Crinetics Pharmaceuticals Inc Aktie

Hello, everyone. Thank you for joining us, and welcome to the Crinetics Pharmaceuticals First Quarter 2026 Financial Results. [Operator Instructions] I will now hand the conference over to Gayathri Diwakar, Head of Investor Relations. Gayathri, please go ahead.

Thank you, operator. Good afternoon, everyone, and thank you for joining us to discuss the first quarter 2026 results. Today on the call, we have Dr. Scott Struthers, Founder and Chief Executive Officer; Isabel Kalofonos, Chief Commercial Officer; Dr. Alan Krasner, Chief Endocrinologist; and Tobin Schilke, Chief Financial Officer.

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.

Slide 2. 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, 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. In addition, this call will include certain non-GAAP financial measures. A presentation of the most directly comparable GAAP financial measures and reconciliations thereto are included in today's news release accessible from the Investor Relations section of our website. 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 review 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.

Thanks, Gayathri. Thank you for joining us on today's call. Moving on to Slide 4. This has been another strong quarter of executing our plan to make Crinetics the premier endocrine company. Crinetics is committed to translating the complexities of cutting-edge endocrinology into real value for patients. And with the launch of Palsonify, we are delivering on that commitment every day. We've made great strides in building the business by consistently adding patients every week to the pool that will be helped by Palsonify for many years to come. The consistent positive feedback we continue to receive from both patients and HCPs is especially gratifying.

We have also meaningfully advanced our deep clinical stage pipeline with 4 major trials running and recruiting nicely. These represent blockbuster opportunities across several areas. And we continue to grow the pipeline with multiple compounds and IND-enabling activities with more to come from our ongoing discovery efforts. We have built a company that has proven it can discover, develop and deliver its own novel therapeutics, and we are well capitalized to continue to execute this growth strategy and drive value creation. I'm very proud of our team's strong execution across all dimensions of the company's first launch. This collective effort has translated into 232 additional patient enrollments and $10.3 million in net product revenue for the quarter. And we are making strong progress with access, including continually driving higher conversion from enrollment forms to patients starting Palsonify and growing reimbursement as coverage on formularies expand.

We expect low discontinuation rates based on our clinical studies. Therefore, the number of patients on Palsonify should continue to compound. We continue to see momentum build on all fronts in the second quarter. While it's early days, we are confident in our growth trajectory. Palsonify sets a new standard of care for the treatment of acromegaly and is on track to become the most prescribed brand. Over the last few weeks, we've continued to advance Palsonify globally, including the European Commission approval of our MAA, the JNDA submission in Japan by our partners at SKK and our MAA submission in Brazil. These milestones underscore the strength of Palsonify's clinical data and the significant unmet need amongst patients around the world. As we expand internationally, we are taking a disciplined market-by-market approach, prioritizing geographies with clear regulatory and reimbursement pathways and pacing investment in line with an increasingly dynamic global pricing and access environment.

All in all, it's clear that Palsonify is positioned to become the leading acromegaly treatment, and Crinetics has an exceptionally equipped team to bring it to the patients in need. With our early commercial success, continued clinical execution and a robust balance sheet to support the advancement of our innovative pipeline, Crinetics is well positioned to generate value for all stakeholders in both the near and long-term.

I'll now turn the call over to Isabel to discuss the Palsonify launch in more detail. Isabel?

Thank you, Scott. Turning to Slide 6. The Palsonify launch continues to build on its strong momentum. I'm incredibly proud of our team. Their execution has led to a strong demand across all patient segments, expanding the breadth and depth of prescribing activity and solid reimbursement coverage. Palsonify establishing itself as a new standard of care in acromegaly, addressing a clear need for an effective, safe and convenient treatment to control the disease.

Moving to Slide 7, starting with patients. As Scott mentioned, in the first quarter alone, we secured 232 new patient enrollment forms. This performance reflects strong execution in the field and demonstrates that we are expanding beyond early adopters and clinical trial transitions to reach the broader acromegaly population. As expected at this stage of launch, the majority of new enrollments continue to come from patients switching from existing therapies. We are seeing meaningful breadth and switching behavior with patients coming from all acromegaly therapies, including lanreotide, octreotide, cabergoline, oral nucleotide and combination regimens. We are very pleased to see that Palsonify is performing consistently across this diverse patient base with physicians and patients experiencing its benefits regardless of prior therapy. Importantly, both controlled and uncontrolled patients have switched to Palsonify, reinforcing its versatility across different clinical profiles.

We are also encouraged by the expansion within treatment-naive patients. From the fourth quarter in 2025 to the first quarter in 2026, treatment-naive patients increased from 5% to 15% of total enrollments. We believe this is a positive signal of growing physician confidence and over time, we expect sustained growth in the share of naive patients. Providers are increasingly viewing Palsonify as a reliable solution across a broad range of patient profiles. As previously discussed, our strategy remains focused on driving adoption among both treatment-naive and switching patients, while expanding the overall market.

Palsonify's differentiated profile, including rapid onset of action in as little as 2 to 4 weeks, sustained symptom and IGF-1 control and convenient once-daily oral dosing positions it well to address key limitations of existing therapies. We are already seeing early signs of this potential. Approximately 15% of first quarter prescriptions came from patients reinitiating therapy after discontinuing prior treatment, which is an encouraging indicator of Palsonify's ability to expand the treatment population over time.

Our patient strategy continues to focus on empowering the patient voice and ensuring early and seamless access to treatment as described on Slide 8. This includes rapid initiation through our Quick Start program and comprehensive health support. We also support patients with a robust suite of services designed to meet patients' needs throughout their treatment journey, including education delivered by our endocrine nurse educators and engagement through our patient ambassador program. Our ambassador program connects with patients through multiple digital and social channels as well as live patient ambassador programs. The patient stories being shared reflect a diverse range of experiences on Palsonify, including individuals who were previously uncontrolled on existing therapies and who have achieved meaningful IGF-1 reduction along with clinically important symptom improvement. We believe this will motivate patients to more proactively manage their acromegaly and to initiate informed conversations with their physicians about Palsonify.

Via CrinetiCARE , we are providing comprehensive support to help navigate insurance coverage and minimize friction in the prescribing process. Together, these efforts reinforce our commitment to supporting patients, amplifying their voices and helping them take a more active role in their care. Turning to Slide 9. I'm very pleased with our marketing and field execution. We continue to expand our prescriber base. As of March 31, there were 263 unique prescribers, up from over 125 at the end of 2023. This represents an important and expanding foundation for future growth. At large treatment centers, we are seeing top prescribers begin with a gradual number of patients with highly positive responses. In many cases, broader adoption is currently limited not by interest, but by appointment availability, which reinforces our confidence in underlying demand. Consistent with the prior quarters, enrollments remain evenly split between academic and community settings, reflecting broad relevance across practice types.

Awareness of Palsonify continues to build, supported by targeted media reach, a strong presence at major congresses and a growing body of scientific publications. This includes a recently published indirect treatment comparison demonstrating Palsonify's value relative to other therapies as well as 2 oral sessions at the American Association of Clinical Endocrinology, including a late breaker that presented the first 6 real-world cases highlighting Palsonify's efficacy in both treatment-naive and uncontrolled patients. Our commercial execution continues to support educational programs and peer-to-peer engagement. Overall, we are very pleased with the positive experience prescribers have with Palsonify, which reinforces our confidence in continued adoption and growth.

From an access standpoint, approximately 70% of patients on therapy at the end of first quarter were reimbursed a meaningful improvement from last quarter, and patients have continued to transition from quicker start to reimbursed product. Over time, we expect nearly all patients to have coverage for Palsonify, and we will continue to provide quicker start when needed to ensure initiation of therapy as soon as possible. We are also seeing most prior authorizations approved for 12 months and aligned with the label, reflecting payer confidence in both the clinical profile and durability of benefit.

Turning to Slide 10. Payers appreciate Palsonify's unprecedented safety and efficacy, which continues to be reinforced with new research and publications. As I mentioned it, we recently published in the Journal of Clinical Endocrinology and Metabolism, a comparison of PATHFNDR-1 results against other approved acromegaly therapies. The analysis showed placebo-adjusted IGF-1 normalization of 79.7% with paltusotine, more than double what has been reported for both subcutaneous or oral ocreutide. This efficacy data, coupled with Palsonify's fast of action and symptom control are resonating strongly with payers. We continue to have highly productive discussions with top payers across the country, including regional and self-insured employer groups, supported by compelling clinical presentations that are resonating clearly. These conversations are translating into results. We are achieving formulary wins earlier than the typical decision time frame, reinforcing the strength of Palsonify's value proposition.

Moving to Slide 11. Importantly, we have now achieved over 60% coverage and remain on track to exceed our 75% coverage goal by the end of third quarter of 2026. Our national account directors will continue to meet with payers in the next quarter to continue to accelerate coverage. We have delivered this progress with improved speed to therapy and continued operational efficiencies across prior authorization and appeals.

Collectively, this reinforces that payers recognize the meaningful clinical benefit of Palsonify and the value of keeping people living with acromegaly in sustained biochemical and symptom control. Overall, our experienced commercial team is executing extremely well. The value proposition is clearly resonating with all stakeholders, and we are encouraged by the trajectory of the launch as we continue to expand access and improve outcomes for patients.

I will now hand the call to Alan to discuss the pipeline.

Thanks, Isabel. As we launch Palsonify, we continue to advance our deep homegrown pipeline. This pipeline continues in the Palsonify tradition of using novel and meticulously designed small molecules to interact with therapeutic endocrine receptors to improve the health and lives of our patients. Like Palsonify, we work to create truly new and needed treatments, which are easy to use for the patients and for their health care providers. As a clinical endocrinologist, I have long been frustrated by what I call no better option inertia, and the history of acromegaly care is a great example of this. For decades, we have been telling our acromegaly patients treated on depot injections that their blood tests look okay. Therefore, they are okay. Even if the patient wasn't feeling okay, there was very little we could do about it anyway.

We knew that there were a lot of unsolved problems, not the least of which was unstable control of acromegaly symptoms even when blood test results suggested normal or close to normal IGF-1 levels. That's where Palsonify came in. It was long past time to break the inertia and create a better option, one that for the first time was approved with a rigorous demonstration of IGF-1 normalization and symptom control. And the patients don't have to wait a long time to achieve these goals. Palsonify for acromegaly is only the first candidate on this pipeline slide and the potential patient impact across our pipeline is enormous. Atumelnant is another great example of a Crinetics pipeline candidate. It has a novel mechanism of action that has already resulted in unprecedented biomarker and clinical responses in short-term Phase II studies.

The Phase III COLMCAH adult and Phase II/III BALANCECAH pediatric studies are actively enrolling with a great deal of patient and investigator interest. We are also excited to begin enrollment into the Phase II/III equilibrium ADCS study in the near future. Additionally, we will report interim data from our Phase II CAH open-label extension later in the year.

When I look at Slide 13, I see a lot of scientific creativity addressing long-standing inertia in clinic and plenty of opportunities for significantly better therapies to address many endocrine and endocrine oncologic disease states. We don't settle for the status quo at Crinetics. We don't do inertia.

I'd like now to update you on our activities at major medical conferences. I recently returned from the American Association for Clinical Endocrinology meeting where Palsonify data were featured in 2 well-received oral presentations. As Isabel mentioned, one of these was the first description of real-world experience using Palsonify presented by a prescribing physician. There is no better way for practicing health care providers to learn about a new product than discussing with each other personal observations of how patients do with the treatment. We have heard many powerful anecdotes from patients and these real-world results are very consistent with what we are hearing. Diligence study and follow-up does not stop just because a product is approved. The Annual Endocrine Society Meeting is coming up in June, and there will be several Crinetics data communications, 3 of which are oral presentations. One of these oral presentations will summarize results of up to 2 years of long-term safety and efficacy data from the Phase III PATHFNDER-OLE studies.

Another oral presentation will detail final results from the Phase II TuCAN study results for eptumelimib in the treatment of adult congenital adrenal hyperplasia, or CAH. And the third, we will present new dosing data from the ongoing single-center study evaluating Aomelimet in patients with ACTH-dependent Cushing's syndrome. With the great potential across the Crinetics pipeline, I expect we will be presenting at these and other meetings for many years to come.

With that, I will hand the call to Tobin for a financial update.

Thank you, Alan. Turning to Slide 16. Our financial results for the first quarter 2026 demonstrate a balance of disciplined execution and strategic investment as we advance the development of our pipeline and commercial launch of Palsonify. In the first quarter, we recognized $10.7 million in total revenue, consisting of $10.3 million in net product revenue from Palsonify and $0.4 million from our licensing agreement with our Japanese partner, SKK. Cost of product revenue in the first quarter was $0.2 million. Prior to Palsonify's approval last September, manufacturing costs were expensed through R&D as 0 cost inventory. If we were to include the cost of products sold that was previously expensed as 0 cost inventory, the cost of product revenue would have increased by less than $0.1 million.

To date, we have only distributed 0 cost inventory and expect to continue to do so for the near term. Our research and development expenses for the first quarter were $100.1 million compared to $85.1 million in the fourth quarter. The increase compared to the fourth quarter is primarily due to the ramp-up of ongoing Phase III trials as well as the initiation of the Phase II/III pediatric study of adamelimab in CAH.

Selling, general and administrative expenses were generally steady at $50.8 million for the first quarter compared to $53.7 million in the fourth quarter. The fluctuation compared to the fourth quarter reflects timing variability of commercial investment. We ended the quarter with $1.3 billion in cash, cash equivalents and investment. As of April 23, 2026, we had approximately 105.4 million shares of common stock outstanding. On a fully diluted basis, we had 123.5 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 17. We are maintaining our guidance for GAAP and non-GAAP operating expenses in 2026. We expect GAAP operating expenses to be between $600 million and $650 million. We expect our non-GAAP operating expenses, which exclude cost of product revenue, stock-based compensation, depreciation and amortization to be between $480 million and $520 million. Based on our current operating plans and cash position, we project that our 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 ongoing clinical trials in carcinoid syndrome, adult CAH, pediatric CAH and Cushing's and continued advancement of our early pipeline, including proof of concept for 9682.

I'll now turn the call back to Scott for some closing remarks.

Thank you, Tobin. Turning to Slide 19. Palsonify sets a new standard for the medical treatment of acromegaly. I'm very pleased with the progress we have made on the launch. We are optimistic that the trajectory ahead of us will make it the most prescribed treatment for these patients. As we approach the halfway point of 2026, Crinetics is in a unique position of strength with fully integrated capabilities, a deep pipeline and robust balance sheet. We are nicely advancing this innovative portfolio of clinical programs and the site activations and enrollment trends in all studies are positive. I look forward to sharing meaningful data from these programs as they mature.

Beyond our late-stage trials, we are continually innovating on our early-stage programs and moving them forward towards the clinic as well as beginning new discovery efforts. We've also taken a new step for the company in establishing a collaboration with Dr. John Kopchick at Ohio University for the discovery of oral non-peptide growth hormone antagonist. Dr. Kopchick is a leading innovator in the field and discovered pegvisimod, the only commercially available growth hormone antagonist. We look forward to working with him to potentially create a new oral add-on therapy.

As you've seen today, we are not just executing a launch. We're building a premier endocrinology company. With Palsonify setting a new standard of care in acromegaly and ongoing Phase III studies for carcinoid syndrome, atumelnant advancing toward 2 important indications, 9682 exploring the potential of an entirely new platform, a discovery engine that keeps replenishing what comes next and a uniquely experienced team to carry it forward, we are well on our way to transforming the lives of people living with serious endocrine diseases and creating lasting value for all stakeholders in the near and long term. Thank you for listening, and we look forward to your questions.

[Operator Instructions] Our first question comes from the line of Joe Schwartz with Leerink Partners.

I have one on atumelnant and one on 9682. First, we noticed that you've added a balanced CAH update for '26. What will that entail? Can you give us a sense of the quantum of data you'll report and what you hope to demonstrate there? And then second, where are you now in terms of enrolling the BRAVIS 2 study dosing cohorts? And when do you think we might get our first taste of data out of that program? Also, at what point do you make the investment decision to expand the range of tumors you might target?

Thanks for both questions, Joe. Let's see, taking them in order. How about -- let's talk about the BALANCE pediatric study. So, a reminder, this is a cohort-based study starting first in 12- to 18-year-olds looking at doses and confirming the translation of our expected doses in pediatrics from the adults. And there's 2 cohorts there that are mandated and then a possible third cohort. We're not changing our guidance. We hadn't said it wasn't coming this year.

We're just reminding folks it may come this year. And especially if we don't need that third optional cohort, we will have data on the 12- to 18-year-olds as we begin going down the age groups. In terms of 9682, we are in the dose escalation phase, marching up the doses. We don't think it's prudent to give guidance as to when that may or may not come about. But the enrollment and enthusiasm in both that and all the CAH programs and the Cushing's program and the carcinoid syndrome program are very high. And so 9682 will make the decisions on the additional cohorts as we get to an effective or a tolerated dose. But we've already set out some key cohorts we're going to be expanding in the expansion phase.

Your next question comes from Gavin Clark-Gartner from Evercore.

Great to see the progress. For Palsonify, I just wanted to confirm, for the cumulative enrollment that pie chart you showed the 15% of naive patients, that's cumulative since launch, right? What was the percent of naive patients that came in specifically in the first quarter?

Thanks, Gavin. Let me hand that over to Isabel, but we are pleased with the overall execution across all dimensions of this launch. And I've got a lot of questions over the years, where do you think the primary group is going to be? And I think the answer I've given is everybody. Our source of business is every single group. And in addition to those naive, the folks who are coming back to care represents an early victory on our planned Phase II of the launch when we start focusing more heavily on. But maybe, Isabel, you want to comment a little bit more about the naive population.

Just to clarify the 15% is specific to first quarter. And our market research showed that basically, the messages on PATHFNDR-2 are resonating really well with the community. We're helping shift long-standing perceptions. We are successfully reframing or as a true first-line option rather than a second-line alternative. The efficacy story is landing really well. And as Alan mentioned it, 3 of the 6 patients highlighted at the AAC poster were naive patients who have remarkable results. So, we see this group really expanding in the future, and we expect to be actually dominating in this group.

