, CRN09682 in patients with SST2-expressing tumors. Today, I want to focus on atumelnant and why we believe ACTH antagonism is a very promising approach for both CAH and ACTH-dependent Cushing's syndrome or ADCS. ADCS is a rare but devastating disease that endocrinologists will tell you is among the most difficult diseases to treat medically. The multitude of symptoms and disfiguring physical changes that occur in the body can be overwhelming. If untreated, ADCS results in significant morbidity and premature mortality. We hear from patients with ADCS that they feel a profound loss of control, which may reflect the unstable nature of this disease characterized by unpredictable exacerbation patterns. There are also often difficult years leading to a clear diagnosis followed by cycling through many different treatment options, not to mention unrelenting financial, psychological, physical and emotional burdens. Many patients with ADCS are very sick and the risk-benefit profiles of existing medical therapies are not ideal for the long-term control of this disease. Although the first-line treatment for ADCS is an attempt at surgical removal of the positive tumor, many patients are not cured by surgery. Uncured patients typically undergo attempts at medical therapy, but predictable prevention of disease exacerbation cycles at tolerable doses can be difficult to achieve. Often, patients need to undergo repeat pituitary surgeries, radiotherapy or in the most severe cases, bilateral adrenalectomy. There remains a significant unmet need for a simple and reliable medical treatment for this life-threatening condition. This is why we are eager to proceed with the research necessary to evaluate whether atumelnant might represent a significant step forward for the many patients who have been waiting for a new dependable approach. Moving on to Slide 10. Here, we see a more detailed view of the cause of ADCS and atumelnant's mechanism of action. Cortisol is an essential glucocorticoid hormone produced in the adrenal glands. Its main purpose is to make it possible for our bodies to cope with any kind of stress, including illness or injury. Although we can't live without it, if we are exposed to too much cortisol, we can get very sick. Exposure to too much cortisol or cortisol-like medication is called Cushing's syndrome. Cushing's syndrome is most commonly caused by taking too much exogenous glucocorticoid prescribed for a variety of conditions. However, Cushing's syndrome can also arise from endogenous or spontaneously occurring causes. Most endogenous Cushing's syndrome is caused by overproduction of ACTH by pituitary gland tumors. The normal function of ACTH is to stimulate the adrenal glands to produce more cortisol, and it stimulates growth for the gland. Sometimes tumors that secrete too much ACTH arise outside the pituitary gland. When this happens, it is called ectopic ACTH syndrome. The key driver in both pituitary disease and ectopic ACTH syndrome is ACTH. Together, these conditions are called ACTH-dependent Cushing's syndrome. These tumors secrete ACTH autonomously, which means they do not depend on CRH secretion to drive disease, and therefore, ADCS would not respond to CRH receptor blockers. For nearly a century, since the discovery of ACTH, blocking the ACTH effect at the adrenals has been a long-sought fundamental treatment target for ACTH-dependent Cushing's syndrome. Atumelnant is a once-daily oral tablet and is the first ACTH receptor antagonist tested in humans for the treatment of ACTH-mediated disease. As you know, we have already reported promising Phase II results from the studies evaluating atumelnant for the treatment of another ACTH-mediated disease, congenital adrenal hyperplasia. But now let's focus on ADCS. Turning to Slide 11. In June 2024, we reported initial results from an ongoing collaboration with colleagues at the NIH. In this single-center Phase Ib/IIa study, participants with active ADCS were initially treated with 80 milligrams of oral atumelnant once per day for 10 consecutive days with frequent measurements of biomarkers. These biomarker assessments included 24-hour urine collections for free cortisol, or UFC, which is the recommended primary endpoint for registrational trials in Cushing's disease. UFC responses occurred within days of starting atumelnant. The magnitude and speed of efficacy in this disease is unprecedented and if confirmed in longer-term trials, atumelnant could represent the single and reliable medical treatment greatly needed by people suffering with ADCS. In the NIH study, atumelnant was generally well tolerated. All patients experienced a decline in serum cortisol below 5 micrograms per deciliter. Although these patients were minimally symptomatic, they were promptly started by protocol on low-dose physiologic oral cortisol, otherwise known as hydrocortisone replacement therapy. All patients did well with no worrisome episodes of acute adrenal insufficiency, and most patients at the end of treatment still had normal urine free cortisol levels, even though they were taking small amounts of exogenous cortisol. Currently available cortisol-lowering drugs can cause glucocorticoid deficiency, and some patients develop unpredictable episodes of acute adrenal insufficiency. For this reason, many physicians who treat ADCS are becoming increasingly interested in a proactive block and replace approach, in which low doses of glucocorticoid are started earlier rather than later when initiating Cushing's medications. The idea is to prevent potentially dangerous episodes of adrenal insufficiency rather than waiting for them to happen. Determining what is the best way to replace glucocorticoid with atumelnant treatment is an important consideration for our clinical development program. As in our acromegaly program, we strive to not only assess biochemical biomarker responses but also the overall patient experience in our studies. We saw that participants in the NIH-ADCS study experienced improvement in many of the myriad symptoms of Cushing's even within the short treatment duration of that study. Since reporting these initial data, additional doses of atumelnant have been explored at the NIH. We look forward to sharing these newer results at an upcoming medical meeting. We will also be initiating an operationally seamless global Phase II/III study in the first half of this year, the design of which I will now review. EQUILIBRIUM ADCS is a seamless Phase II/III study, which allows us to capture the many operational efficiencies of continuing sites opened in the Phase II part of the study into the Phase III part. The purpose of the Phase II is to evaluate safety and efficacy of a range of doses of atumelnant in patients with active ADCS over a treatment period of 3 months. Based on our short-term dosing data from the NIH study, it looks like a simple single dose of atumelnant would very effectively and rapidly correct the excess cortisol output from the adrenals in most patients with ADCS. Now that we are entering Phase IIb, it is important to confirm this with longer-term dosing and to identify the right dose of atumelnant to use in the confirmatory Phase III part of the study. You can see that we are testing the dose range of 20 to 80 milligrams per day of atumelnant in the Phase II segment. We are testing lower doses than those used initially in the proof-of-concept NIH study, and this is a testament to the potency of this unique mechanism of action. The 20-milligram dose is being studied in an open-label arm in which glucocorticoid replacement can safely be used reactively only if needed based on the occurrence of a low serum cortisol result. The 40-milligram and 80-milligram doses will be evaluated in a randomized placebo-controlled segment of Phase II. At these higher doses, we will be evaluating the utility of a proactive approach in which glucocorticoid replacement and atumelnant will be initiated at the same time. Based on the results of the Phase II part of the study, an atumelnant dose and glucocorticoid replacement paradigm will be selected for the Phase III part. The Phase III part is powered to show a statistically significant difference in 24-hour urine-free cortisol output between the active treatment arm compared to the placebo arm. An open-label extension or OLE long-term treatment segment is also included in the study. Overall, the EQUILIBRIUM ADCS study is designed for efficient and comprehensive assessment of the safety and efficacy of atumelnant in the treatment of ADCS, a disease which historically has been among the most difficult to treat medically. We believe moving the century-old treatment paradigm forward is long overdue for these patients, and we are excited to get this important study started in the first half of this year. With that, I'll turn it to Toby to walk through our financial results.