Yes. And just to add on to that, remember, this comes back to our overall strategy of laying the groundwork, getting people experience and then starting not just to focus on switching market, but growing the market and bringing people back to the care that they need, that they gave up on because of the problems associated with the current level of care like Alan was talking about. The inertia is not something that we want to do. We're not going to -- we need to move past that.

That's super helpful. Super quick follow-up. What's the scope of the CAH data that's coming at end of this year?

Well, I think you'll just have to wait and see for the abstracts, but it's a beautiful molecule, and we very much like it.

Your next question comes from the line of Yasmeen Rahimi with Piper Sandler.

This is Liam on for Yasmeen Rahimi. Congrats on another outstanding quarter. Just looking forward at the Palsonify launch, could you provide some color on how you think 2Q will compare to 1Q? And how do you really see starting forms evolving over the next 4 quarters? Or I guess like what would be considered a steady-state starting form number?

I'll let Toby take that one.

Thanks, Liam. When you step back and zoom out, as Scott mentioned, we've accomplished a lot in the first quarter. You've seen the growth of the naive patients is the first question answered, the penetration into the discontinued patients and sort of just the depth and breadth from payer coverage and the increasing number of accounts that we penetrated over time. However, there's always puts and takes. So, for instance, we had the momentum in the fourth quarter of 2025, where we had some patients who had joined and became enrolled from the OLE and some kind of early adopters and a handful of hand raisers there. So that it's really tricky to kind of forecast where we're going to be. However, we like the momentum that we're building, and we're really confident in our trajectory.

And I think something that has been very nice to see is just how well the team across all the dimensions of the company, whether it's sales or medical affairs or even the back office stuff. It's all working very smoothly. The engine is coming, and we're building momentum.

Your next question comes from the line of Max Skor with Morgan Stanley.

So, regarding Palsonify, with 70% reimbursed, what's the form to paid conversion rate? And how should we think about timing for the remaining 30%?

Well, first, let me complement the market access team. 70% at this early point in the launch is really superb for a molecule in the rare disease space like this. But do you want to comment a little bit more on some of the dynamics as well?

Yes. Thank you for the question. As Scott pointed out, we're very pleased that 70% of the total systems and the patients are getting reimbursed, and we are working through moving those quicker starts into reimbursed patients. That's moving at a good pace. I'm not going to mention the specific metric, but we're expecting all of them will eventually be converted to reimbursed drug.

Your next question comes from the line of Jon Wolleben with Citizens.

Just one for me on Palsonify. When we think about the unique prescriber base, do you have a sense of how many acromegaly patients those prescribers have under their care? Just looking for some commentary about kind of the deepening of the prescribers as well as the broadening over time.

Yes. Thanks. And as we've said in the overall strategy the last couple of times, we're trying to get a broad set of experience so that we can then begin to expand the market and get people in and focus then on depth. And I think we're succeeding on both aspects of that. We're getting a broad set of prescribers at the top pituitary centers and out in the community, and those are starting to show depth in some of those prescribers and some are just new to the drug. Maybe you want to add a little bit to that.

We are very pleased with the results. I mentioned earlier in the call, 50% of the prescriptions are coming from community and 50% are coming from PTC. But the 50% from community are coming from 70% of our total prescriber base. That's really promising because it means we are expanding the market, building a broad base of prescribers that are having really positive experience and are starting to put the second, third and fourth patient on drug. Answering your question on how many patients those doctors represent today, approximately 1,400 patients.

Our next question comes from the line of Jessica Fye with JPMorgan.

Just curious, as you enroll the registrational atumelnant trials, do you anticipate being able to provide the Street with commentary on the ongoing safety profile, maybe based on like blinded safety data as it accrues?

Thanks, Jess, and welcome back. Yes, let me just say that every day, we're accruing patients every week. And the safety profile continues to be what we've always communicated it to be, which is very, very favorable. But maybe I should let Alan give a more physician-oriented answer to that.

Yes, I mean, all trials, especially major Phase III, Phase II/III trials are carefully monitored for safety. Sometimes the efficacy results, of course, are blinded. But there are always medical monitors following both safety and efficacy as well as external data monitoring committees. In general, when the trial -- when these trials continue, that means the risk-benefit profile has been analyzed and it has been found to be safe to go forward. I don't know that we would come back to make public announcements, but you can be sure that this is -- when the trials continue, things are going along as expected.

And maybe just to be absolutely clear, with continued experience, we see continued good safety profile with nothing that has changed our mind or perspectives on that whatsoever. And as we add more patients, anything in the past that might have been concern to some, not so much us, continues to be diluted by more and more experience, both in the adult ongoing Phase III in the rapidly recruiting pediatric study where everybody is super sensitive to safety, of course, and in the ongoing OLE experience. So that experience base grows every day, and we continue to be pleased with the profile of atumelnant, both on a safety and efficacy point of view.

Your next question comes from the line of Dennis Ding with Jefferies.

Congrats on a strong first quarter. I have one on Palsonify. So, it seems like each doctor so far is prescribing it to 1, maybe 2 patients. What's the feedback from them who have used it so far? And what's preventing them from prescribing Palsonify to more patients? Is it just confidence in getting these scripts approved? Or maybe penetration is just gated by the timing of patient visits?

Thanks, Dennis. Let me correct your premise. It is not true that they've only prescribed to 1 or 2 patients. It depends on how many patients they have and how often they're able to see them. But we have some who routinely are switching patients or adding to new patients. And just as we've said since the beginning, the major challenge is just getting that darn appointment. But we're hearing tons of positive feedback in an anecdotal sense that we're now starting to publish as evidence. We're getting good coverage, good reimbursement and everything is moving along just as we expect. So, nothing is getting in the way other than a little bit of time and a little bit of finding those darn appointments.

Got it. And if I can have a follow-up. For your preclinical oral TFHR antagonist, how do you think about this approach going after the receptor versus going after the autoantibodies? I mean one might say that completely hitting the receptor might get patients to go into a hypothyroid state that might require a Levo supplementation. So curious how you're thinking about that.

Yes. So just like our other programs, we're really going after the core target of the disease. And it's super specific to go after the receptor. And remember, there's this whole other branch that are going things downstream of the receptor like the anti-IGF antibodies. But at its core, what we've shown in a preclinical setting is a great degree of specificity, ability to achieve dose response. And if necessary, we could take add-back approaches like levothyroxine, which almost every endocrinologist is familiar with. Alan, maybe you want to elaborate on how we're thinking about developing this drug.

Yes. No, I mean, I agree with Scott. It is the fundamental driver of the disease states in multiple organ systems is via -- it's mediated by the TSH receptor. So that's where we really want to target the therapy. The autoantibodies in Graves disease are very -- they come and go. The wax and wane with time. It's unpredictable as to when antibodies are even there versus how much antibody is there and what form of antibodies are there. These are polyclonal antibodies that are very heterogeneous. So even measuring them in a laboratory isn't necessarily predictive of clinical things. So, it's very hard to react to autoantibodies and chase them, especially in the disease state, which the natural history is for these things to kind of appear and disappear. I think targeting the TSH receptor is much more reliable and I hope will prove to be much more effective and long-term solution for patients.

Your next question comes from the line of Kate Delloruso with LifeSci.

Congrats on all the progress this quarter. Just a quick one on Palsonify. I know it's early days, but I was wondering if you had any insights on real-world compliance or adherence thus far that might be captured your patient resources like the CrinetiCARE platform.

Yes. Thanks, Kate. Just a reminder, we've had great compliance and persistence throughout the clinical trials, open-label extensions, and that trend continues as we go into the real-world setting. But maybe you want to comment, Isabel?

We are very pleased with the positive experience that patients are having on Palsonify. You see a fast set of action in 2 to 4 weeks. You see symptom control and IGF-1 control. And that has led to the patients to continue on therapy. So, the patients that started in fourth quarter are on therapy today. We see a very positive trend on adherence and compliance.

And if I just extrapolate from these anecdotes we're hearing about how patients feel better. The converse of that is when you stop, you know what good is like and you are reminded what bad is like again. So, as we think about these enrollment forms each quarter and the natural history of acromegaly, it's important to remember that this is a lifelong disease, and we've developed a lifelong treatment. And so each quarter, we're adding hundreds of people who I think we can help not just through providing a good drug, but providing the whole ecosystem through CrinetiCARE and our other services to help them manage their health care, help them get to reimburse for their drug and help them stay on the care that they need.

Your next question comes from the line of Alex Thompson with Stifel.

I guess when might you be in a position to give us some more clarity around time lines for the paltusotine carcinoid Phase III and the AML adult study? I guess asked another way, both of those trials have primary completion dates for 2027 on clinicaltrials.gov at this point. Is it possible we see data next year? Or are we going to have to wait until 2028?

Well, look, as I said earlier, Alex, it's not prudent to comment on time lines at an early stage of a trial like this. And you have to throw an estimate on clinicaltrials.gov. But we've done a whole bunch of different things as we've grown the company to help ensure that we can maximally recruit our studies. And these go from things like internalizing our U.S. clinical operations. So those are relationships at sites where we've had studies before and now it's with our own Crinetics staff who have low turnover and stay as a relationship for the duration of the study. And those people are also then, of course, the likely prescribers of the drug. And so, we've seen an acceleration in site activations. We've also put in various structures to help make sure that the sites are screening effectively. We've been very pleased in the CAH study that almost every site as soon as it's activated, starts screening immediately.

And you don't always see that in these types of clinical trials, but it's great evidence about the enthusiasm of the investigator and the patient community. And similar in carcinoid syndrome, remember what a tough, tough disease this is and what really solid data we showed in the Phase II program. We recently had an investigators meeting there. And again, a ton of enthusiasm and a very positive response. So, we are working hard to make sure we can bring in these time lines at the fastest possible pace, and we've built the company to do that. So it's -- we had a discovery engine, I think most people recognize. The development engine, there's a lot of stuff behind the scenes that most people forget about, but it's complex and it's really running well. And now we've built the commercial engine and the commercial engine is coming, too.

Your next question comes from the line of Tyler Van Buren with TD Cowen.

This is Nick on for Tyler. Congrats on the progress and on the quarter. Can you discuss what proportion of revenue came from new patients this quarter compared to patients rolling over from last quarter? And also, what was the overall growth of the patient enrollment forms month-over-month in Q1 and as you moved into Q2?

I'll let Toby take that.

Yes. I don't think we were going to comment on the revenue from new patients versus carryover patients. But when you step back, I think that as we look at this data and sort of the growth that we've had in enrollments, we're feeling very good about the trajectory of things. The team, like as Scott and Isabel mentioned, are building the relationships and they're doing it in a very steady fashion. And we're quite pleased with the progress and just the response to Palsonify in the field.

Your next question comes from the line of Douglas Tsao with H.C. Wainwright & Co.

Congrats on the progress. I'm just curious if you could provide a little bit more on the 15% of patients who are returning to therapy. I'm just curious if you have a sense of were they in the system still and routinely seeing a clinician but chose not to be receiving sort of injectable therapy and were very quick to come on as soon as Palsonify was available? Or were these patients who somehow heard about the drug and then decided to sort of reenter sort of treatment?

Yes. Thanks, Doug. Again, let me give some credit to the team. They've been piloting some of the programs they're planning on deploying more widely to do exactly this and bringing these patients back to care. And so, some of it is from that and some of it is spontaneous. But maybe you want to comment a little bit, Isabel.

Well, we are really pleased because we are bringing back to patients that have given up on their treatment, even though they have a chronic disease where symptoms continue to advance. So, these patients that have discontinued therapy remain in the system. They were primarily discontinued due to the burden of the treatment and the fact that those treatments don't deliver, right? You continue to have symptoms at the end of the cycle, you have painful injections and after what you just give up. So, for us, it's great. None of them has discontinued for more than 2 years, some of them just a few months ago. And we have reengaged them. And that reengagement takes our media programs, our participation on the program and also some specific tools where we are working to identify them with the practice. So, these are very early outcomes in a group that has given up, but it's very encouraging for us because it means that we can expand the market.

That's really helpful. And just maybe on the switch patients, I'm curious, do they generally just come in -- I mean, how many visits to see the doctor do they need? Are they generally coming in, talking about the clinicians saying, yes, I would like to do this and they sort of get the ball rolling with the patient start form -- or do some patients need a couple of visits to sort of go through an education process?

Yes. So, there's a little bit of a mix. But before we hand this to Isabel, let me just tell you one anecdote I heard recently -- I had recently firsthand where I was talking to a couple of HCP friends of mine, and they were telling me about a couple of different patients that had come in and asked for Palsonify. And their initial reaction was, well, this is a -- you're on a second-line therapy. I'm not sure a first-line therapy will be what you need. And yet it worked anyway much to their surprise. And so, everybody was happy with that, and that story is propagating as well. But you want to comment, Isabel?

Yes. When it comes to the switching patients, I will first comment that we are very pleased that they are coming from all kinds of previous therapies, octreotide, lanreotide, combination therapy, cabvergolin, Mycapssa. So, we are taking share from pretty much all those switches. And the beauty of Palsonify is that it's performing really well across the board. So that shows the versatility of our drug and that confirms the efficacy and the benefit also having a once-daily therapy. When it comes to how long it takes to convince patients, it's like everything in life. Some patients are more ready to do that change because they are having the symptoms, because they feel uncontrolled because they hear about the convenience of our treatment, all of that makes them ready to switch. Other patients want to hear from other patients. That's why we have our Embassor program to hear stories. Other patients want to have a second opinion with the doctor. But that's what we are seeing across the board as patients have interest in learning more and many patients are joining our Embassor events.

That's really helpful. And Scott, can I just ask a quick follow-up in terms of your anecdote. I mean just given their reaction, I mean, does that suggest that even very well-educated clinicians with Palsonify don't necessarily have a full appreciation of the data and the strengthness of it because just given the PATHFNDR results, I mean, I don't think anybody should be surprised that the drug would work or that it wouldn't be applicable to everybody with acromegaly.

Yes. No, it's not that it wouldn't be applicable to everybody. It's just that we're seeing kind of even more than we expected in the real-world setting than what we saw in the PATHFNDR studies. Because remember, we -- the PATHFNDR had 2 parts of the spectrum, 2 ends. The patients who are untreated at all in PATHFNDR-2 and the patients who are very well controlled on the injectable depots. But what was missing was all those patients in the middle who aren't that well controlled, who might be on combination therapy, and we only had a small amount of data on that from Phase II. And so, what we're learning in the real-world setting is that even if you're on a combination therapy, some patients are getting better on Palsonify.

Even if you're on something like pasarreotide, which is a mixed receptor that people advance to after they fail on lanreotide and which has a variety of different problems associated with it, even those patients are getting switched and doing well. So I think we're all just a little bit surprised at how well this has done in the real-world setting, which is why it's so critical that we capture the real-world evidence and start to get that out there, not just through word of mouth, which is already happening, but through publications and formal presentations of evidence.

Your next question comes from the line of Richard Law with Goldman Sachs.

Congrats on the results and progress so far. Two questions for me. The first is we saw sales from other products from many other companies impacted by the severity of weather in Q1. Was there any seasonal effect that impeded Palsonify sales in moment form in Q1? And do you believe there's a pent-up demand as a result in Q2? And then I have a follow-up on eimelimab.

Look, we're very pleased with just the overall consistent launch and the way the team is performing, and I couldn't be happier. I think we've got enough time for the eimelimab question.

Yes. I think just kind of following up to what you said earlier about safety monitoring, something like that. Can you discuss like what data sets that you can -- that you believe can help derisk the safety profile related to ahead of that Phase III CAH study? And then I think in the ongoing trials, you mentioned that you guys do monitor the safety or the data monitoring will monitor safety. Is there -- if there's a lower grade like liver tox signal, would that get reported to you? Like what level and what quantity of level of that signal gets communicated to you guys?

I'll let Alan answer the technical part of that. But in my view, there's not really anything to derisk anymore. We're at a normal Phase III, and it's moving forward in a very nice fashion. Alan, maybe you want to give people some comfort with the specificity of the rigor that goes into our overall safety monitoring, including the Phase III.

Yes. So, all clinical trials, including Phase III clinical trials contain within it extensive safety monitoring, which generally includes regular visits with health care professionals for physical examinations as well as a battery of routine safety blood tests, EKGs and other important things, too, that are generally -- that are routine for clinical trials. All these safety data are very carefully monitored by well-trained professionals all the time. The all the safety data is available in real time to the medical monitors in particular. And this is followed very carefully. And as I said earlier, generally, when a trial is continuing, that means all the safety checks are as expected. And I feel very confident in our compounds and in our trials, including the ongoing trials. Yes.

And maybe to even put a finer point on it. You really think that IRBs around the world would let us start dosing 12-year-olds or soon even younger if they had any question about the safety or risk benefit of this drug. I don't think they would, especially as we get into kids.

Our next question comes from the line of Catherine Novack with Jones.

Just one on Palsonify in Europe. Can you give me your thoughts on potential pricing dynamics here and when you expect to see revenue from individual countries and which countries may be first?

Yes. Thank you. Look, we're focused on executing on the U.S. launch. And I'm really pleased that we've received the approval in the EU. We've submitted in Brazil. We've submitted in Japan. And all of this is building options for us around the world and I think showing the strength of the drug with the receptions we're getting from these global regulators. But like everybody else in pharma and biotech, we're monitoring rapidly how all the pricing and access situations are evolving. And we're navigating this uncertainty in a very disciplined market-by-market approach. We'll be prioritizing geographies with clear regulatory and reimbursement pathways. And also importantly, we're pacing the investment in these international activities, again, to preserve the option value without overcommitting too much capital. And just to be clear, we're not preparing for revenue from international operations this year, but we will be prepared for early launch in 2027.

Your next question comes from the line of Brian Skorney with Baird.

Congrats on the quarter. I also wanted to get some thoughts maybe on the ex-U.S. launch you mentioned sort of thinking about prioritizing where reimbursement may be favorable given sort of the IRA dynamics. But how do you think about where there might be higher value areas through either genetic clustering or just diagnostic clustering being a driver of demand? Like I think in Northern Ireland, there's a genetic cluster of the R304 mutation, maybe Brazil seems to have better diagnostic infrastructure than other areas. So, are there any areas that you kind of point to where the pool of identified patients may be particularly meaningful?

Yes. So, first, there's not really a genetic clustering to acromegaly, except as you say, in the Irish giants, which is one of a relatively small population where there is a genetic component to the acromegaly. So the distribution of incidents is pretty much global, but some health care systems are better at identifying patients and/or keeping them under care. But we need to balance that against also the reimbursement landscape and the regulatory certainty in those regions. So, all those things we're taking into account, but it's a little too early to comment in detail on the specificity of our international plans.

There are no further questions at this time. This concludes today's call. Thank you for attending. You may now disconnect.

Welcome to Crinetics Pharmaceuticals Fourth Quarter and Full Year 2025 Financial Results Conference Call. [Operator Instructions]

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, CRN9682 (sic) [ 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 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 atopic ACTH syndrome. And the key driver in both pituitary disease and atopic ACTH syndrome is ACTH.

And 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 that 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. And 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 the 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 9682.

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 CRN9682 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. Operator?

[Operator Instructions] 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 are -- 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.

Congrats on the EQUILIBRIUM study initiating and the very innovative design. Just wanted to ask a question on PALSONIFY. I would love to maybe get color around how maybe starting scripts shaped up into January and February. And if you saw any trends -- just trends going from December to the beginning of the year, and I'll jump back into the queue.

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?

Yes. I think it's premature to sort of comment on extrapolating that 200 enrollment form. We feel very pleased about that number. And just because there's a lot of headwinds and tailwinds that you have. You have -- at the beginning of a launch, there's some patients who were on our open-label extension program who came on to commercial supply. But then you have kind of continued momentum through increased field interactions going forward.

I think on your second question, you talked about the time it takes from the Quickstart patient program as well?

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 touch points along that way. And because it's relatively early days in the launch, it's difficult to kind of 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.

Congrats on the progress and enjoyed the prepared remarks on ADCS. Just maybe I could fit in one more on the launch, but a little bit less so on the near term, a little bit more on the medium term. Just over the course of the year, do you -- what do you expect the cadence to look like? Is it going to be lumpy because it's kind of an orphan launch and -- or is it going to be more linear or exponential as we exit the year? Curious to get your thoughts on that.

And second, since you mentioned the 0 cost inventory, can you tell us what level of sales that inventory equates to roughly?

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 details 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. Thanks for the question. I think the main purpose -- one of the main purposes of the Phase II part is to find the right dose for Phase III. And then in Phase III, it would be a traditional prospective parallel group, placebo-controlled comparison trial.

The primary endpoint is pretty much set by the FDA, and that is the percentage of patients who achieve a normal urine free cortisol at the end of treatment. This is a 24-hour urine collection, which sort of measures the integrated output of cortisol over that period of time.

And the hurdle for the study is to show there's a statistically significant increased proportion of patients who achieved that goal on drug versus placebo. Yes, what we will learn from Phase II is the dose. It is very unlikely we would change that primary endpoint, however, for Phase III.

Our next question comes from Joe Schwartz with Leerink Partners.

Thanks for the update. I was actually curious on 9682 and wondering if you can give us any insight into how you're selecting patients for the BRAVESST trial. Are you -- do you have a working hypothesis for particular biology that are more likely to respond to it based on the turnover of their disease or their SST receptor density? Have you detected any signals in preclinical data? And how do you hope to put relative to current options?

Thanks, Joe. I got to say 9682 is currently the apple of my eye. The compound is -- it's something we worked so hard on both from a concept and from a development and an optimization point of view. And the patient selection is really very simple. We have a basket study with all kinds of different patients with somatostatin 2 receptor-expressing tumors.

The core criteria is they have to have on a somatostatin PET scan, higher density in tumors compared to the liver. And they have to have progressive disease or why would they come into a clinical trial like this. And we're very pleased that the reception by the community has been strong and the screening queue of patients is always there. So we're just working our way through it.

In terms of preclinical models, we showed some fabulous data with essentially small cell lung carcinomas, which are a high-grade lung neuroendocrine tumor. And we've done some other tumor models. But so many people have cured tumors in mice that we're now at the real point where we're looking at these different tumors in humans. And the reason we designed this study is in such a broad way is we want to make sure we capture the different populations of patients who can benefit.

And as a reminder, it's not just neuroendocrine tumors, of which it will range from relatively slow growing neuroendocrine tumors, grade 1 or grade 2, up to more aggressive grade 2 or 3 and even up to neuroendocrine carcinomas or like small cell lung is a very aggressive point of view. But we'll also be looking for patients with meningiomas, which are almost always somatostatin receptor positive and often very difficult to treat.

We'll be seeing perhaps some HR-positive breast tumors, head and neck tumors. And as we start working our way up the dose escalation, defining the tolerability profile, we may start to see some hints, but what we really look for is signals when we get into those expansion cohorts. And as you saw from the trial design, it really allows us to bring in any type of 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. And 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. And I think this is just a cleaner study.

Okay. And then when you have the Phase II results, will we be learning just what dose you'll be moving forward? Or will you guys be giving us -- will you be giving out data on the endpoints as well?

Well, I think it's a little early to be too specific, but I do think that we'll want to communicate Phase II results at appropriate scientific conference. It's important for the community to realize the experiences we're seeing in Phase II to help motivate investigators and patients to sign up for Phase III.

We now turn to 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 take the last part, and you want to take the first part, Alan? So I don't think PRRT is a prerequisite or really that relevant for 9682. PRRT is great, and it demonstrates that somatostatin targeted therapies are really important in these populations. But it's not for everyone, and it's not always easy to get. And so we're not requiring people to step through it or -- anyway, I just want to remind folks that this is a much more democratic therapy than a radiotherapy.

And let me just add, though, that in a Phase I oncology trial, traditionally, you would be enrolling patients who've been through other therapies, including things like PRRT in the past. And these are patients often who are sort of out of the conventional options at this point in time. And -- but I do agree, though, with time, in theory, this mechanism of action, it could be sort of a non-radioactive PRRT someday where it is used sort of in an earlier -- at an earlier stage of treatment than we would test in a Phase I trial.

In terms of what we're looking for, we're in a dose escalation phase now in the study, and we are -- traditionally in an oncology study, what we would stop when we get to a maximally tolerated dose, these days, you don't necessarily have to go that far. But in general, we want to see the primary sort of endpoint for this part of the study is safety and toleration.

We hope this would be fairly well tolerated for all the reasons we've been through in terms of why this kind of approach might result in not only an effective well-targeted therapy, but also a well-tolerated one.

But of course, we also, as part of the clinical care for these patients with sort of advanced cancers, they will also be having regular imaging studies, CT scans or MRI scans to measure the size of their tumors. And we follow formal RECIST criteria to understand if there are -- if there is stable disease, partial responses or any -- according to the standard RECIST criteria, we would classify this.

This is kind of a long-term prospect though. Many of these tumors are on the slow-growing side. So that kind of response data will take time to evolve over time. But certainly, we hope to have enough information coming out of this dose escalation study to go into the expansion part of the protocol where we would kind of enroll more patients with the most likely to respond tumors, including some of these non-neuroendocrine tumor SST2-positive kind of tumors that we know of, such as meningioma. I hope that's helpful.

We now turn to Dennis Ding with Jefferies.

I have 2 on the NDC. 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.

Thanks, Dennis. Yes. So this is Scott. I'll take the big picture and then hand it off to Alan for more about expression. So I'm really interested in this whole notion of using small molecule targeting for a variety of payloads. And I think it offers just some core benefits compared to antibody targeting or peptide targeting, for example.

As you know, with an antibody targeting, you're always going to be limited to a relatively long time in circulation. You're going to be limited by the types of epitopes you can address. You're going to be limited by bioconjugation reactions to the linkers and payloads that are suitable. And all that goes away when you just stay with small molecule chemistry like 9682.

And we first pioneered this idea in the radiotherapy space and spun out Radionetics, which is doing very well. Thank you very much. And now we're continuing in the non-peptide space for first neuroendocrine tumors, as you say.

I do think because of the way the radio imaging is used and radiotherapies are used, the bulk of those patients in routine care are neuroendocrine tumor patients, but that's growing pretty rapidly outside of that. And the general strategy is to see where the science and the medicine takes us. So it's -- I expect this to take us outside of our core neuroendocrine tumors, which is 100% synergistic with the carcinoid syndrome program.

And as I think about it in discovery, we are just beginning with this platform. So I can imagine additional types of payloads, maybe targeting SST2 first because it may be that this payload may not be for all SST2-expressing tumors. But we're also exploring other types of targeting because GPCRs that recognize these peptide hormones are often very difficult to target antibodies.

And we're looking at various different types of payloads, what else can we do? So it's a blue sky area of research, and I'm very excited to see where it goes. So I talked for a little while, Alan, but maybe you want to address about line of therapy and expression.

Yes, it's a really good question. Does -- is there any change in SST2 receptor expression over time as patients receive various treatments. And what I can say is one of the eligibility criteria for this Phase I study is positive SST2 receptor expression as documented on clinical receptor -- nuclear medicine imaging studies that go to take kind of scans. So we know...

That's part of the screening, not just historical.

Correct. So patients have to have known SST2-expressing tumor at the time of enrollment into our study. So we know they're still there in our patients. I think as a general rule of thumb, it may depend on what kind of tumor you're talking about, but certainly, the well-differentiated neuroendocrine tumors, generally, the SST2 receptors hang around 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 9682.

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 to transition to just paid treatments. So that's how I see the evolution of the plan.

Okay. And then Scott, to your point that sort of 9682 is sort of now the apple of your eye, and I think this is the most you've talked about sort of an interest in terms of expanding on this platform. And I guess I'm just curious how we should think about or how you're thinking about sort of the pace of innovation on this side of the business versus sort of your initial focus on sort of endocrinology.

So, thanks, Doug. Great question. We are still really committed to endocrinology. Don't take this as anything other than the newest and shiniest drug in our pipeline, and I'm really looking forward to seeing something come from it.

But we'll -- we are working very hard to expand the endocrine side of the business. One of the things I've been learning as we've launched and I've been doing ride alongs with some of our salespeople and our MSLs is how useful it will be in the future for us to walk into an office and be able to talk to them about there are various types of patients. They're acromegaly patients, they're Cushing's patients, they're CAH patients. And some of them even see neuroendocrine tumor patients. So I think there's a huge synergy there.

But now as we start moving from neuroendocrine tumors into -- and carcinoid syndrome into perhaps treating the tumors themselves. I just do want to see where this technology can take us. So it's early days. We're waiting to see how 9682 performs and what we can learn from it. It's a whole new platform, but we're planting seeds and this tree should bear fruit one of these days.

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.

Yes. No. I mean we don't have a field force out there talking to docs about CAH. So I think that's more a question for the folks out there with that drug. But I will say that I do think the things we're learning about acromegaly and the acromegaly prescribers and the community endocrinologists, many of whom do see CAH patients, and the capabilities we're building are directly transferable to the CAH patient population.

So it's part of the whole synergy that we've thought to build both in our pipeline and then later in the marketplace by focusing on endocrinology, which is something that Alan and I have done our whole careers and many others here in the company have spent their whole careers on. So we've consistently talked about we are not just a sponsor coming in with a new molecule and plan to be gone from endocrinology, we're a part of that community, both as sponsors of clinical trials and now selling drugs and -- but also 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 [ place ]. 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.

Great. Good morning. Welcome. My name is Jess Fye. I'm a biotech analyst at JPMorgan, and we're continuing the 44th Annual Healthcare Conference today with Crinetics. You're going to hear a presentation from the management team, and then we're going to go into some Q&A. [Operator Instructions] So with that out of the way, I'm excited to turn it over to Crinetics CEO, Scott Struthers.

Thanks, Jess, and thank you all for coming. It's great to see you. Thanks you online that I know are listening and appreciate seeing some of our fellow shareholders and new shareholders and future shareholders. I've been coming at this podium here with Jess since, what, 2018, and we started with telling you about CRN808, which was our first molecule and first-in-human data. And then as 808 evolved into paltusotine for the treatment of acromegaly, we updated on that. And then we started to talk about building a pipeline behind it and building a company behind it. And today, I want to talk about building a business behind it. Reference our forward-looking statements.

So 2025 was a breakthrough breakout year for us. In many ways, it's a culmination of the many years of work that we've done since 2008 when we started the company. One of the bigger achievements, of course, was managing to get approval of a broad label for Palsonify for the treatment of acromegaly on its PDUFA date. And what I must say was a perhaps the right word is dynamic time at the FDA. And I'm very proud of the team that managed to do that. But then we followed through with a successful launch. We reported on that last week. I'll give you a little bit more details on that today. We reported positive Phase II data on atumelnant, our second internally discovered compound that I think has the potential to transform the treatment of CAH.

We initiated Phase III studies in carcinoid syndrome for a second indication for paltusotine in adult CAH with atumelnant and a new compound, 9682 in the Phase I/II study in NETs. We're building a fully integrated company at this point. Last week, we added to our balance sheet, and we're funded through 2030 with roughly $1.4 billion in the bank. This is a solid foundation for us to build a business. This carries us -- this funding carries us through the potential approvals for carcinoid syndrome, CAH, the approvals for atumelnant and gets us through the rest of the decade. I think we've seriously derisked the company with that.

So here's our pipeline. Here's an overview of our pipeline, leading with paltusotine, followed by atumelnant in its indications, 9682. And what you can see from the populations of patients on the right that in these rare and orphan diseases, there is significant potential both to help people and to build significant value from this pipeline. And if you scroll this pipeline forward a few years, we begin to see when those approvals may hit and the depth of the late-stage pipeline we'll have as we go through the rest of the decade. And we continue to work on our internal discovery efforts. I should mention every one of these molecules has been internally discovered. The patents go into the 2040s at the earliest and continue on from there.

And we continue to work on a number of different things shown on the lower left that I think some will be emerging next year -- or sorry, this year, 2026 into the clinic. And in some cases, we found it better to work with some of our partners. So Sanwa or SKK, we licensed paltusotine for Japan rights. The technology for non-peptide targeting that led to 9682 is also very intriguing for the delivery and targeting of radiopharmaceuticals. And so we spun out Radionetics Oncology for that.

And then endocrinology touches every cell on every animal in the planet. And we're a dog lover company, and we thought we could help dogs in some way, too. So we partnered with Loyal to use the tools of endocrinology to extend the lifespan of large breed dogs. That may come out of the blue to some of you. But if you'd like to learn more, Celine, the CEO, is right over here in the second row, and you can catch her after the meeting. But endocrinology has so much potential to change human health that I just look at this and think about all the new things we can be doing as well.

But first, let me spend a moment on the business. So we got the approval September 25 for Palsonify for the treatment of acromegaly. It was a broad label for newly diagnosed patients, patients switching from standard of care. And I'm very pleased that now as a company, we've been able to conceive of, develop, get approval and actually deliver a drug to patients, and that doesn't happen very often. I think there was, what, 31 NCEs, small molecules last year, and we're proud to be one of them. But we're more proud that now there's more than 200 patients have enrolled in the last quarter for Palsonify. And all our OLE patients rolled over into commercial drug. We've had patients in the open-label extension for 4 years plus and 90-plus percent of people in the trials have enrolled into the open-label extensions and just a good acceptance of the drug from the patient population.

And this came with a broad set of prescribers, more than 125 unique prescribers and getting that experience with the initial patients is important because they've got a lot more patients that I think they will begin to switch and/or treat. And this is from a broad group, not just in the academic centers, but about half the scripts are coming from the community endocrinologists. And we find that the community endocrinologists sometimes are much more accessible than, say, at the pituitary centers, where you may need to wait for 6 months or a year to get your annual appointment. But some of the community endocrinologists have been calling patients, telling them about Palsonify or manage their patients every few months. So that's been a great source of support for us.

Also, our payer group has done a great job of telling the payer community about the value that Palsonify can bring. And we have extensive patient services program, including a quick start program. So if there's any delay in getting an approval for their drug within the first few days, if they can't get that approved, we send them a Quick Start program while we help them work with their insurance company on getting approval. And more than -- roughly half the bottles are getting approved and shipped to patients before they need to get on the Quick Start program. So we found that a good evidence of payer acceptance.

And this is all through the medical exception or mostly through the medical exception. We did have a nice announcement from CVS Caremark covered us on formulary last week. But when we are getting these prior authorizations, the vast majority of them tend to be for 12 months. So that is also good evidence of payer acceptance. And you put all this together and last year, we achieved somewhere around a little over $5 million. We'll report the full audited data in our quarterly earnings call. But a successful launch by the numbers.

But more importantly, from Crinetics point of view is what this means for people. And we've gotten to know we've had patients as part of our development and design program in all our programs. And these 3 patients are the first of our patient ambassador program. Some have been on the drug only weeks or a few months. Some has been on for 4 years. And the stories that we're hearing from them and others are really gratifying.

Megan went down several ring sizes because of the reduction of the swelling of her hands, which allowed her to wear a wedding ring again. That's kind of a big deal. David is a musician and loves playing, but was inhibited from that, either guitar or piano just because of hands and swelling. And Ashley has been on for more than 4 years now and has been eager to complete the OLE shift to commercial supplies and is now going to be one of our ambassadors.

And we'll expand this program. These are just the first 3, but patients want to hear from patients, and they'll be out helping and teaching not just about Palsonify, but what it's like to manage acromegaly and how to help navigate the health care system. We've got a broad set of services, both to help patients manage this. We've got a hub called crineticare.com, where you can call and get support from nurses. We've got nurse educators. We've got field reimbursement specialists. We're really trying to provide a comprehensive solution to patients and their providers.

And part of that is because, I guess, one of the realizations. For those of you who don't know me, I'm a discovery guy at heart. And as we started approaching the launch, what we realized is that making a good drug is just a small start of the whole problem. So if you look at this, there's 36,000 patients with acromegaly in the U.S. And our initial Phase I of the launch is focused on these folks in the left, 10,000 patients who are actively being managed. And surprisingly, so the standard of care for acromegaly are what are called these injectable SRLs, which are large gauge needles each month, and there's a variety of challenges with it.

But it's a standard of care and only 3,000 of those 36,000 people are on that drug. And some remain untreated, this 4,500 remain untreated. I don't think they've all been cured by surgery. So we can do a lot just in this initial phase. But perhaps more troublesome is in the center of the next phase that we're just beginning later this year, there's another 9,000 patients who have dropped out of care for one reason or another. Sometimes they may be given up on the drug or maybe they think they've been cured even if they're not.