Thank you, Alan. Turning to Slide 14. Our financial results for the fourth quarter 2025 reflect our continued disciplined execution and strategic investment in advancing our pipeline and commercialization of PALSONIFY. In the fourth quarter, we recognized $6.2 million in total net revenue, consisting of $5.4 million in net product revenue from the U.S. commercial launch of PALSONIFY and $0.8 million from our licensing agreement with our Japanese partner, SKK. Our total revenue for full year 2025 was $7.7 million. Cost of product revenue in the fourth quarter was $1.1 million. Prior to PALSONIFY's approval in September, manufacturing costs were expensed through R&D as 0 cost inventory. To date, we have only distributed 0 cost inventory and expect to continue to do so for the next several quarters. The cost of product revenue from this quarter relates to the expansion of our commercial manufacturing capacity as well as the distribution and fulfillment costs of PALSONIFY. Our research and development expenses for the fourth quarter were $85.1 million compared to $90.5 million in the third quarter. The decrease is a result of start-up costs for our ongoing clinical studies that were recognized during the third quarter. Selling, general and administrative expenses were $53.7 million for the fourth quarter, generally steady compared to the $52.3 million in the third quarter since our field force, commercial team and corporate functions were already in place prior to approval. We used $326.2 million of total net cash for the full year 2025, reflecting continued clinical development and commercialization activities. This result was favorable relative to our guidance range of $340 million to $370 million, primarily due to working capital timing and a modest increase in cash flows from employee option proceeds during the fourth quarter. We ended 2025 with over $1 billion in cash, cash equivalents and investments. This does not include the net proceeds of $380 million from our January 2026 public offering. Immediately after our January 2026 public offering, our cash, cash equivalents and investments totaled approximately $1.4 billion. As of February 13, 2026, we had approximately 104.7 million shares of common stock outstanding. On a fully diluted basis, we had 121 million shares outstanding. This includes our outstanding options, unvested restricted stock units and shares expected to be purchased under our employee stock purchase plan. Moving to Slide 15. For 2026, we expect GAAP operating expenses to be between $600 million and $650 million. We expect non-GAAP operating expenses, which exclude cost of revenue, stock-based compensation, depreciation, and amortization to be between $480 million and $520 million. The anticipated increase in operating expenses relative to 2025 reflects the ongoing investment in the recently initiated clinical trials as well as the inclusion of a full year of commercialization activities supporting PALSONIFY. Based on our current operating plans and cash position, we believe that existing cash and investments will be sufficient to fund our operations into 2030. This provides us with significant runway to execute on the commercialization of PALSONIFY, pivotal readouts for the ongoing clinical trials in carcinoid syndrome, adult CAH, pediatric CAH and ADCS and to achieve proof-of-concept for CRN09682. I'll now turn the call back to Scott for some closing remarks.