And the other part at the end in Phase III is that there's roughly 17,000 patients walking around in the U.S. today that have not yet been diagnosed. It takes 5 to 10 years to be diagnosed with acromegaly. And it's really easy once you suspect acromegaly to diagnose it. But that 5 to 10 years, they're accumulating damage from uncontrolled hormone levels. And so we're going to launch efforts to try and improve that diagnosis. And I've been asked flat out if Palsonify can ever be a blockbuster drug. And I think most people think it's a niche little market because of that 3,000 people of injectables, and they think maybe we'll get some share of that.

And I'll just say here today, very clearly, if it's not a blockbuster someday, I think we've screwed up. Look at this number of patients at the price that we have with this, it's roughly somewhere less than 5,000 patients per $1 billion of revenue. If we can't help more than 5,000 patients, we've not done our job.

So the second indication for Palsonify is the treatment of carcinoid syndrome. We reported some great Phase II data a little while back where you could see the reduction in the symptoms, which is flushing and severe diarrhea and some individuals going from 6, 7, 8, 10 flushing episodes or diarrhea episodes a day down to normal levels, which is essentially 0 for flushing, and a couple of times a day, a few times a day for bowel movements and reduction in the severity. And we've launched a Phase III trial in this with more than 20 sites activated. The first patient enrolled last November. It will have an OLE to look at real-world evidence. But here's another 18,000 to 34,000 people in the U.S. with carcinoid syndrome. And we know this mechanism of action works. So there is a potential here for another large indication and frankly, to help a large number of people.

Our second molecule, which we internally discovered is atumelnant, which is an ACTH antagonist. For those of you who don't know, a guy named Harvey Cushing discovered a disease called Cushing's disease in 1910. We discovered ACTH in the 1930s as the main driver of adrenal activity. All of us in endocrinology have known that an ACTH antagonist would have some very powerful uses, but it wasn't until we managed to come up with atumelnant that we've been able to test that in the clinic. This is the first and only -- and it's once daily oral again. It's an MC2R antagonist, which is the ACTH receptor. And it selectively blocks the ACTH receptor on the adrenal, which is the only place this receptor is expressed and the only thing it does. It's a professional regulator of the adrenal cortex.

And the ACTH is made by the pituitary gland. It controls the stress response pathway. It controls metabolism. And when it gets out of control in things like congenital adrenal hyperplasia, where the adrenal starts making androgens instead of glucocorticoids and the androgens are things like A4 that are marked down here. We believe that then atumelnant can block those and help treat some of the symptoms of the disease. And I'll get into that in a little bit in the next slides.

So with CAH or congenital adrenal hyperplasia, as I said, the adrenal is not really working anymore. It's not making cortisol, which you need to survive. So you got to take some cortisol back. But it's making these precursors to cortisol, much of which are androgens. And in women, these cause infertility issues, hirsutism and both men and women, it causes infertility and in men, it leads to testicular adrenal rest tumors. And until recently, the only tool we've had to manage it is giving them more glucocorticoids. And if you give too much glucocorticoids to try and push down those adrenal androgens, well, then you start getting Cushing's disease because you have too much glucocorticoids and you start getting loss of glucose control, weight gain. There's a variety of other problems with glucocorticoids like osteoporosis.

So there's a wide range of patients out there with CAH. Some have high adrenal androgens, but they've maintained normal glucocorticoids. Some have normal adrenal androgens, but they can only do it with high adrenal -- with high glucocorticoids. And many are very high in both still. Now this is routinely diagnosed at birth. So it's not a question of finding patients, it's a question of treating them. And so our vision for atumelnant is to have an uncompromising path to controlling both dimensions of these hormones so a single pill once a day can eliminate that excess ACTH-driven adrenal byproducts and allow the patient to just take normal physiologic replacement doses of glucocorticoids.

And we're well on that path with our Phase II data. Earlier last year, we showed the dose response in 3 cohorts from 40 to 120 milligrams. You can see dramatic reductions in this biomarker A4 with nice dose-dependent suppression. And these were all given with a dose of atumelnant in the evening, measure A4 in the morning, and we were very pleased with those results. But while we were getting ready for Phase III, we had a little extra time. And so we decided to test 80 milligrams again. but in a different paradigm, giving it in the morning when it is a little more convenient for some people.

But also in the first 3 cohorts, we kept them on a stable dose, whatever dose they were on of glucocorticoids. In this fourth cohort, we reduced the glucocorticoids as best we could to normal levels. And what you can see is that even despite the morning dosing and despite the glucocorticoid reduction, you essentially have the same data you had if you kept the glucocorticoids high. So the glucocorticoids weren't mattering for the effect of the drug. And that's shown perhaps a little more clearly here, we're focused just on the time course for Cohort 4. In green, you can see the serum adrenal androgens going down dramatically within 2 weeks and then maintaining that reduction throughout the 12-week treatment period of the study.

At the same time, we're lowering the glucocorticoid dose to where 7 out of 10 of these patients are getting to normal levels of glucocorticoid replacement. And there's no rebound in the adrenal androgens. So like we hypothesized, we've now been able to dissociate adrenal misactivation from the glucocorticoid replacement. And our goal for Phase III then is to look at the ability of atumelnant to let people achieve normal hormone levels on both dimensions. Study is designed as a responder analysis so that those people who get there on drug compared to placebo will tell us the answer.

Now of course, we've got a variety of secondary endpoints. I was super pleased in the Phase II program that we're also seeing some clinical outcomes. We had multiple women who had been amenorrheic or oligomenorrheic return to normal menses. We had testosterone lowering in women. We had reductions in polycythemia, which is excess red blood cells due to excess androgens. I think now as we go into Phase III with longer treatment periods and glucocorticoid reductions that perhaps we'll be able to see some of the effects on the reduction of excess glucocorticoids, which should result in weight loss or waste improvements or HbA1c reductions. And so we're very excited and moving as fast as we can to ramp this study up. It's already active and going.

Importantly, though, atumelnant continues to be well tolerated throughout the whole program with stable glucocorticoid doses and if the glucocorticoid doses are reduced, we've seen no additional elevations of liver function tests in the Cohort 4 or in the open-label extension. We now have over 750 weeks of cumulative CAH patient exposures from the Phase II and the OLE. We have more than 200 overall participants who've received atumelnant to date across the clinical program, including CAH. We have a parallel Cushing's study going on, that I'll talk about another day and all the healthy volunteer and clinical pharmacology studies. So we're very pleased with that drug.

And then coming back to its potential, roughly 12,000 patients in the U.S. and 5,000 kids. The data we've shown so far shows rapid and sustained reductions in these adrenal androgens despite reducing glucocorticoids to normal levels in 7 out of 8 patients. And overall, we're very happy with the benefit risk profile. The pediatric trial is getting underway in the first half of this and the Phase II open-label extension has now got roughly 25 patients enrolled in it. Those patients will continue to provide a cohort that we can follow and monitor both biochemical and clinical outcomes, and we'll be reporting on that as the data becomes available.

9682 is our newest entry into the clinic. This is a whole new platform, similar to what we did with the Radionetics platform, where we're using small molecules as drug targeting agents instead of like antibodies in an ADC. And small molecules come with a variety of advantages over antibodies for drug targeting. For one, you can tune every dimension of chemical space to get the pharmacology or PK or biodistribution you want. You're not limited just to an antibody, which is typically difficult to have a short half-life on because really, you want to deliver your payload and then get out of the way. And it allows for chemical synthesis rather than bioconjugation reactions and fermentation.

But 9682, we've extensively optimized to target the somatostatin 2 receptor. The targeting ligand is not Palsonify. It's a separate molecule we've optimized to bind with high affinity and drive internalization of the receptor. The linker has been optimized to be stable in plasma and only cleaved inside the intracellular compartments. The payload is a payload we borrowed from the ADC world, and we're starting now a Phase I/II trial in this -- in patients with SST2 positive expressing solid tumors.

Now if you look just at the neuroendocrine tumor space, there's probably 11,000 to 21,000 people that are being treated now with various antitumor agents, a large number more with neuroendocrine tumors or not. The standard of care in neuroendocrine tumors is to use a somatostatin-targeted PET scan to stage and characterize the disease. So all of these patients are getting tested for somatostatin expression. So we'll go into patients who we know express the target in the tumors at a level we think is adequate.

But as that has been -- field has been developing, I think we saw at this today or this week or last week and the success of the other radiotherapies like Lutathera, many of these are targeting SST2 receptors. And what we're seeing is that as you start looking at other types of tumors, many of those also express somatostatin receptors. The vast majority of head and neck, paragangliomas, meningiomas, small cell lung cancer is a high-grade neuroendocrine tumor. There's a population of ER-positive breast cancers that are somatostatin positive. So the potential for this could go well beyond neuroendocrine tumors, and we're just figuring that out now.

But I think the difference between this and the radiotherapies is it democratizes therapy. You don't need to go to a center. You don't need to be radioactive for a couple of days and not go back to your family. This is something that any infusion center in any country oncology clinic can manage. So very excited to see this. The screening queue has been full since we opened the study. We're working our way up dose escalation cohorts, then we'll get into expansion cohorts. I'm really excited to see that progress this year.

So wrapping up, if I look forward to 2030, I think you'll see us emerging as a premier endocrinology business. This is a business that will be sustainably growing and funded by revenue, not just equity capital. We should have 2 marketed products with 4 approved indications, and I showed you the potential for those indications. Moreover, our efforts in discovery and development should result in another 7 clinical pipeline candidates working their way in. Some will be late stage by this time.

And finally, we continue to invest in our discovery labs, and there's a bunch of new targets that I'm very excited for the group to get started on that we'll tell you about someday in the future. But put all this together, and I think it's a fairly unique profile for a company. And I've been very privileged to lead a great group of people with a very unique company and culture. But I've also been grateful to the support of many of you who've been long-standing supporters and owners of the company along with us and management. So just take a moment to thank all my staff who's delivered all this, the patients, the investigators, you and others and take your questions. I've got Toby, our Chief Financial Officer; and Isabel, our Chief Commercial Officer, to help if I don't know the answers. Thank you.

Great. [Operator Instructions] I guess maybe starting with Palsonify and just expanding on the launch a little bit. Can you talk about the top priorities to drive Palsonify's growth in 2026? And maybe I'll just add on to that a little bit. When you have north of 200 enrollment forms across 125 unique writers, what's your interpretation of kind of the interplay of those 2 numbers?

Go ahead, Isabel.

Thank you. Well, our goal is to become the new standard of care in acromegaly, and we are very pleased with the very strong beginning in that journey. So for 2026, our priority is to expand our prescriber base and penetrate more into the community segment, but also into the PTC centers and get breadth of utilization. We really want to have champions for our drug. We are transforming the lives of patients. And as the product continues to deliver sometimes above the clinical trials in the real world, we want to also disseminate more of that data in real-world publications and case studies as we go in 2026.

Second, we really want to activate the patients. Many patients in rare diseases and particularly in acromegaly has settled with the current conditions or had given up hope and are not in any treatments. We think we can bring them back. We have a drug that delivers a fast onset of action, great control of the disease, meaning symptom control and IGF-1 control, and it's easy to take. It's a once daily dose. So we have the full package to bring them back. And at the beginning of that journey of activating the patients is really a start with our peer-to-peer program and really for the patients to hear from other patients.

And last but not least, we are going to be focusing on execution with payers. We have been successful in these medical exceptions, and we have gotten many of our prescriptions reimbursed. We're going to get to more of that. And we are very actively presenting our value proposition with payers. We have several meetings set up. We want to be in as many formularies as possible, really covered to label. And as Scott mentioned, we started this year with CVS covering us over 27 million lives to label, no step edits. That's what we want to achieve in the execution of 2026. So our goal is to continue to grow and to have as many patients as possible benefiting from this great therapy.

In terms to your second question, well, we are very pleased to see that it's no one prescriber driving the market, that we have many physicians that are giving the opportunity to their patients to be on drug. And every one of those physicians will see the experience. They are in a trial period and they have a second patient and a third patient, so that will help us grow. So we are very pleased that it's not coming from 3 or 4 prescribers, but that we see a broad base of patients -- of prescribers associated to those enrollments.

And you mentioned CVS. So can you talk a little bit more about just how patient access to Palsonify has played out so far, how you anticipate payer coverage, access and frankly, gross to net dynamics evolving from here?

We have a very strong payer team. And in general, the commercial organization and the medical affairs organization, I'm very pleased that they are so focused on execution and are true advocates of the patients. So our market access team has a very strong hub with sell services. One of them is, of course, benefit verification and accelerating and partnering with our specialty pharmacies to ensure that many of those claims get reimbursed right out of -- after the enrollment is received. And as Scott shared, about 50% of those have been covered in a short period of time, many of them within 72 hours. We have a very strong label. We have a right package for those prioritizations, and we are moving relatively fast through those medical exceptions.

If the patient doesn't have the coverage or it takes a little bit longer to get that through, we go through the Quick Start program. And once they are in the Quick Start, we, of course, continue to partner with the physician of the specialty pharmacy to move that to a reimbursed claim. One thing that has been positive for us is because the drug works so fast within 2 or 4 weeks, we submit that data in addition to the additional clinical notes. So the average movement between Quick Start and reimbursed time lines in rare diseases is about 57 days. We're trying to stay within that or less, and we'll continue to proceed on that. And of course, we have several meetings set up with payers, and we have a very strong value proposition to deliver and it's resonating well with them.

I think for your second question in terms of gross to net, right now, we have no plans to discount to commercial payers. So our gross to net is driven by 2 things, basically, the mix of business between the commercial payers and the government pay. And then secondly, sort of the mix of business that's happening in 340B institutions and non-340B institutions. So those are kind of the key drivers of where the gross to net will play out over the next year. And right now, it's pretty early innings, but we'll see how that plays out, but we're really comfortable with our early estimates.

Can you say where you see those -- the mix of those 2 either so far in the future?

Yes. Right now, based on sort of our early estimates and sort of prior mix, we thought about 60% of patients would be commercial pay, about 40% would be Medicare and Medicaid. And it's really early to say on the PTC mix right now. Primarily, those are driving the 340B institutions. So those are -- that's the big swing factor.

Maybe we can touch on carcinoid quickly, but what are the next key milestones for the carcinoid program? And when could we expect pivotal data?

So we're actively enrolling now and enrolling sites still around the world. The next big milestone will be completion of enrollment, and that will start the clock ticking to when we expect to report data. Typically, don't want to guide to exactly when we expect that enrollment to finish because you never know and you never know when that last patient is going to come. But one of the things we've done is our Chief Operating Officer, Jeff and his team, has been working on a variety of different things that many of you may find boring, but are really important in terms of accelerating our clinical trials. Some include that we've now started monitoring and doing all the contracting work in the U.S. ourselves rather than through CROs, which starts the relationship earliest in the clinical trials with the people that will end up being our prescribers. Others are how we construct these contracts and incentive schemes with CROs and with sites.

Shifting to atumelnant and thinking about that Cohort 4 data you recently released, what are the arguments to expect or not expect similar results in Phase III?

Look, I think we've shown throughout the development program that atumelnant can completely block the ACTH receptor for most patients and -- most people, excuse me. And we've shown this in multiple ways. So Cohort 4 data was not a surprise to me and shouldn't be -- have been a surprise to the community because I've been explaining why we expected it. Even in our Phase I, when we took healthy volunteers and we challenged them with massive doses of ACTH, they still maintained a very low adrenal activity. And so between that and in our Cushing's study at the NIH, where every patient is getting to very low glucocorticoid levels. This is a disease where they have excess glucocorticoids and everybody is getting down into the normal range.

And now with all the data in CAH, everything points towards from an efficacy point of view or pharmacology point of view that we should have very high degree of response and responders. The wildcard in CAH really comes down to compliance issues and managing high-quality clinical trials, which, again, is something to easily underestimate how hard it is to do that. But what we showed in our Phase III program for Palsonify was very high-quality data with making sure we got the right patients in without protocol violations and a very solid data set to work with. So we're trying to replicate that as part of building a company that can do good global clinical trials.

So that kind of takes me to my next question, which is it sounds like you're emphasizing almost a methodical approach to executing the study to kind of ensure the best results. So how should we think about the time lines for Phase III enrollment and data? And I guess related to that, how does the availability of chronicity factor into those -- to that thinking?

Yes. So the reality in rare disease clinical trials is that the bulk of patients entering the trial come from outside the U.S. It's a cultural thing in the U.S. So the short answer is that I don't expect the launch of chronicity to hinder our ability to recruit the trial, primarily because most of the patients will be ex U.S. But in the U.S., maybe it will even help us a little bit because we're building -- we, meaning the endocrine community, are building an awareness that you can treat your CAH in ways other than glucocorticoids. And I think that's important.

Chronicity has been a big advance for the field and people really have been benefiting from it. But not everybody is getting to the level of hormone control that I think they could get to with atumelnant. So we're more than welcome to recruit patients who are on chronicity into our Phase III program. We specifically were requested that by our investigators. We'll see if we get enough to have a decent cohort for a post-hoc comparison. But I think from a recruitment rate, I don't think it makes a difference one way or another.

What about on the kind of safety side? Have you seen any other elevations in liver enzymes with atumelnant since you disclosed -- since what you disclosed last January?

Yes. So just for those of you who don't know the story, we had one LFT last year that was reported as an adverse event that we couldn't rule out as being drug-related or not. And it got a few people a little anxious, did not get the regulators or us particularly anxious. But the short answer to your question is nothing else new in the Cohort 4 or the OLE or that whole population of people that we've been studying the drug in that I described in the slides.

And what about thinking about taking atumelnant outside the U.S. What's your kind of international strategy?

From development or commercial?

Commercial.

Commercial. So we have done clinical trials around the world, typically 20 to 25 different companies -- countries. The endocrine community is very international and close knit. And in the long run, we need to serve people well beyond the United States. But I think as you all know, right now, is a complicated period, and it's a complicated period because of MFN and drug reimbursement things. I think that we'll have much more clarity in how that all plays out by the time atumelnant gets approved and it's launching in the U.S. But we're developing it around the world. We even have sites in Japan, so we'll have a Japanese population for atumelnant as well.

Okay. Great. I think we are out of time, so we'll stop it there. Thank you.

Thanks again, Jess. Thank you, everyone.

Thank you.

Welcome to the Crinetics Pharmaceuticals Corporate Update Conference Call. [Operator Instructions] I will now turn the call over to Gayathri Diwakar, Head of Investor Relations. Please go ahead.

Thank you, operator. Good morning, everyone, and thank you for joining us to discuss today's corporate update. On the call, we have Dr. Scott Struthers, Founder and Chief Executive Officer; and Dr. Alan Krasner, Chief Endocrinologists. Also joining for the Q&A portion will be Isabel Kalofonos, Chief Commercial Officer; Tobin Schilke, Chief Financial Officer; and Dr. Garnet Howells, Global Product Leader. Please note there's a slide deck for today's presentation, which is in the Events and Presentations section of the Investors page on Crinetics website. In addition, the press release is issued earlier today and is also available on the corporate website.

As a reminder -- Slide 2, 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'll be reviewing launch progress to date, future performance and other data about the acromegaly market as well as plans for Phase III studies for Atumelnant, 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 is 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. Scott?

Good morning. Thank you for joining us for today's update to kick off 2026. First, we're excited to share the great progress we've made on the PALSONIFY launch during its first full quarter after approval late in September. We hit the ground running and the momentum we're seeing is exactly what this community needs. Second, Atumelnant continues to demonstrate its potential to transform the treatment landscape for patients living with congenital adrenal hyperplasia, or CAH. Our goal has always been to set a new standard of care where patients do not have to choose between managing their excess adrenal androgens and enduring the side effects of high-dose steroids.

The data we are sharing today brings us one step closer to making that reality for the thousands of people struggling with CAH. We believe the totality of the Atumelnant data collected to date across healthy volunteers, Cushing's disease patients and CAH patients demonstrates its robust benefit risk profile. Today's update strengthens our conviction in the Phase III CAH study and positions Atumelnant to become the leading medical therapy for people struggling with CAH.

We've proven that our discovery engine can deliver world-class science and that our development organization can deliver compelling data for regulatory approval. Now we're proving that we can deliver our products to patients across the U.S. and get reimbursed. PALSONIFY is just the first step in our journey to redefine endocrine care. Atumelnant is the second step. As you'll see today, we are strongly positioned to turn this landmark year into sustained growth.

Commercial execution remains our top priority for the company. So I want to take a few moments to review the exciting progress we've made on the first full quarter of the PALSONIFY launch. Turning to Slide 5. When we talk about 36,000 people living with acromegaly in the U.S., we aren't just looking at a market opportunity. We're looking at thousands of individual journeys that have been stalled by burdensome, inconsistent treatments. Many have abandoned medical care. Many more have not yet been diagnosed for the underlying cause of what has been troubling them.

Our phase launch strategy for PALSONIFY is designed to meet these patients wherever they are, whether they're currently struggling with monthly injections or have been lost to the system entirely. At this point, we're early in the first phase. We're focusing intensely on the approximately 10,000 switch and treatment-naive patients already actively managed by a health care provider. Succeeding here will bring experience, confidence and voice to both patients and their care providers.

In the second phase, we will identify and activate the approximately 9,000 patients who don't appear to be actively managing their acromegaly. We hope that some of these may have been surgically cured, but it's unlikely to be the case for most of them. This phase will begin later this year and build on the momentum from the first phase. Over time, our goal in the final phase is to accelerate the diagnostic process itself.

It takes 5 to 10 years to diagnose acromegaly, and during that time, damage accumulates. This is a daunting but very important challenge. We'll begin laying research groundwork this year to define potential approaches to solving this problem. Let us not forget that the success in these efforts will not just grow the markets for PALSONIFY, will help thousands of people living with acromegaly get the care they need and deserve.

Turning to Slide 6. Our goal for PALSONIFY is to become the leading medical therapy for acromegaly. We believe that the metrics shown here demonstrate that we are off to a great start. From a patient perspective, the feedback has been strongly positive. Some patients were eagerly awaiting approval. They and others who are only more recently heard about PALSONIFY are starting to ask their HCPs for it. Others have heard about it from their HCPs and decided to give it a try.

We are seeing people switching from injectable peptide depots and oral octreotide. We are seeing people receiving PALSONIFY as their first-ever medical therapy for their acromegaly. All of our 22 U.S.-based open-label extension patients have switched to commercial supplies. To date, we have processed more than 200 enrollment forms. On the provider side, we have healthy uptake across a broad base of prescribers in all regions of the country.

Our messages of efficacy and speed of onset of action are resonating. Built on the strong execution of our commercial and medical teams, we now have more than 125 unique prescribers with roughly 50% of them in smaller community-based practices and the rest practicing in pituitary treatment centers or PTCs. This reflects our approach of deploying the field force, both in the community and to the centers from the start. Over time, we expect this ratio to tilt further towards community prescribers, of which there are many more than prescribers in the PTC setting.

Finally, our payer-facing team has been very active meeting with all key payers. We've already secured early formulation -- formulary inclusions. These are sooner than expected given that this is not the typical time of year for payers to update their plans. Currently, we are pleased to see that with the help of our patient support program, CrinetiCARE, that roughly 50% of filled prescriptions are rapidly reimbursed before needing to ship a bridging supply through our Quick Start program.

We are also pleased to see that the vast majority of prior authorizations are for 12 months so the patients have a full year without worrying about their insurance for PALSONIFY.

Finally, we're pleased to report that this activity has resulted in over $5 million in unaudited net PALSONIFY revenue for the fourth quarter. On Slide 7, you'll see that while we're very pleased to have achieved the metrics of success above, it's the individual stories of how people have benefited from our efforts that resonate the most with us here at Crinetics. I've personally known some of these patients for years and seeing the clinical development of PALSONIFY translate into life-changing results for them, is extremely meaningful. On this slide are stories of Megan, David and Ashley. They are the first 3 ambassadors in our PALSONIFY, patient ambassador program.

At the start, ambassadors will have been on PALSONIFY anywhere from a few weeks up to 4 years, and they are all excited to share with others about their experience both with PALSONIFY and navigating their health care journey as someone living with acromegaly. Patients want to hear from other patients, and we will ramp up this activity in 2026 as more and more patients have treatment experience on PALSONIFY and qualify to become ambassadors.

Building on the success of the discovery, development, approval and launch of PALSONIFY, now let's turn to our second candidate, Atumelnant. On Slide 9, a reminder that we designed Atumelnant to transform the CAH treatment paradigm. Since CAH was first characterized, people living with this genetic disease have been trapped in a zero-sum game between the consequences of uncontrolled adrenal androgens and the Cushing's syndrome like adverse consequences of exogenous excess glucocorticoids. The data we are sharing today demonstrates with Atumelnant, this trade-off could no longer be necessary.

As a reminder, we added Cohort 4 to the Phase II study to evaluate Atumelnant's ability to lower A4 while tapering glucocorticoids to physiologic dosing levels and to assess dosing of Atumelnant in the morning versus the evening. Alan will share the details, but at a high level, the findings from Cohort 4 are what we expected from our prior Phase I and II results. Because of Atumelnant's unique mechanism of action, it can block wexcess production of adrenal androgens even in the context of low physiologic replacement doses of glucocorticoids.

These results, together with confirmatory results from the first patients reaching 13 weeks in the open-label extension of Phase II, reinforce our conviction in the Phase III CALM study in adults with CAH. All data so far point towards a highly differentiated profile that we anticipate will propel Atumelnant to become the preferred medical therapy for the treatment of CAH after it is approved.

Importantly, Atumelnant continues to be well tolerated with a growing safety database, including more than 750 weeks of adult CAH patient exposure. To date, we have well over 200 participants exposed to Atumelnant in a combination of healthy volunteer, clinical pharmacology, Cushing's and CAH studies. We continue to be encouraged by the very favorable benefit risk profile across the board. With that, I'll turn the call over to Alan to discuss today's Atumelnant results in more detail. Alan?

Thank you, Scott. Before we get into the data, I'd like to take a moment to briefly review Atumelnant's unique mechanism of action and why it is an attractive approach for the treatment of CAH. For decades, the only way to reduce excess adrenal androgen production in this disease was to increase glucocorticoid doses to suppress ACTH production. Glucocorticoid treatment, though, is an inefficient means of reducing adrenal androgen. And unfortunately, many patients end up on high doses of glucocorticoid and still have high androgen levels.

Atumelnant is the first and only agent tested in humans that selectively blocks the ACTH receptor found only in the adrenal glands. The ACTH receptor is a single choke point in the system, which likely explains the potency seen with Atumelnant to date. Data from the first 3 treatment cohorts from this Phase II CAH study demonstrated that treatment with Atumelnant results in marked androgen reductions when baseline glucocorticoid doses remain fixed.

In addition, data from healthy volunteers in the Phase I study showed that the ACTH antagonism provided by Atumelnant could withstand huge surges of ACTH exposure. Based on the totality of data, we hypothesized that when glucocorticoid doses are reduced in the presence of Atumelnant, the reduction in adrenal androgen levels would be sustained, and Cohort 4 is the first test of this hypothesis.

In contrast, CRF1 antagonist, one of which is approved, can be circumvented through other pathways, most notably stimulation of ACTH production by arginine vasopressin. Slide 11 shows published Phase III data from the study, which evaluated the approved CRF1 antagonist, crinecerfont in adults with CAH who prior to the trial took high doses of glucocorticoid. We can see that androgens as measured by androstenedione or A4 levels were reduced at 1 month when glucocorticoid doses were fixed. This reduction in androgen nearly evaporated after a period of glucocorticoid dose reduction from weeks 4 to 24, although A4 levels were still improved compared to placebo.

Slide 12 shows our vision for Atumelnant. We believe Atumelnant will represent another level of care in which patients and their health care providers can pursue both goals of medical therapy in CAH that is achieving low physiologic doses of glucocorticoid replacement without losing the reduction in androgens. Furthermore, we believe Atumelnant could be a treatment for the broadest possible spectrum of people with CAH who need treatment for those who happen to be on high doses of glucocorticoids, but also those who have elevated levels of adrenal androgens regardless of glucocorticoid dose.

Slide 13 explains why there are 2 goals for the treatment of CAH. Excess androgen can cause a host of problems, including infertility, acne and polycythemia or elevated red cell counts in males and females. In females, it is associated with menstrual disorders and hirsutism or excessive hair growth. On the other hand, glucocorticoids when used at supraphysiologic doses to treat high androgen levels can cause their own panoply of medical problems, including diabetes, weight gain, osteoporosis and cardiovascular disease. We have previously reported improvements in menstrual function and resolution of polycythemia even within the 3-month treatment period of this Phase II study. We will be carefully documenting clinical outcome improvements in the longer-term Phase III CALM-CAH study getting underway.

Here, we see the Phase II TouCAHn study, which was designed primarily to evaluate safety and to identify the doses of Atumelnant, which best lowered A4 levels in adult patients. The study evaluated 3 different Atumelnant doses in patients with classical CAH who had elevated A4 levels while using supraphysiologic doses of glucocorticoid before the trial. Unfortunately, as we mentioned, patients suffering with high androgen levels despite high glucocorticoid doses are all too common in clinical practice.

During the 3-month treatment period, patients in Cohorts 1 through 3 stayed on fixed doses of glucocorticoid based on the dose they were taking prior to the study. We have previously reported results from Cohorts 1 through 3, and we will review those results shortly. In Cohort 4, we are again using 80 milligrams per day of Atumelnant as we did in Cohort 1. However, in Cohort 4, the protocol required glucocorticoid dose reductions to the physiologic range if tolerated. A major objective of Cohort 4 was to assess if A4 reduction seen with Atumelnant would be sustained in the face of these glucocorticoid dose reductions.

We also explored in this study whether the timing of the Atumelnant dose affected A4 lowering. Atumelnant was dosed in the morning in Cohort 4 and given in the evening in Cohorts 1 through 3. More on this later when we review the design of the Phase III study.

Today, we are newly reporting top line results from Cohort 4, the final group to complete the study. 10 patients enrolled in this cohort, 2 withdrew consent after enrollment and therefore, discontinued early. The A4 data in this cohort will be from the 8 completers, but the safety data always include data from all dosed patients. Slide 15 shows the robust A4 declines we saw in all 4 cohorts despite all patients starting with very high A4 levels at baseline. It is notable that the A4 reduction we see in the new Cohort 4 is similar to what we saw at the same dose of Atumelnant previously, despite the fact that glucocorticoid doses were reduced in Cohort 4.

When looking across all 4 cohorts, we see the magnitude of response increasing with increased dose, which we will leverage in Phase III as we will see later. Furthermore, there was no discernible effect of dose timing on the magnitude of effect in this small set of patients. I'd also like to point out a technical factor, which is very important when interpreting these data. The A4 blood samples in Phase II were obtained before the morning glucocorticoid doses. These, therefore, represent the maximum A4 values that would be seen in the course of the day since they are furthest in time from the patient's previous glucocorticoid dose.

In Phase III, we will be measuring A4 after the morning glucocorticoid dose when these levels are lower. We'll review this further when we discuss Phase III design. Slide 16 shows mean glucocorticoid doses and mean A4 levels over time in the Cohort 4 patients. A4 responded dramatically to Atumelnant in the first 2 weeks as we have seen in all the cohorts. Further, the A4 reduction in Cohort 4 did not rebound despite 7 of 8 patients having their glucocorticoid doses successfully reduced to the physiologic range. Mean glucocorticoid doses at baseline by chance happened to be a bit lower in this cohort compared to the others, but these glucocorticoid dose reductions are meaningful and represent yet another stress test that Atumelnant passed.

We previously shared data shown in this figure from the published CRF1 antagonist Phase III trial. The lowered A4 achieved by crinecerfont during the first 4 weeks when glucocorticoid doses remain fixed were largely lost as GC doses were reduced from weeks 4 through 24. In Slide 17, we can qualitatively see that the A4 reductions achieved with Atumelnant within 2 weeks are sustained through 12 weeks. The baseline A4 levels in the Atumelnant study were higher than those in the crinecerfont studies, so quantitative comparisons should be made with caution. However, the shapes of these curves appear to be very different. And if this holds true in the Phase III trial, this could translate to a highly differentiated product profile for Atumelnant.

We also want to share an early data snapshot from the Atumelnant open-label extension trial with you. Please note, this is an ongoing study that has not yet completed enrolling participants. Participants were eligible for this trial if they completed one of the cohorts in the core Phase II study, which includes Cohort 4. The starting dose of Atumelnant was the same dose assigned in the core study. However, there was a gap between the end of the core study and the start of the OLE for most participants.

As is the case with most OLE studies, here, we are trying to simulate real-world clinical practice scenarios in which investigators would have control over both Atumelnant and glucocorticoid doses. However, like the core Phase II study, this protocol instructs investigators to lower glucocorticoid doses to the physiologic range as tolerated.

Slide 19 shows A4 levels over time in the 7 individual subjects who had at least 13 weeks of treatment in the OLE as of the data snapshot from last month. Please note, all 7 of these participants are continuing in the OLE. So far, across the 3 doses used at initiation, we are seeing a median 72% A4 reduction and impressive glucocorticoid dose reductions occurring within a short time of treatment covered so far.

I would note that one patient treated with 80 milligrams seen in this slide is the first one who has been treated with Atumelnant for longer than 3 months. I'm intrigued by what appears to be a progressive decline in A4 after week 13 because this pattern is consistent with the idea that efficacy may improve with time. Recall that we have previously presented MRI data from this study showing adrenal gland volume reductions even within 3 months in these patients who have long -- lifelong hyperplasia of the adrenal glands. This could translate to less androgen-producing capacity over time. Although we cannot make a conclusion from one patient curve, I eagerly await longer-term treatment data from this study and from the Phase III study.

Overall, the OLE data so far are quite convincing or quite encouraging, showing these patients are well along the way to achieving both goals of CAH treatment. This slide shows the most common adverse events reported in the 4 completed cohorts of the Phase II core study. Overall, headache and fatigue were among the most common reported adverse events. These symptoms are commonly reported in this patient population. There were no hepatic transaminase adverse events in Cohort 4 or in the OLE.

Not unexpectedly, in Cohort 4, 2 cases of glucocorticoid deficiency were reported. These reflected nonspecific symptoms believed to be a result of insufficient glucocorticoid dosing, which can be seen when these doses are reduced. One case of adrenal insufficiency in Cohort 4 also reflected similar symptoms with the addition of the objective finding of orthostatic changes in blood pressure. Across the cohorts, no adverse events were classified as serious.

With greater than 750 weeks of combined patient exposure so far and over 200 individuals dosed, Atumelnant has been well tolerated. There were no serious adverse events or discontinuations due to adverse events in the Phase II core or OLE studies to date. As we have shared previously, the Phase III CALMs-CAH study is designed to evaluate the safety and efficacy of Atumelnant. It is a 32-week randomized, double-blind, placebo-controlled trial with a targeted enrollment of 150 patients.

This is the first major study in CAH in which the eligibility criteria include all patients with CAH who need therapy, including those who have elevated levels of adrenal androgens, elevated glucocorticoid doses or both. The sample size is well powered to demonstrate a statistically significant difference between Atumelnant versus placebo in the proportion of participants who achieved normal levels of A4 while being on a physiologic glucocorticoid dose. Quite simply, this primary endpoint reflects the real goals of medical therapy in CAH, sustained androgen reduction and low replacement doses of glucocorticoid.

Like all Crinetics drug candidates, we aim to show that Atumelnant is not only safe and uniquely effective, but also a simple-to-use drug for the broadest possible spectrum of people who need treatment. This slide summarizes the many reasons why we have confidence in Phase III. Firstly, based on the totality of clinical data, the starting Atumelnant dose of 80 milligrams once per day is expected to achieve the primary endpoint therapeutic goals in many patients. However, the study does allow for an up titration to 120 milligrams once per day for those who may need some additional A4 control.

This relationship between dose and response is very reminiscent of the situation we encountered emerging from Phase II with paltusotine, and we are employing a similar single step up titration option used successfully in the PATHFNDR Phase III studies. In addition, the longer duration of the trial should allow plenty of time for patients to reduce their glucocorticoid doses to the physiologic range with the goal of avoiding glucocorticoid withdrawal symptoms. Also, Atumelnant will have more time to reduce glandular hyperplasia, which, as we discussed, might translate to extended androgen lowering even after the acute effect we've already seen in our short-term trial.