Thank you, Toby. To wrap up, Crinetics is well positioned for an exceptional 2026. We're simultaneously executing across our entire portfolio. We're driving the U.S. launch of PALSONIFY while actively advancing our global regulatory path. On that front, we're pleased to announce that today, we received a positive CHMP opinion for PALSONIFY in the treatment of acromegaly, a milestone that reflects both the strength of our data and the potential benefit for patients in the EU. In addition, we continue advancing clinical trials of paltusotine, atumelnant and our novel non-peptide drug conjugate CRN09682 across multiple endocrinology and oncology indications. Finally, in discovery, we're rapidly advancing our early-stage assets to fuel the next wave of growth. We remain committed as ever to transforming the lives of people with endocrine diseases and creating long-term sustainable value for all of our stakeholders. Finally, I'd like to say that 2025 was a great year. Thank you to everyone who helped us achieve our most substantial year yet. With that, I'll turn it back to the operator to begin Q&A.

First question comes from Maxwell Skor with Morgan Stanley.

Congrats on all the progress. So now that you've outlined the Phase II/III design today, were there any key learnings from the Lancet's GRACE data or the FDA's relacorilant CRL that informed how you're thinking about clinically meaningful endpoints or just overall study structure?

Thanks, Matt. I'll let Alan handle that question. Thank you.

Well, actually, so the basic structure of a Cushing's disease study is well precedented. The primary endpoint, for example, is known to be normalization of urine-free cortisol for drugs in which you can measure cortisol as the biochemical marker for Cushing's disease activity. Relacorilant and other glucocorticoid receptor antagonists actually prevent endocrinologists from using cortisol as a marker of activity because they block the glucocorticoid receptor and result in compensatory rises in cortisol. So it's a different metric, I would have to say. In the case of the glucocorticoid receptor antagonist, you have to use sort of downstream surrogates like measuring the improvement in glycemia that can be seen when you treat Cushing's. In our case, I think we can measure both cortisol itself as well as important corollary clinical outcome benefits like improvements in glucose and improvements in blood pressure, et cetera.

We now turn to Yasmeen Rahimi with Piper Sandler.

Congratulations on the initiation of the EQUILIBRIUM study and its innovative design. I would like to ask about PALSONIFY. Can you provide some insights on how starting scripts developed in January and February? Did you observe any trends from December to the beginning of the year? I will return to the queue afterwards.

Yes. Thanks, yes. Look, I'm super pleased with the launch of PALSONIFY. I'm particularly pleased by the stories we're hearing back from prescribers and patients and the real-world experiences that are starting to accumulate. And I think you'll start hearing about those experiences now that people are out there starting to think about case series and other types of reports, and I look forward to that throughout the year and in the coming years, actually. So I don’t really want to get into quantitative comments on trends for the quarter. It's still early days, and we have a lot of work to do. But generally, I'm very pleased that patients are starting to benefit from the hard work we put into this for the last many, many years.

Yes, Yasmeen. We are very pleased because our strategy is really resonating. Efficacy first is an important message for us. And what we are hearing back from physicians and patients is that particularly the fast onset of action and the symptom control are resonating. The fact that it works in 2 to 4 weeks is really allowing the physicians to have an early positive experience as well as the patients. So we are focusing on execution across the board, activating the patients, activating the physicians and continue to engage with payers successfully. Thank you.

We now turn to Alex Thompson with Stifel.

Congrats on the quarter as well. Maybe as a follow-up here, could you comment as to whether you think sort of this 200 enrollment form that you recorded in 4Q is a reasonable run rate moving forward? Is that a bolus? Or are you seeing consistency with what you saw in 4Q? And if you're not able to sort of answer that, can you talk about the sort of time from enrollment form to commercial therapy?

Yes. Toby, why don't you respond?

I believe it’s too early to make any comments regarding whether the 200 enrollment figure can be considered a consistent rate moving forward. We are quite pleased with that number, especially given the various challenges and advantages we face. At the start of our launch, some patients transitioned from our open-label extension program to commercial supply. Additionally, we expect to gain continued momentum through increased field interactions in the future. Regarding your second question about the time it takes from the Quickstart patient program, could you elaborate on that?

Yes. I guess from when you receive an enrollment form to when you're getting on reimbursed therapy or on Quickstart, how long is that?

Yes. We haven't really guided to that. What we're really pleased to say right now is that at the initial point of kind of measurement, about 50% of patients are reimbursed for commercial or Medicare and Medicaid and the other 50% go on to that Quickstart program. We have a few touchpoints along that way. And because it's relatively early days in the launch, it's difficult to predict how long those patients will come off Quickstart and be on reimbursed care. But the first bottle they get is for 30 days, and then we have check-ins every 15 days thereafter.

We now turn to Tyler Van Buren with TD Cowen.

Congratulations on the progress and I appreciated the remarks about ADCS. I would like to hear more about the launch focusing on the medium term rather than the short term. Over the course of the year, what do you anticipate the pace to look like? Will it be inconsistent due to being a unique launch, or do you expect it to follow a more steady or rapid growth pattern as the year ends? I'm interested in your insights regarding this. Additionally, since you mentioned the zero-cost inventory, could you provide an estimate of the sales level that inventory represents?

Yes. Thanks, Tyler. So I did a lot of biophysics earlier in my career, and we were trying to fit curves to data points. And I can say I suspect it will be lumpy, but I don't think there's enough data to start fitting an exponential or a linear curve to this yet. The team is out there every day. We're getting great uptake around the country with a broad set of prescribers, and they're getting more comfortable with it. But we've got other things coming up. We had a pretty good snowstorm this last week, and that showed up a little bit. So I think it will be lumpy. And we're experimentalists at this point, not theoreticians. Do you want to comment a little more, Isabel?

Yes. We are on target for our goal to become the #1 acromegaly treatment in the future. And we are continuous in our execution that we had described before. First, we are focusing on the switching of the market and naive patients. Then we want to focus on expanding the market. We don't only want to have patients on PALSONIFY, but we want to help transform care and elevate care as a premier endocrinology company that we want to be. We want to be the partner of choice. So many patients have lost hope and are not on treatment that we think we can bring them back. So as physicians and patients gain experience with our drug and given that the drug is delivering better, even better in the clinical trials in the real world, we expect that we'll be able to continue to expand the marketplace.

And maybe to your second question, Tyler, on the cost of product revenue. I'm so glad you asked that question. It always makes the CFO happy. And we have a little bit additional detail on our Form 10-K that we just recently filed. So as you would note in our income statement, we have about $1 million of cost of product revenue noted in the fourth quarter. And in Page 72 and thereafter on our Form 10-K, we broke that down a little bit more, and we said that there was about $826,000 related to manufacturing readiness and a second supplier qualification and then another $250,000 of that $1 million allocated towards sort of packaging, distribution fulfillment. We noted also that there was less than $100,000 related to the 0 cost inventory that I referred to in my prepared remarks. So looking forward, we kind of expect cost of product revenue, if you were to do apples-to-apples, you would see of that $5.4 million, we would see about that $250,000 in that less than $100,000 of being cost of product revenue.

We now turn to Gavin Clark-Gartner with Evercore ISI.