Participants in the Phase III study will take their Atumelnant dose in the evening to best match the timing of the maximal concentration of drug exposure to the normal ACTH surge that occurs early in the morning. The data from Cohort 4 presented today indicate that many patients would also succeed with morning dosing. However, it is possible that some individuals in a large group see further benefit from nighttime dosing. As discussed earlier, in Phase III, we will be measuring A4 after the participants take their morning glucocorticoid dose, which literature suggests should allow full androgen reduction to be seen.

To summarize the clinical data, in Cohort 4, we have demonstrated a 67% reduction in A4, consistent with our earlier 80 milligram cohort. This A4 reduction was sustained while 7 of 8 participants reached physiologic glucocorticoid doses. There was no discernible impact of morning versus evening Atumelnant dosing. The overall safety database shows that the drug continues to be well tolerated. And needless to say, we are all very excited about the Phase III program that is already underway. With that, I'll turn it back to Scott for closing remarks.

Thanks, Alan. You know, we often talk about the inflection point of a company transitioning to a commercial stage. But today, you're looking at what it actually looks like in practice for Crinetics. 2025 was a landmark year for us, not just because we conceived, discovered, developed and received approval for our first drug, but because we are now proving that we can deliver it to the patients who need it and get reimbursed.

As we enter 2026, we're operating to advance our mission on all fronts. Our commercial engine is humming. The launch of PALSONIFY is winning because it treats the whole patient, biochemical control and symptom control. But look at the breadth of the pipeline behind that it will follow the path built by PALSONIFY. Today's results from the TouCAHn study and its OLE illustrate the impact we can make for people living with CAH.

Our Phase III CALM-CAH and Balance-CAH trials target one uncompromising goal, healthy hormone levels for every patient, adult and pediatric. We believe Atumelnant will redefine the standard of care for CAH because we are treating the misfunctioning adrenal itself, reserving steroid use for physiologic replacement only. In parallel, paltusotine is advancing in Phase III for the treatment of patients with carcinoid syndrome, and we're pioneering the next wave of targeted therapeutics with our NDC program led by CRN-9682, currently in a Phase I/II trial for patients with SST2 expressing cancers.

Today isn't just about one drug or one launch, it's about the emergence of a sustainable, independent, creative leader in endocrinology and the adjacent fields that endocrinology can impact. This is just our beginning. Thank you all for your continued support. Operator, we're now ready to start the Q&A portion of the call. Thank you.

Absolutely. [Operator Instructions] Our first question will go to the line of Yasmeen Rahimi with Piper Sandler.

Congrats on the outstanding launch matrix as well as the CAH Atumelnant data. I think that -- my first question is on the really remarkable 200 starting forms. The danger sometimes becomes that analysts and investors take the 200 over the quarter reported and think about linearity as we go into 1Q 2026 and beyond. Would really appreciate Isabel's and Tobi's color and thoughts and Scott's on how we should be thinking about sort of uptick in the first few quarters of this year, and I'll jump back in the queue.

Thanks, Yas. Appreciate the comments. Yes, let me let Tobi take this for a second.

Thanks, Yas. We're really pleased to achieve this enrollment forms. It's difficult at this point in time to extrapolate going forward. However, it is a really strong start, and it reflects the execution of the field team. It reflects the messaging that we've delivered upon leading with efficacy and the onset of symptom control for PALSONIFY. And we're really encouraged by what we're seeing in the first quarter of launch.

Our next question will go to the line of Gavin Clark-Gartner with Evercore ISI.

Congrats on the really great updates. I was just hoping for Atumelnant and CAH, you could synthesize the case for why you believe you will be able to drive commercial switches from chronicity down the line? Like what are the key attributes and the data here that will enable that? What other data will you be generating in Phase III to make this case?

Yes. Well, thanks, Gavin. It's still a little early, but the profile that's emerging is really a very strong case for Atumelnant. And in many ways, it's very reminiscent of the emergence of PALSONIFY in its class. And if you look at what PALSONIFY was facing, it was a standard of care that really wasn't there, it wasn't where it could be. The one other oral competitor was BID. And the things that have stood out for PALSONIFY, I think, also will stand out for Atumelnant.

First, we're seeing rapid, rapid decrease in adrenal androgens, 2 weeks. Second, it's sustained. And this not having to compromise between glucocorticoids and adrenal androgens, I think, is something that's really important. Third, we're measuring in Phase II and in Phase III, we didn't talk so much about it today, but when we reported the earlier data, we noted a whole bunch of different ways in which patients were feeling the effects of the drug, and getting benefit even in the short 12-week period.

And I think that will only continue to be an important factor in the Phase III program where it's longer and larger numbers of patients, so you can start to see these. So not just treating the biochemistry, but the symptoms and the impacts of the disease. And finally, just a fairly mundane thing, but it's sure is easier for me to take a drug once a day than twice a day. So I think that's just a simple little thing.

Our next question will go to the line of Tyler Van Buren with TD Cowen.

Congratulations on 2 great updates to kick off the new year. Tough to ask just one, but I'll ask one on, again, the Cohort 4 Atumelnant data. So given that you tested a relatively rapid tapering of the GC dosing in Cohort 4, can you elaborate more on the transition to Phase III when there's a more gradual GC tapering, what impact that might have? And also just the evidence suggesting a reduction in adrenal gland volume may result in further A4 lowering?

Alan?

Yes. Thanks for the question. So 3 months, you're right to say, is kind of a short time to get a large group of people to reduce doses of glucocorticoid in this situation. Remember, these are patients who've been taking high doses of glucocorticoids for many, many years, if not all their lives. And we know that when you start out at a high dose and reduce that dose, patients' bodies who are used to the higher exposure to glucocorticoid, they can start to feel these nonspecific glucocorticoid withdrawal symptoms.

And I was even in this 3-month study, a little worried that we might run across a lot of that in this period of time. However, as we see in our data, it actually was doable in most of these patients. Now remember, this is a fairly small group of patients just in Cohort 4. When we get to Phase III and we have 150 patients, we might need to go slower on that taper in order to get everyone used to the lower doses of glucocorticoid. But I'm quite confident the duration of the Phase III trial, I think leaves us plenty of time to do that safely and in a well-tolerated way.

Yes. Another thing I was surprised that we saw within 3 months with this ACTH antagonist that we reported previously is sometimes very dramatic reductions in the adrenal gland volumes. Remember, these are, by definition, overgrown hyperplastic adrenal glands, and they've been that way pretty much for the whole lives for these patients. And the fact that we can see structurally reduced volumes is impressive. We don't know that, that correlates yet with biochemistry. But in theory, we will have less tissue manufacturing androgen over time of exposure with the drug when the adrenal glands do shrink. So we shall see with greater exposure and greater time and greater numbers of patients in Phase III. But certainly, what we're seeing so far is very encouraging.

Our next question will go to the line of Leland Gershell with Oppenheimer.

Congrats from us also on the progress, both commercial and pipeline. Just one question on Atumelnant. Great to see the GC reductions while maintaining androgen suppression. But just wondering with that one patient who wasn't able to, Scott, do you think that's just a question of dose response if you use a bit more Atumelnant that the patient would be able to? Or do you think that there'll just simply be some patients who -- because of biology, perhaps because of high levels of ACTH that those will outcompete the drug and maybe prevent them from being able to taper their glucocorticoids?

Yes. Thanks. I think you're referring to that OLE patient who had a minimal effect, but noticed they're on 40 milligrams. So...

Was it about the patient who didn't -- wasn't able to get the physiologic GC?

Oh, is that what you meant, Leland? Sorry, I wasn't quite sure, out of the 7 out of 8.

It's 7 of 8, yes, exactly right, yes.

Okay. Yes, yes, yes. So on that particular one, I think that's more just a timing issue than as much as anything else. But maybe you want to comment, Alan.

Yes. This was a patient who had difficulty with symptoms of low glucocorticoid exposure, and it was determined the patient really shouldn't rapidly titrate down. We're following that same patient in the open-label extension, and we're already seeing with time, the patient has been able to significantly reduce their glucocorticoid doses. So yes, I mean, I think it's -- that's an example of why 3 months is a little bit short even for everybody in a small group.

Yes. And so back to the mechanistic side of your question, that's why I thought you were talking about the OLE data where you noticed that one of the patients has had a very modest decline in A4 and they're only on 40 milligrams. So as part of that protocol, they'll be able to go up to 80 milligrams and then 120 milligrams if they need it. But mechanistically, there's no reason to believe that any patient with CAH should be somehow resistant to Atumelnant.

The adrenal gland -- the adrenal cortex is dependent on ACTH signaling. Atumelnant blocks that very effectively. And so that should lower activity of the ACTH signaling into the adrenal for anybody with CAH. And the question about are there just some patients with so much ACTH that they'll overcome this antagonism, I think we answered that very clearly in Phase I, and I keep reminding people of it. But remember, in Phase I, in our MAD's portion of the study also on 80 milligrams that we saw a rise in ACTH with time as you lowered glucocorticoid negative feedback.

And then we gave them this whopping dose of ACTH as an ACTH challenge test, which is far more than any CAH patients is going to see and probably even more than any ectopic ACTH secreting tumor is going to make. And we're still able to keep those patients adrenally insufficient. And so that's why I've guided all along that we were not worried about the ability of Atumelnant to maintain adrenal suppression in the face of glucocorticoid lowering, but it's also nice to see the actual data.

Our next question will go to the line of Joe Schwartz with Leerink Partners.

Congrats as well on the strong updates across the board. I was wondering if you could talk for a moment about the endpoints you're using to document potential clinical improvements for the patients who are being enrolled in CALM-CAH, which clinical manifestations might have the greatest potential to improve and which ones might be expected to be more challenging to impact or document in CALM-CAH?.

Joe, thanks for the question. We've already shown in Phase II improvements in menstrual functioning. And I expect with a greater sample size, we'll be able to talk about more of that, I hope, in Phase III. We also showed biochemical resolution of polycythemia. This is something that's not often thought about here, but it's well known that excess androgen exposure stimulates the growth of red blood cells. And these patients with polycythemia by definition, have excess red cell mass. This is not necessarily a good thing because it can predispose to thrombosis and blood clotting problems.

This was resolved in all the patients who came into the Phase II study with polycythemia within the 3-month period. So I expect more of that as well. We shall see. The other manifestations of hyperandrogenism, for example, these are more long-term issues to try to document, things like hirsutism and excess hair growth can take time. But we will be looking at some interesting features of this disease in Phase III that we haven't explored yet, including, for example, fertility in males, which is a problem in this patient population, and we hope we can help with. So there's a lot of...

And TARTs, you know, and TARTs...

Yes. And there's the testicular adrenal rest tumors that are not uncommonly found and then we will follow the size of those by ultrasound very carefully. And we'll be doing that in the pediatric CAH study, too, where there is -- I would hope we might be able to help children or adults with that problem as well. These are painful tumors in the testes, which can also cause and promote infertility in males.

Yes. The other thing I think we are hopeful that we may see in the longer-term studies is some of the effects of reducing the glucocorticoids, which are not something you can see in the very short term. But remember, excess glucocorticoids drive weight gain, elevated HbA1c. I think there's some opportunities there as well.

Our next question will go to the line of Cory Jubinville with LifeSci Capital.

Congrats on these updates. You have here in a footnote on Slide 6 that 81% of prior auths are a minimum 300-day duration, which seems really impressive. For the 20% of scripts that aren't, I guess, can you speak to the expected duration there? Are these 6-month reviews? Are they monthly reviews with each new script? And I guess, are there any prespecified clinical criteria required to allow patients to renew their prior auth like achieving certain IGF-1 thresholds? And I guess just to be clear, have you received any pushback at all from payers on the availability of generic depot injectables, whether it be step-through edits or otherwise?

Thanks, Cory. I'll remind folks, it's still a little bit early days. But maybe, Isabel, I think you're on the line. Can you address Cory's question?

Sorry, I couldn't hear your question.

He was asking about -- go ahead, Cory. Repeat yourself a little bit.

Yes. So on Slide 6, you have this footnote that 81% of prior auths have this minimum 300-day duration. The 20% of scripts that aren't, what are the duration there? Are the 6-month reviews? Do they need to be reviewed each renewal cycle? And are there any prespecified criteria required for patients to renew their script, whether it would be achieving a certain IGF-1 threshold, et cetera? And then have you received any pushback at all from payers on the availability of generic depot injectables, whether it be step-through edits or any other prior auth requirements?

Thank you, Cory. Yes, we are very pleased that over 80% of the prior approvals are coming over 12 months. And the other of them are coming primarily at 6 months, over 10% of them and a few are coming at 3 months. So a really good initial response from payers. And a few of them actually came from indefinite time, particularly Part D.

In terms of any requirements, no, they are being prescribed to label. So that's great news. And there are no restrictions or prior authorizations -- I'm sorry, step edits that are required. So we are seeing a really good patient dynamic, and we haven't gotten any pushback related to generic use. So overall, it's going really well, and we continue to meet with payers, deliver on our value proposition messages, and we are executing to target when it comes to getting those prioritizations moving as fast as possible.

Our next question will go to the line of Alex Thompson with Stifel.

Congrats on the updates as well. I guess maybe on Atumelnant, obviously, with all the caveats of shorter duration and small numbers, I wonder if you could comment on the proportion of patients across Cohort 4 and the OLE that were able to achieve functionally your Phase III primary endpoint of GC normalization as well as A4 control.

We did have some patients who met that criteria, even though in the Phase II study, as I mentioned, we are looking at a different perspective of A4 control. Remember, in Phase II, we're measuring the androstenedione levels before the morning glucocorticoid doses that the patients take. That's kind of the worst-case scenario, A4. And in Phase III, based on regulatory precedent, we will be looking at it at a time after glucocorticoid dosing when we expect even lower levels of A4. When we look at the totality of data, we're quite confident we will be able to show that difference between patients on drug versus placebo. And we're getting underway, and we're excited.

Yes. And maybe just more directly, in Cohort 4 already, 25% hit the primary endpoint despite these caveats. It's not exactly the primary endpoint, but are there at full control, and the rest are headed there. And same thing in the OLE, everybody is heading in the right direction. So with a little more time, I think there'll be an the ability to dose titrate. We're super confident in the way this is playing out.

Our next question will go to the line of Jon Wolleben with Citizens JMP.

On these updates. Just kind of piggybacking on the prior question, can you discuss in the Phase III protocol, the glucocorticoid reduction? Is this a forced reduction? Or is it only once patients achieve normal A4 levels? I'm just wondering if you could talk through kind of what those 2 different reduction periods look like and the differences between that and what you did in Phase II?

So in Phase II and in Phase III, the glucocorticoid dose reductions will not be based on A4 levels. They will be based on protocol instructions to -- at certain visits to reduce the dose as long as the patient tolerates it from the standpoint of glucocorticoid withdrawal. And so it will be, in a way, a similar set of instructions to what we did in Phase II, which we already saw in 3 months was pretty successful. So I expect with the additional time even in more patients, reducing the vast majority of patients to the physiologic range will be very doable.

Our next question will go to the line of Maxwell Skor with Morgan Stanley.

This is Selena, on for Max. On CAH, how does the positive Cohort 4 data helped informed dosing, specifically in CALM-CAH, would you expect more patients to be maintained on the 80 milligrams dose at week 20 versus titrated to 120 milligrams?

Yes. I think broadly, we've seen that 80 milligrams should be good for the majority of patients, if not all, eventually. It's a little bit of a question of time versus dose as well, right? As Alan was mentioning, we expect the efficacy to improve with time as these -- as he calls it, angry adrenals calm down with the blanket of Atumelnant on them. So I think it's also similar to what you've seen in the PALSONIFY program, right? So 80 milligrams should be good for most, if for some reason, not, then they can go up to 120 milligrams.

Our next question will go to the line of Brian Skorney with Baird.

Just on the PALSONIFY launch, just trying to back out some things from the $5 million figure. I think this would imply something on the order of 250 prescriptions. It was a pure demand number. Was there any inventory build in the quarter to think about impacting next quarter? Or is 250 prescriptions in the quarter a reasonable way to think about building out from in terms of demand in subsequent quarters?

Tobi?

Yes. Thanks. It's a great question. I think that what we're seeing from our specialty distributors and our specialty pharmacy is a healthy level of channel mix and that what we're seeing is all of those there have been reorders within the quarter and that they're managing within the prescribed inventory levels, which are typical in the industry. So the numbers you talk about there in terms of -- you have to think about monthly bottles versus sort of scripts per se. But when you do that, what we're seeing is healthy signs in the trade that the $5 million reflect the demand that's being generated for PALSONIFY.

Yes. And just to clarify, I think I heard something about 250, but we reported more than 200 enrollment forms.

Our next question goes to the line of Dennis Ding with Jefferies.

I had 2 real quick. For CAH, one biomarker that was missing was 17-OHP. So curious why that was left out, if you can comment if the changes in Cohort 4 were similar to what was presented before. And then number two, with regards to the OLE study, I think there was a footnote that said 2 out of the 7 patients have not yet had their GCs reduced yet. Can you confirm that? And any thoughts on why that is?

Yes. Thanks, Dennis. Despite our tendencies to want to produce a predis on the treatment of CAH for each data release, we kind of held back some things for scientific meetings. But the 17-OHP looked a lot like it did before. We'll report out testosterone levels and hydroxy steroid levels and other things at upcoming meetings. Alan, do you want to talk about the OLE?

Yes. So the OLE is a very early data snapshot. And yes, patients -- remember, the doctors have control over exactly when either Atumelnant or glucocorticoid doses are changed. And yes, there were a couple of patients who haven't had a change. But again, this is based on investigator judgment as to when it's the right time for an individual patient overall, we do see in the group as a whole, significant reductions. And again, all these patients are well on track to achieving both therapeutic goals of CAH.

Our next question will go to the line of Rich Law with Goldman Sachs.

Happy New Year and congrats on the data. Can you discuss the CALM-CAH composite endpoint in terms of what are the criteria for the A4 reduction there to meet? And also what proportion of patients are needed for success? And then also based on today's Cohort 4 data, what proportion of patients do you think could achieve that A4 reduction within that first period and do not need that second period of GC reduction?

Maybe I'll let Garnet take this one. Garnet is our global product lead for Atumelnant. Can you answer them, Garnet?

Yes, of course. So for the Phase III, it's actually not a composite, it's a responder endpoint. So patients need to achieve both a physiologic dose of below 11 mg per meter square per day of GC hydrocortisone equivalent as well as A4 below the upper limit of normal. And we're very highly powered to detect a delta between placebo and active. In fact, the study is actually sized to account for the overall safety database requirements. So that's the Phase III component.

As far as the second question goes, I mean, I think we're very encouraged by the Phase II Cohort 4 data, as you've heard from Alan and Scott. And so I'd be confident that we would see a large number of patients hitting the primary endpoint even after that first period of 12 weeks of GC reduction, which is slightly longer, just 10 weeks of actual GC tapering in Phase III relative to the 8 weeks that was conducted in the Phase II study.

Our next question will go to the line of Douglas Tsao with H.C. Wainwright.

Congrats on progress. On Atumelnant, I'm just curious, we saw in the initial Phase II data, some patients had some early clinical responses in terms of resumption of menses. Have you seen sort of that occur more broadly in the open-label extension? If you could just sort of provide some color on what you're seeing clinically in patients who have had sort of longer exposure to the drug beyond just the sort of the biochemical measures that we're obviously focused on.

Alan?

Yes. No, Doug, it's a great question. I would hope and expect to see further clinical outcome improvements with longer-term exposure. You just need to remember that so far on the OLE, we've only had one patient who've gone a longer period of time than 3 months with listing. So give us some time, but we certainly fully intend to report at scientific meetings updates on the OLE. And of course, it's the Phase III trial where we'll be doing a placebo-controlled evaluation of safety and efficacy for a significantly longer period of time.

We have one more question.

Yes. One last question goes to the line of Catherine Novack with JonesTrading.

Congrats on all of the fantastic data. Just a quick question on the reimbursement approval for PALSONIFY. Obviously, very early days, as you said. Do you get a sense if it's improving over time? And what is your ultimate realistic target in terms of percent approvals for prior auths?

Great. Let's let Isabel take that question. Isabel, are you there?

Yes. Thank you, Catherine. Well, first of all, Catherine, our goal is to start getting into formulary. And as we had shared in the past, we hope that after 6 to 9 months, most of the formularies will [indiscernible] and given our strong value proposition and the demand that we are generating, we are expecting that those formularies will be primarily in business based on our label, so first line and second-line use without any additional step edits. Of course, we are working towards that, and our goal is to be at over 75% in the first -- in the next 9 months.

Thank you, Catherine. And with that, we will conclude both the Q&A session as well as today's Corporate Update Conference Call. Thank you for your participation, and enjoy the rest of your day.

Welcome to the Crinetics Pharmaceuticals Third Quarter 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 third quarter 2025 results. Today on the call, we have Dr. Scott Struthers, Founder and Chief Executive Officer; Isabel Kalofonos, Chief Commercial Officer; and Toby Schilke, Chief Financial Officer. Also joining for the Q&A portion will be Dr. Steve Betz, Founder and Chief Scientific Officer; Dr. Dana Pizzuti, Chief Medical and Development Officer; and Dr. Alan Krasner, Chief Endocrinologist.

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. Slide 2. 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 is 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 to everyone joining us on today's call. This is a landmark year for Crinetics. It's a rare privilege to be part of a team that has taken a molecule conceived in our own labs, developed with our own global clinical trials and is now bringing it to patients as a commercial stage biotech.

With PALSONIFY, we are now redefining efficacy in acromegaly as both biochemical and symptom control. When you think about it, the last time you know of someone who made an appointment with their HCP to complain about their lab results.

On Slide 5 are pictures of people we've gotten to know, people who have acromegaly, carcinoid syndrome, CAH and have helped guide the vision for PALSONIFY and Atumelnant. We've worked with the acromegaly community for over a decade. We've listened to their stories and hopes, stories from Ellen about the frustration of symptoms that injections don't fully control or from Wendy about the simple desire to feel like yourself again. We recently observed acromegaly awareness Day and utilized this important moment in time to both drive broader consumer awareness of the disease and advance our patient engagement strategy.

Our own Chief Endocrinologist, Dr. Alan Krasner, and acromegaly patient Tony, were featured in numerous broadcast media interviews across key PALSONIFY markets. These broadcasts will continue throughout the month of November, pointing viewers and listeners to acromegalyreality.com. I am proud we can help them and many, many others struggling with acromegaly enter a new era of therapy with PALSONIFY. My hope is that PALSONIFY brings them freedom, freedom from the symptoms and freedom from the burdens of managing their disease. I hope they can focus on their lives while PALSONIFY fades into the background as just another pill that they take in the morning.

PALSONIFY is just the beginning. We've proven that we can discover important new drugs, proven that we can conduct high-quality global clinical development and are now in the early stages of proving that we can bring them to people struggling with acromegaly as a commercial company. We plan to apply that same focus intensity to carcinoid syndrome and CAH and the other serious endocrine diseases in our pipeline. We're just getting started.

With Slide 6, I'm excited to share that the launch of PALSONIFY is going very well. Isabel will share more details. Our goal is to make PALSONIFY the first-line treatment of choice for acromegaly. In the initial 31-week days since approval, we've already made significant progress, and the team is executing seamlessly. The first patients received their bottles of PALSONIFY only 11 days after the PDUFA date.

All U.S. patients in our open-label extension studies are in the process of transitioning to commercial supplies. As expected, the bulk of our initial patients are those switching to PALSONIFY from other therapies. However, we're also pleased to see a number of patients who are newly diagnosed starting with PALSONIFY as their first medical therapy. We are making headway activating the pituitary centers and have had very good reception from community endocrinologists, some of whom are proactively calling their patients to have them come in to talk about PALSONIFY.

I've spent a lot of time in the past few weeks with our field force and their enthusiasm and knowledge of the practitioners and offices in their territories is impressive, but we aren't relying on just the sales force. It's our entire field team, MSLs, field reimbursement specialists, nurse educators, our clinical development team and executives. We're all out there trying to help improve the care of people with acromegaly.

I'm also pleased that our early experience indicates that payers also recognize the value of PALSONIFY. Prior authorizations have been mostly straightforward and in some cases, reimbursement has been approved for up to 12-month supplies even before we've secured formulary coverage. Because of our proactive work with payers, we're seeing meaningful numbers of patients starting on reimbursed PALSONIFY.

I look forward to January when we'll have a full quarter's worth of launch metrics to share with you. At that time, we will update on revenue, new patient starts, number of unique prescribers and further characterize what we're seeing on the payer reimbursement side of the business. We are currently in the earliest days of Phase 1 of our 3-phase strategy illustrated on Slide 7 to help more people with acromegaly get the care they need. The focus of Phase 1 is to concentrate on switching patients already on injectable SRL depots and other therapies to PALSONIFY. This is a readily identifiable population regularly visiting their HCP offices.

In this phase, we also think that PALSONIFY's rapid onset of action will make it the medical therapy of choice to treat newly diagnosed patients. Looking ahead to next year, while we continue to serve both switching and naive patients, we will also begin additional efforts towards returning previously diagnosed patients back to care. There are multiple reasons why these 1,700 patients have discontinued medical therapy recently. We hope that PALSONIFY will provide a path for them to return to the care they need.

From there, we will extend our efforts to reach the approximately 7,500 patients who have unfortunately been lost to follow-up after diagnosis and returning them to medical care. There can be multiple reasons why these patients have discontinued medical therapy. It won't be easy and it will take time, but we believe that PALSONIFY will offer these patients a path back to care as well.

The third and final phase will be to improve the time to diagnosis of acromegaly. Diagnosing acromegaly is easy once you suspect it, but suspecting it can be challenging even for experienced providers. We anticipate launching specific initiatives later next year and our general efforts to improve acromegaly awareness and its treatment options should start making a difference sooner. The story of Crinetics is not just the acromegaly launch, it's about our execution across the entire pipeline shown on Slide 8. I want to emphasize the strength and depth of what we've built through our internal discovery and development efforts.

On the discovery front, we remain committed to holding our clinical candidates to the highest possible standards. Unfortunately, during IND-enabling tox studies, we identified weaknesses in our lead TSH candidate for Graves' disease. Therefore, we're delaying the IND time lines as we prioritize and activate the best of the backup molecules. We're also delaying the time lines for our SST3 agonist program for ADPKD as we conduct follow-ups to the core IND-enabling studies.

Given the launch of PALSONIFY and acromegaly and the multiple late-stage programs in development, we will no longer provide regular updates on the timing of preclinical programs until those programs dose their first patient in a Phase 1 study, but rest assured, we are committed to not only advancing the late-stage pipeline, but also to expanding the clinical pipeline and our discovery activities continue unabated. We expect the clinical pipeline to continue to expand in 2026 and the years to come.

Moving to the top of the pipeline. carcinoid syndrome is the second indication in development for paltusotine. People with carcinoid syndrome struggle with debilitating and frequent flushing and bowel movement episodes. Like in acromegaly, standard of care for these patients is painful monthly depot injectable SRLs. Based on our Phase 2 data, we believe paltusotine could offer consistent daily control of these in an oral formulation.

Our Phase 3 study shown here on Slide 9 is designed to evaluate its efficacy and safety in both naive and switch patients and the OLE study will also evaluate control of the underlying neuroendocrine tumors. More than 20 clinical sites have been activated and are currently screening patients for this study. Complementing paltusotine is CRN09682, the first candidate from the non-peptide drug conjugate program. 9682 is comprised of a novel ligand targeting SST2 to drive internalization into tumor cells, a novel linker that is cleaved only in the tumor cell and a payload to be delivered, in this case, MMAE.

We believe 9682 will be differentiated from other current modalities, and as shown on Slide 10, we are studying it in the BRAVESST2 Phase 1/2 basket study in patients with SST2-expressing tumors. This includes neuroendocrine tumors as well as other types of tumors that overexpress SST2.

The first 6 sites in this study have been activated and are actively screening patients. The enthusiasm for this study from both investigators and potential participants has been high. This is an important study for Crinetics. It's designed to provide the first human proof of concept for our entire NDC platform, and we're thrilled for it to be underway.

Moving on to Atumelnant on Slide 11. In the first 3 cohorts of our Phase 2 ICANS trial for congenital adrenal hyperplasia, or CAH, Atumelnant showed a remarkable ability to highly suppress adrenal androgens in these patients. As you know, we added a fourth cohort to look at morning dosing instead of evening dosing as well as the ability to lower adrenal androgens while simultaneously reducing glucocorticoid therapy towards physiologic levels.

Patients in this fourth cohort have recently completed their 12-week treatment period, and we continue to see favorable benefit risk profile. I look forward to sharing the data from Cohort 4 in January once our analysis is completed, along with initial data from a handful of patients from prior cohorts who have now reached the 13-week assessment in the open-label extension study.

Now moving on to the design of our global Phase 3 CALM-CAH trial of Atumelnant in adults with CAH. The study shown on Slide 12 builds on the strong top line results from the first 3 cohorts of our Phase 2 study. It's designed to provide a novel therapeutic paradigm for CAH, where atumelnant is used to treat the disease itself and glucocorticoids are only needed for physiologic replacement.

People with CAH deserve physiologic levels of both, and that is why we are utilizing a novel uncompromising primary endpoint that combines both goals. This is a very high bar, but appropriate for the level of efficacy we expect from Atamelin. I'm pleased to report that the first sites for the CALM-CAH trial have been activated. Screening is underway, and we expect the first patients to be randomized before the end of the year.

Moving on to Slide 13, which shows our BALANCE-CAH study for pediatric patients in more detail. We believe it is crucial to address both high androgen and glucocorticoid levels in pediatric patients because each can cause significant clinical sequelae, and we designed our clinical program with that goal in mind. This study is operationally seamless Phase 2/3 design with a Phase 2 dose selection during which glucocorticoids remain stable, followed by a Phase 3 portion in which new patients will be randomized and have the opportunity to taper glucocorticoids. Eligible patients from both phases will have the opportunity to enroll in an open-label extension. We look forward to enrolling the first patient before the end of the year.

With that, let me turn the call over to Isabel to provide additional color on the launch of PALSONIFY for acromegaly. Isabel?

Thank you, Scott. Turning to Slide 16. Based on our strong label, our strategy is to establish PALSONIFY as the foundational care for acromegaly. To that end, I'm pleased to share the launch is off to a very good start. Since the approval, our team has been engaging with stakeholders and executing across all aspects of the launch. Our field team is reaching patients, physicians in the community and in academic setting and payers, and we are hearing encouraging feedback.

Starting with the patient on Slide 16. Our strategy is to activate both switch and naive patients by reinforcing PALSONIFY's consistent IGF-1 and symptom control in a once-daily order. It has been exciting to see that our omnichannel marketing and messages are resonating, and we are beginning to see enrollment forms that from patients who requested PALSONIFY specifically.

We're also encouraged by the fact that all of the 22 U.S. patients in the OLE are in the process of transitioning on to commercial product. As expected this early in the launch, 95% of our filled prescriptions are from switch patients, reflecting the demographic to the acromegaly population. However, it is encouraging that we are already starting to see enrollments from treatment-naive patients. This supports our thesis about the significant unmet need in both of these patient segments and represents a good start to Phase 1 of our overall strategy.

Moving into to healthcare providers on Slide 17. Even 1 month prior to approval, PALSONIFY had high levels of awareness among academic and community physicians. Building on this foundation, our field teams had called on more than 95% of our highest priority prescriber targets, most of whom are in academic centers. We are leveraging PALSONIFY's unique label, which includes symptom control to engage with healthcare professionals.

We believe our efficacy-first messaging is resonating with providers because they prioritize both symptom and IGF-1 control alongside ease of administration. Our sales force is using these messages in the priority PTC centers and high-volume community practices, while targeted marketing extends our reach to the broader community. At this point, we are seeing about 70% of prescribers coming from the community setting and 30% of prescribers coming from PTCs.

This is encouraging because it demonstrates that PALSONIFY is also attractive to community-based prescribing physicians. In the PTC setting, our broader field-facing team is working through the typical administrative processes to support uptake. This includes taking a comprehensive approach by engaging both endocrinologists and nurses as well as pharmacists and support staff.

Finally, turning to payers on Slide 18. Our payer simple launch engagement work has positioned us well to understand the payers' coverage landscape. So far, we have had follow-up meetings with plans covering majority of lives and the feedback in our broad label and overall value proposition remains consistently favorable. We are pleased to see coverage approvals coming across commercial, Medicare and Medicaid plans. For those that are approved, prior authorization decisions are taking only a few days, and we are encouraged to see some approvals for up to 12 months even in the early days of the launch.

Medicare patient support program and field teams are helping patients navigate their treatment journey. We are seeing a balanced mix of reimbursed patients and those on our Quick Start program. Our team is actively working with plans to transition quickest start patients on to reimbursed product. As expected, we anticipate the full formulary process will still take the standard 6 to 9 months.

Overall, our commercial team is doing an excellent job executing against our plan. We look forward to providing launch metrics in the first quarter once we have had a full quarter of experience behind us. As Scott mentioned it, in addition to revenue, we will provide the number of new patient starts, the number of [GE] prescribing physicians and updates on our progress with payers. Our goal remains to make PALSONIFY the first treatment of choice for all acromegaly patients, and we are perfectly on pace relatively to our expectations.

With that, I will hand the call to Toby for our financial update.

Thank you, Isabel. Turning to Slide 20. Our financial results for the third quarter of 2025 reflect our continued disciplined execution and strategic investment in advancing our pipeline and commercialization of PALSONIFY. In the third quarter, we recognized $0.1 million in revenue from our licensing agreement with our Japanese partner, SKK. As expected, we did not recognize any revenue related to the launch of PALSONIFY in the third quarter due to the timing of approval, which was close to the end of the quarter.

Under GAAP, we recognize PALSONIFY revenue upon delivery of product to our specialty distributor and specialty pharmacies. Product was shipped in the first few days of the fourth quarter, as Isabella stated, so we have recognized revenue in the fourth quarter. Our research and development expenses for the third quarter were $90.5 million compared to $80.3 million in the second quarter. This increase reflects our continued investment in our clinical programs, including start-up costs for our late-stage clinical trials and ongoing advancement of CRN09682, the first candidate from our novel non-peptide drug conjugate or NDC platform in early-stage clinical studies.

Selling, general and administrative expenses were $52.3 million for the third quarter compared to $49.8 million in the second quarter. This increase reflects our investments to drive the successful execution of PALSONIFY's launch, including onboarding and deploying our field force, strategic marketing initiatives and the growth of corporate functions to support our commercial team.

We used $110.7 million of cash in operations during the quarter, reflecting continued clinical development and launch preparation activities. Cash used in operations was slightly higher than anticipated this quarter, primarily due to timing of payables. We ended the quarter with $1.1 billion in cash, cash equivalents and investments. As of October 28, 2025, we had approximately 94.9 million shares of common stock outstanding. On a fully diluted basis, we had 111.9 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 21. We are maintaining our guidance for net cash used in operations in 2025 and continue to expect that we use between $340 million and $370 million. Based on our current operating plans and cash position, we maintain our guidance that existing cash and investments will be sufficient to fund our operations into 2029. This provides us with significant runway to execute on multiple value-creating milestones, including the U.S. commercialization of PALSONIFY and the advancement of the rest of our pipeline.

I will now turn the call back to Scott for some closing remarks.

Thank you, Toby. Slide 23 lays out the major commercial and clinical catalysts that we expect to drive significant value starting early next year and continuing over the next 18 to 24 months. Commercially, our entire focus is on executing a strong U.S. launch trajectory for PALSONIFY. We're already seeing the validation of our strategy with prescriptions coming from both community endocrinologists and the major pituitary centers. Initial feedback from patients, physicians and payers is positive. As I mentioned, we'll provide detailed launch metrics from the full Q4 results in January.

We also have a great deal of momentum in the clinical pipeline. We have a key near-term data readout for the T2CANS study, which will include data from Cohort 4 and the initial open-label extension patients from prior cohorts. Beyond that, we have a robust set of late-stage programs advancing. We expect them to produce key data readouts, including from our CALM-CAH adult Phase 3 trial, the BALANCE-CAH Phase 2 pediatric study and our CAREFNDR Phase 3 trial in carcinoid syndrome.