This is Yesha on for Gavin. Just a quick one on PALSONIFY. We were just wondering how payer dynamics are looking so far? And specifically, if you're noticing any significant pushback on the payer side or new cadence in terms of step edits to get on PALSONIFY?

Thank you. So we are very pleased with how market access is progressing, and we don't see real barriers to treatment. So that's very positive. We have most of our coverage already based on our label. So our prior authorizations are proceeding, and we are proceeding well with medical exceptions as well. So we continue to monitor the marketplace and engage with the payers. And if we ever have any step edit, we moved very quickly from the coverage of treatment to a clinical review, and that has moved very fast in the process. So, so far, as we announced in fourth quarter, 50% of the claims have been reimbursed and 50% of them moving to Quickstart. And we remain committed to move that Quickstart in less than the average of rare diseases less than 57 days.

We now turn to Brian Skorney with Baird.

This is Luke on for Brian. So on the ADCS study, there's a mention that the Phase III endpoints may change based on Phase II data. I suppose is that something that's agreed on in advance with FDA? And can you help us understand what would trigger this change?

Yes, thank you for the question. One of the primary objectives of the Phase II part is to determine the appropriate dose for Phase III. In Phase III, we will conduct a traditional prospective parallel group, placebo-controlled comparison trial. The primary endpoint, which is largely defined by the FDA, is the percentage of patients who achieve a normal urine free cortisol level at the conclusion of treatment. This involves a 24-hour urine collection to measure the overall output of cortisol during that time. The study needs to demonstrate a statistically significant increase in the proportion of patients who reach this goal on the drug compared to placebo. The key takeaway from Phase II will be the dosage. However, it is very unlikely that we would alter that primary endpoint for Phase III.

Our next question comes from Joe Schwartz with Leerink Partners.

Thanks for the update. I was curious about CRN09682 and would like to know how you are selecting patients for the BRAVESST trial. Do you have a working hypothesis regarding specific biological factors that may lead to a better response based on their disease progression or SST receptor density? Have you found any signals in preclinical data? Additionally, how do you see this relative to current treatment options?

Thank you, Joe. I must say that CRN09682 is currently my top priority. We've invested a lot of effort into its concept, development, and optimization. Patient selection is quite straightforward. We are conducting a basket study involving various patients with somatostatin 2 receptor-expressing tumors. The main requirement is that they must show higher tumor density than the liver on a somatostatin PET scan, and they should have progressive disease; otherwise, there would be no reason for them to join this clinical trial. We are pleased with the strong response from the community and there is always a queue of patients for screening. We are progressing through this process. In our preclinical models, we've demonstrated impressive data, particularly with small cell lung carcinomas, which are high-grade lung neuroendocrine tumors. We have explored other tumor models as well. While many researchers have achieved tumor cures in mice, we are now focusing on these different tumors in human patients. We designed this study to be broad because we want to ensure we capture various patient populations that could benefit. It's important to note that we are looking beyond just neuroendocrine tumors, which can range from slow-growing grade 1 or 2 tumors to more aggressive grade 2 or 3 tumors, including neuroendocrine carcinomas such as small cell lung cancer. We will also consider patients with meningiomas, which are nearly always somatostatin receptor positive and often challenging to treat. Additionally, we may explore HR-positive breast tumors and head and neck tumors. As we progress through dose escalation and define the tolerability profile, we anticipate seeing some initial signals, but we are particularly focused on identifying clear signals in the expansion cohorts. Our trial design permits us to include any patient with SST2-positive tumors.

We now turn to Jon Wolleben with Citizens.

A few on EQUILIBRIUM. Wondering how you're thinking about disclosure data from the Phase II before the Phase III, if the same patients are going to be able to roll over? And if you discussed at all with FDA, a randomized withdrawal design and any advantages or disadvantages to what you landed on here?

Thanks for the question, Jon. So actually, the Phase II part is the ADCS study is a 3-month treatment experience. And when they finish that, they would be eligible to roll directly into an open-label extension study, those patients. When we get into Phase III, the same thing, it will be new patients who would also, when they complete that treatment period, be eligible to roll into the same open-label extension. We have certainly looked at the history of development of drugs for Cushing's and randomized withdrawal has been done in the past. For example, LINC 3 was one of the registrational trials for osilodrostat. A lot of methodologic problems with that kind of study design. I think most in the regulatory community would consider what we're planning here, a prospective parallel group trial, placebo-controlled as sort of the most definitive demonstration of drug safety and efficacy. There are carryover effects to worry about in randomized withdrawal designs that you do not have to confront here. I think this is just a cleaner study.

Our next question comes from Katherine Dellorusso with LifeSci Capital.

Congrats on the quarter. Maybe another one from us on the BRAVESST study. Just a couple of questions. I guess if you could comment on what we can expect from an initial data readout here in terms of metrics and cohorts we can expect to see. And then maybe on the bar for safety, what are your internal benchmarks that you're striving for? And I guess, how does that relate to whether or not you pursue a PRRT naive versus experienced patient populations going forward?

I'll handle the last part, and you want to address the first part, Alan? I don't believe that PRRT is a prerequisite or particularly relevant for CRN09682. PRRT is beneficial and shows that somatostatin-targeted therapies are quite significant for these groups. However, it's not suitable for everyone, and it can be challenging to obtain. Therefore, we are not requiring individuals to go through it. I just want to emphasize that this therapy is much more accessible compared to radiotherapy.

In a Phase I oncology trial, you typically enroll patients who have already undergone other therapies, including treatments like PRRT. These patients are often out of standard options at this stage. I agree that in theory, with time, this mechanism of action could evolve into a non-radioactive version of PRRT, possibly used at earlier treatment stages than typically assessed in Phase I trials. Currently, we are in the dose escalation phase of the study. Traditionally, in an oncology study, we would stop once we reach the maximally tolerated dose, but nowadays, that is not always necessary. Our primary endpoint for this part of the study is to evaluate safety and tolerability. We aim for it to be well tolerated for several reasons we have discussed, which suggest this approach could yield an effective and well-tolerated therapy. Additionally, as part of the clinical care for these patients with advanced cancers, they will undergo regular imaging studies, such as CT or MRI scans, to monitor tumor size. We will follow formal RECIST criteria to assess stable disease, partial responses, or any other classifications based on these standards. This process will take time as many tumors grow slowly. However, we anticipate gathering enough data from this dose escalation study to transition into the expansion phase, where we will enroll more patients likely to respond, including those with non-neuroendocrine tumor SST2-positive tumors, such as meningioma. I hope that clarifies things.

We now turn to Dennis Ding with Jefferies.

I have 2 on CRN09682. Number one, what's the big picture strategy here? And I'm curious if you plan to be a major player in oncology. Like if you see good activity in HR-positive breast cancer or small cell, is that an area you would move aggressively into? Or is your priority to remain mainly in endocrinology and in endocrine-related tumors? And then number two, for the Phase I, I'm assuming you'll get a lot of net. So how does SST2-expression change in the second and third line? And if there's any difference in patients who have had experience with LUTATHERA versus those who didn't? And if you can comment on the ORR for chemo in this late-line setting that we should be thinking about once you go into dose expansion, that would be helpful.

Yes, this is Scott. I'll provide an overview and then pass it to Alan for further details on expression. I'm intrigued by the idea of using small molecule targeting for different payloads, as it presents key advantages over antibody or peptide targeting. With antibody targeting, you face limitations related to circulation time, the epitopes you can target, and suitable bioconjugation reactions for linkers and payloads. These challenges vanish when using small molecule chemistry like CRN09682. We were pioneers in this approach within the radiotherapy field and established Radionetics, which is performing well. Now, we're advancing in the non-peptide arena, starting with neuroendocrine tumors. Most patients in routine care for radiotherapy are neuroendocrine tumor patients, and that demographic is expanding rapidly. Our strategy is to let science and medicine dictate our direction. I anticipate expanding beyond our focal point of neuroendocrine tumors, which aligns perfectly with our carcinoid syndrome program. In discovery, we're just beginning to tap into this platform, and I envision additional payload types, possibly targeting SST2 first, since this payload might not be suitable for all SST2-expressing tumors. We're also investigating various targeting methods because GPCRs that interact with these peptide hormones are often challenging to target with antibodies. We’re looking into different payloads and exploring new possibilities, making this a vast area of research, and I'm excited about its potential. I spoke for a bit, Alan, would you like to discuss the line of therapy and expression?

Yes, that's a great question. Is there any change in SST2 receptor expression over time as patients undergo different treatments? I can tell you that one of the eligibility criteria for this Phase I study is positive SST2 receptor expression as confirmed by clinical nuclear medicine imaging studies. This means we know the receptors are still present in our patients. Generally speaking, it may vary depending on the type of tumor, but for well-differentiated neuroendocrine tumors, the SST2 receptors typically remain for a long time.

We now turn to Catherine Novack with Jones.

Thinking about CAH, now that prescribers have had about a year of experience with chronicity, are you hearing anything from them about reimbursement or price point? Do you anticipate having similar pricing power when it comes to your launch in CAH? And similarly, do you anticipate having different price points for pediatrics and adults? Just wondering what we can learn from their launch so far.

Yes. Thanks, Catherine. I think it's premature to really think about pricing at this point in the game. But we're definitely doing our work to make sure we illustrate the full potential value of the molecule in our clinical program. What I can take away from the CRENESSITY launch is it's the first new drug for CAH since glucocorticoids, and it's been doing quite well. And I think there's a hunger for new agents. And I think that based on the pharmacology we've seen so far, atumelnant will be able to do things that no other agents can do for these patients. So I'm excited to expand this in the open-label extension we have going now, where we should have 20-something patients be able to talk about them at some point in the not-too-distant future. But also, I've got great enthusiasm from the investigators I've met and the patient communities I've met for our Phase III program in CAH. And I really look forward to being able to complete that enrollment and start talking about data as soon as we can. We have some more to squeeze from that orange.

We now turn to Douglas Tsao with H.C. Wainwright.

Maybe Isabel, just as a start, I think you indicated that about 50% of patients are initiating therapy on the Quickstart program. I'm just curious if you have any insight or perspective on how we should think about how that might evolve over the next year or a couple of years? Would you anticipate we sort of stay at that level or should it trend down? And then I have a follow-up on CRN09682.

Yes. Over time, the Quickstart program will be less prominent as we get more access, direct access in formularies. So we are expecting that perhaps for the next 18 months, we'll have the program, but eventually transition to just paid treatments. So that's how I see the evolution of the plan.

Thank you, Doug. That's a great question. We remain strongly committed to endocrinology. Please understand that we're excited about the latest drug in our pipeline and eager to see its potential. We're making significant efforts to enhance the endocrine segment of our business. As I've been involved in ride-alongs with our sales team and medical science liaisons, I've realized how beneficial it will be for us to approach healthcare providers and discuss the diverse patient types. There are patients with acromegaly, Cushing's, congenital adrenal hyperplasia, and even neuroendocrine tumors. There's considerable synergy to be gained from this. As we transition from focusing on neuroendocrine tumors and carcinoid syndrome to potentially treating the tumors directly, I'm eager to see where this technology leads us. It's still early, and we're looking forward to seeing how CRN09682 performs and what insights we can gain from it. This represents a new platform for us, and we are laying the groundwork to see positive outcomes in the future.

And our final question today comes from Andy Chen with Wolfe Research.

Just curious if you can comment on your competition growth, recent revenue trajectory in CAH. What do you think is happening here? Do you feel like you have a greater opportunity? Or do you think you have a lesser opportunity given the recent trajectory? Do you think it's slowing down? And if you have any commentary on whether you think certain patient segments are tougher to capture, that would be great.

We don't have a field force speaking with doctors about CAH, so that's more of a question for those involved with that drug. However, I believe the insights we're gaining about acromegaly and the acromegaly prescribers, many of whom also treat CAH patients, along with the capabilities we are developing, can be applied to the CAH patient population. This is part of the overall synergy we aim to create in both our pipeline and in the marketplace by concentrating on endocrinology, which is a focus of Alan's and my entire careers, as well as many others in the company. We've consistently communicated that we are not merely a sponsor introducing a new molecule and planning to leave endocrinology; we are integrated into that community as sponsors of clinical trials and now as sellers of drugs, in addition to our involvement in research and collaborations.

So yes, for me, PALSONIFY is the beginning of the story, and you can see it's a highly differentiated profile all around. And if you start looking at the competitive market in acromegaly, for instance, today, we published in the Journal of Clinical Endocrinology our indirect treatment comparison where we show superiority and a statistically significant superior to a competitor. So we are prepared to deliver as well in our future molecules as well. This is just the beginning.

Ladies and gentlemen, this concludes our Q&A and today's Crinetics Pharmaceuticals fourth quarter and full year 2025 financial results. We'd like to thank you for your participation. You may now disconnect your lines.