At the same time, our BRAVESST2 study for CRN-9682 is underway, and we anticipate initial data from dose escalation and expansion cohorts from this. Our Phase 2/III program for Cushing's disease is also kicking off soon. Behind all this, our discovery engine remains our foundation. We expect new internally discovered candidates to enter the clinic and provide their first early readouts during this period. In summary, we have a deep pipeline, a strong balance sheet and a clear path to continued value creation. We are executing on all fronts and look forward to updating you as we achieve these important milestones.

Thank you for joining us today. We're now happy to take your questions. Operator?

[Operator Instructions] First question comes from Catherine Novack with JonesTrading.

I just want to ask a little bit maybe about some of the data that you showed at NANETS last week. I'm very interesting to see the PFS data in the NET patients with paltusotine that is. Can you tell us what the evidence is for somatostatin receptor ligands in this setting? Will you ever want to conduct survival studies with paltusotine alone?

Thanks, Catherine. Somatostatin receptor ligands are known to be slowing of the growth of neuroendocrine tumors, and that was proven in the CLARINET study with lanreotide. Mechanistically, we expect the same thing out of paltusotine, which is why we're monitoring this in the open-label extensions of the carcinoid Phase 2 and then soon the carcinoid Phase 3, but maybe, Alan, do you want to comment a little bit more on that to clarify what we see and what we're hoping to see.

Sure. Yes, Catherine, so as Scott said, the SRLs have a known cytostatic kind of effect, improving progression-free survival in neuroendocrine tumors in general. We recently presented at NANETS, our exploratory data from our Phase 2 trial open-label extension patients, a small cohort of patients. In general, the PFS in that cohort looks comparable to what you would expect in a long-term trial in neuroendocrine tumors.

Neuroendocrine tumors are very, very slow growing and advancing. In general, the time it would take to do objective response kind of trial, survival kind of trials is sort of out of bounds. It would be very, very long. PFS is usually used as the surrogate of those kinds of outcomes in this tumor type. In general, we're seeing an uncontrolled data, what we would expect to see, and we'll have a lot more data coming from the long-term Phase 3 cohorts as well.

Then just it's disappointing to hear about the Graves' disease candidate, but glad that you were able to catch it early. Any clarity on what model you saw the tox signals? Was it an on-target toxicity? Or do you find that you're hitting a receptor that was unexpected? Any information?

No. It's idiosyncratic finding that really was driving the decision, nothing related to on-target activity. I think we have a very good understanding of the mechanistic biology of the TSH receptor, so that's never something we've worried about.

We now turn to Cory Jubinville with LifeSci Capital.

You mentioned that the sales force has called on greater than 95% of top priority prescribers. Can you just remind us, one, how many prescribers that specifically includes? Two, the concentration of the immediately addressable, call it, 10,000 acromegaly patients that are at those top priority prescriber centers? Three, can you speak directly -- as you speak directly with these centers, what was the initial perception from those docs on PALSONIFY? How many of them have converted to actual prescribers or are actively working to make it part of their practice in the long term?

Yes. Thanks, Cory. Maybe before I hand it to Isabel to answer in a little more detail, just a reminder that we're deeply part of the pituitary community and the endocrinology community more broadly. It's great that our field force has been out there talking now at that level, but they've been out there with warm introductions from those of us who know these people for these prescribers for a long time. I'm really glad to see the response from the community, which has been quite favorable by all comments from all across our field force and directly that I've been hearing from them. We're still working our way through some of the administrative aspects of the pituitary centers, but I think that's well underway. Maybe you want to answer in more detail, Isabel, some of the more specifics that Cory was asking about.

Yes, absolutely. Thank you. First of all, I want to start with your second question. We are delighted that the treatment is very well received by the healthcare professionals, the patients and the payers. With healthcare professionals, they are responding really well to our very simple powerful message on first line of treatment, fast onset of action, fewer symptoms in finally on a pill. It's a very simple message, but it resonates because it really encompasses everything that they were looking for in a better treatment in a new standard of care.

The response has been positive, and that has led to initial prescriptions from both, as Scott alluded to, PTC centers, but also community, where we see 70% of the prescriptions coming from community prescribers and 30% from PTC centers. We're encouraged by the community because many times, community tends to follow PTCs. The fact that both segments are adopting is a really good signal for us on the launch trajectory. When you look at our prescriber base, we have approximately 110 total prescribers, and the 95% doesn't refer to all of those 110 prescribers, but that the initial prescriptions, many of them are coming from members of that list.

I mean, it's interesting, building off that point, it's interesting to see that 70% of scripts are coming from community docs. Can you just help us better understand that dynamic a little bit more? I guess, why are some of these PTC centers, for lack of a better term, lagging behind? Is it just small sample size because we're early in the launch? Or are these community practices just a bit more nimble and you're dealing with some of the bureaucracy at these centers? Or yes, just curious to hear more about your strategy of how to activate centers.

Well, I think that we've seen in some of the other launches that have happened this year and recently, how important it is to think about the community upfront. That's how Isabel designed the whole field force as we were going into it. We deployed out to the community and to the centers in parallel. I think the thing that we've seen with the community, which is I don't know, very rewarding is that they are a little bit more nimble and more willing to reach out directly to patients and call them in and not just wait for the next appointment. If we think about the centers, I think they are more waiting for the patients to come in for their next appointment.

The other thing that we're working with, with the centers, which is pretty much taken care of now, but it takes a little while to get the electronic medical systems so that they have one push button prescribing. It took a little bit to get the pharmacies activated at many of the centers. These are kind of normal administrative things that we've worked through. In no way do we see the centers as being slow. We just are pleasantly surprised at how nicely the communities responded.

We now turn to Yasmeen Rahimi with Piper Sandler.

Congrats to a great start, and thank you for sharing all the color. Maybe one question for the commercially related. I appreciate if you could kind of tell us about how you're thinking about providing free drug while getting reimbursement and how do you make those decisions? Then very excited to look forward to the CAH open-label data early 2026. Help us understand sort of in early 2026, whether you would be able to get to all 10 patients and what you hope to show in that data set? Then I'll jump back in the queue.

Yes. Let me take the second part first, and then Isabel, maybe you can take the first part about -- on the acromegaly side of things. Look, in addition to Cohort 4, patients have been rolling on to the open-label extension. That one has a relatively infrequent sampling, and so the first sampling there is 13 weeks. By the time we get to the early part of the year, we'll then have data from the Cohort 4 patients, plus a handful of patients who've gotten to 13 weeks from Cohorts 1 to 3 in the open-label extension.

Now it's still a relatively small sample size, but we'll start to give a sense of what -- how this is behaving in a real -- more real-world setting where physicians can both reduce glucocorticoids and see what's happening with adrenal androgens. Isabel, sorry, I wanted to take care of that part. Maybe you want to talk about the question she had on acromegaly.

Yes, of course. Our market access team is executing with excellence. Our goal is to partner with our specialty pharmacies. When we get an enrollment form, our specialty pharmacies file the prior authorization to ensure that the claim is reimbursed. That's our first step. That's why we are very pleased that 50% of the claims has been reimbursed.

Then if there is a challenge to the prior authorization, we send the Quick Start program because we want to make sure that while we do benefit verification and we complement any gaps that they have had, either adding some of the clinical records or putting the correct IGF-1 test in the file that we are able to process that in the background while the patients are on drug. We are ready to go with the Quick Start program as soon as possible, but we first give the opportunity to our specialty pharmacies to process the claims.

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

Again on all the progress. I guess maybe just feeding off the question in terms of where you're initially seeing demand in the community versus the centers of excellence. I'm just curious to the extent that you get a sense that this is -- there's awareness within the acromegaly community, who I know has a very active patient group and how much is sort of coming from the ground up versus prescription written by clinicians who as they see their patients are sort of recommending a switch or offering that choice to patients.

Yes. Thanks, Doug. I think it's still very early days, so it's very anecdotal, but we're hearing both, right? We're hearing physicians who talk to patients and tell them about something they hadn't heard of and are ending up switching to PALSONIFY. We're hearing about patients going in asking their doc for PALSONIFY. That's kind of cool, actually. I think it's a mix of both, but it's too early to start putting any sort of numbers to that.

I was just going to say that we have a very experienced dedicated team that had also connections in the community, which is also really helpful, right? They wanted to make sure that across the board, we are nimble, we're executing, and we make sure that -- those physicians that are ready to prescribe has the opportunity to do so.

As Scott said, we are seeing prescriptions that are primarily coming from the prescribers, but we also see prescriptions that are coming from awareness that we have built through our marketing team and advocacy from the patients. Regardless, whichever prescription is done is because both of them agree that it's the best choice for the patients, so both the patient and the physician have to be informed. We are working across the board with those 2 audiences.

I'm just curious, and I know it's anecdotal, but I'm just curious in terms of prescribers as well as patients, what is interesting them? Is it the convenience of an oral therapy? Or is it really just the standout efficacy that were shown in PATHFNDR-1 and PATHFNDR-2 as a better treatment option for patients?

Go ahead, Isabel.

We have a mix actually. It's very interesting. Some of the doctors are very intrigued by the fast onset of action of the treatment and the fact that it's a reliable disease control. They see that also as the first treatment choice for some of the switching patients, but also naive patients.

For example, we have a naive patient that has surgery but had a residual tumor. The patient now has reached 3 weeks on treatment. The physician did a second IGF-1 test, and he was really pleased to see that the patient was controlled, less than upper limit of normal in the IGF-1 test, but also saw an improvement on symptoms like swelling. That kind of experience is going to motivate that physician to put more patients on treatment as well as that patient is going to also share that experience later on with patients. We are very encouraged by that.

We also see some patients that want to travel. We have -- or that their job description requires that they are free from the burden of the injections. That is also resonating, for instance, we have a firefighter that, of course, didn't want to come every month to the appointment. In addition to having -- not wanted to have the painful injection, had lots of breakthrough symptoms. Both the efficacy and the ease of use were important to him and the physician, so that's the kind of experience we're hearing from the field.

Yes. The other one that I was told about is an ER doc, Doug, who got just burned out on the injection, so reached out to his doc to switch. Again, these are just -- these are anecdotes, but they're very heartwarming, honestly.

That's really helpful to hear, and it's good to hear that feedback around the sort of broader value proposition of the product.

We now turn to Maxwell Skor with Morgan Stanley.

This is Selena on for Max. Has the timing of benefit verification for the Quick Start program met your expectations? When do you expect to have clear visibility into the breadth and depth of prescribing trends?

Well, I think the prescribing trends will update you further in the -- as we finish out the quarter, and we'll see and gain experience with that over time.

Isabel, maybe you want to talk about the Quick Start program.

Yes. Of course, at the moment that we send the Quick Start program, benefit verification is happening in the background. Some of them are issues that are easy to resolve, like there was missing IGF-1 test or is missing clinical data. Other plans are requiring a little bit more. On average, in rare diseases, it takes around 57 days to be on Quick Start program, and we are trying to be below that number.

Yes. That's -- and then to kind of add to that, that's why we were pleased that we're already seeing patients getting on reimbursed PALSONIFY before we even have to give them the quick start program. That's been good to see. Not all of them, but some.

Yes, 50-50, which is really good results early in the launch. Because what we're seeing actually that is really encouraging is that payers are reimbursing to label as we had anticipated. We are also seeing that once it's approved, those approvals are coming for 6 to 12 months. The patient will continue on drug before any additional documentation is required.

We now turn to Richard Law with Goldman Sachs.

Congrats on the results so far. Based on your launch experience with PALSONIFY so far, what has been going well for you? Where can you see improvements? It would be great if you can talk about it in context of like commercial, Medicare and Medicaid segments. I don't know if it's too early because I assume most of these patients are coming from commercial. Yes, it would be great to hear how you things going well across these segments and where you can do better. I have a couple of follow-ups.

Yes. I mean, broadly, I'm super pleased with the way the team is out there performing and the response to the community. Any improvements are really incremental, but maybe you want to comment on some of your favorite pieces, Isabel?

Yes. Well, I was very pleased we have Dragon channel very early in the process. I believe that the team is executing with excellence across the board. Our sales team, our marketing team, our market access team and also commercial operations having the right tool. We know who to target and where the physicians are and where the patients are. So going very well, our CRM activation, our omnichannel strategy to create awareness, both with physicians and patients, our sales team executing and having great success in getting access with both community and PTC centers. and really delivering very powerful and simple messages. That is going really well and is resonating very well.

We also had a successful initial advisory boards, and we're continuously getting feedback from the doctors as to what resonates with them and what else they would like to see in the future. That's also shaping our communication plan for [indiscernible] next year. We want to continue to create urgency. Some of those physicians are following the appointment cycles, waiting for the patient to come. A lot of what we want to continue to do is to create that sense of urgency. Those early positive experiences that we are seeing, that the physicians are seeing and the patients are seeing are very important for us, and we'll continue to translate them as testimonials in the future to continue to drive the uptake of the drug to our final goal, which is making PALSONIFY the new standard of care and continue to expand the acromegaly market.

Then what about the insight to the segments? Are these mostly commercial so far? Then maybe comment on Medicare and Medicaid segments.

Interesting. There is a mix. We have commercial patients, Medicare patients and Medicaid patients, and we had claims approved for all 3 segments. One last point. is following the market trend, basically, the majority of them are commercial claims, but basically very similar to the actual payer mix.

Then what is the turnaround time and that range of that for payers to approve PALSONIFY, assuming that patients already met the prior authorization requirements, including step edits. What's that turnaround time for payers to approve?

Let's get a little larger sample size before we start doing calculations like that, right? Still a little too small to -- a little early in the launch to do that.

Then just one more. In terms of the payer rebate, I know you guys are not doing payer rebate for commercial. Is that still the case?

That's correct.

That's correct. We are not planning to do that.

Reminder folks, let's try and keep to one part question. We got a bunch more people waiting in line.

We now turn to Tyler Van Buren with TD Cowen.

This is Nick on for Tyler. Congrats on the progress so far in this launch. My question is you reported that 95% of filled prescriptions today are from switch patients, which we've talked about a little bit now. What's the plan to reach additional treatment-naive patients? Which do you expect will be the largest drivers of long-term growth?

Yes. I think if you look at the -- what we've said in the past, there's roughly 500 patients a year coming on to medical therapy. It's kind of a trickle of those new patients. The fact that we're starting to pick those up, I think, goes very much to the profile of the drug, like this one patient that's already controlled 3 weeks in. I mean that's awesome.

I think the bigger challenge then is, as we talked about this phase -- 3-phase strategy is getting to those patients who, for whatever reason, are not on medical therapy, but should be. There's roughly 4,500 treatment naive. Some of these are patients who probably are not at the level of control that they should be, and so we're digging into that. I think like many rare disease therapies, once you start getting the word out there that there's a new therapy that's not the burden that you have with the depots that we'll start to get people back. Those are the ones -- those first ones in Phase 1 are just the tip of the iceberg because the next part are these patients who've discontinued therapy and/or have been lost to follow-up and bringing those back in is another very significant group.

Then, of course, the big aim is to really start to improve awareness and find better ways of getting people to suspect acromegaly so that you can do an IGF-1 test and diagnose it. there's 17,000 people out there that the best we can tell that have yet to be diagnosed, but they're getting damaged to their joints, their heart every day. We'll be launching a variety of different efforts to do that more specifically next year. I think even these awareness things that we're doing like Alan's interviews with Tony, I think that's going to start helping sooner rather than later.

I have been in the field together with our sales team, and I was having a conversation with one of our key prescribers in a key center. He answered the way I think about this, who is not the right patient for PALSONIFY. Early on, of course, we're going for the switch and naive patients. but we believe that this treatment will help us expand the market over time.

We now turn to Andy Chen with Wolfe Research.

This is Brendan on for Andy. In the opening remarks, you mentioned aiming to position PALSONIFY as a first-line therapy. We're curious to know how you expect to do that with generics currently on the market.

Well, that's an easy one. I mean, if you look at the label, it's indicated for the treatment of acromegaly in-patients who have not had adequate response to surgery or for whose surgery isn't indicated or appropriate. The biggest reason why you want to go on to PALSONIFY in that situation for the new patients is like that one I mentioned, they're controlled in 3 weeks. We got great data from PATHFNDR-2 showing 2 to 4 weeks to get people controlled, whereas in the depots, your first dose adjustment isn't for 3 months. You don't even know if that first dose works after 3 months, and then you go to the second dose, so you wait until 6 months.

Then you may need the highest dose until you're 9 months out before you know whether it works. That's not the right medicine, so PALSONIFY is really the best option for somebody newly diagnosed. I don't see an argument that whether it's generic or not matters.

Yes, we are not seeing that kind of pushback from payers also. We see that the value proposition is resonating really well with them, and they understand the value of the treatment. The reduction of waste applies whether it's generic or not generic. The fact that patients continue to have -- is irrelevant to whether it's generic or not. Also, as you know, generics don't have the support services that we are able to offer like a Quick Start program, the co-pay for the patients, 0 co-pay for commercial patients and all the support that they will get.

We now turn to John Wolleben with Citizens.

Congrats on the progress. Scott, you kind of discussed the 3 phases of PALSONIFY 's launch. I was hoping you could talk a little bit about the timing of the sequence and how you think about moving from one phase to the next, if there's benchmarks you want to hit in each one or if it's going to be more of a continuum. Just wondering how to think about you guys tackling these different buckets of patients.

Yes. I don't mean to imply it's a sequence, but it's a sequence of enhanced efforts. I really want the group out there in the field focusing on those patients in the first phase and getting the word out so that we have broad prescriber base. I think you're seeing that already with the response of the community.

Then, in addition, because it will take some time to work our way through all those Phase 1 patients. Before we're done with that, then we also would start getting more active in finding ways to bring patients back to care. That may be -- that may take a variety of different forms. It's really just about how we layer on our efforts rather than go from one phase to the next, if that makes sense.

Do you think the current sales force is rightsized to handle that expansion over time?

Yes, absolutely. I think we're doing very good in the coverage. It's a fairly concentrated prescriber base. We were planning for the community from the start. I think it's more about the types of activities that we do to try and help find these patients who need to come back to care, improve diagnosis rather than just switching efforts from one thing to another.

We now turn to Jessica Fye with JPMorgan.

I wanted to follow-up on one of the earlier questions. What should we be most focused on when we take a look at the Cohort 4 data for Atumelnant? What are you going to be watching for similarly in that Phase 2 OLE data? I guess, stepping back, how much of a read is Cohort 4 or these initial OLE patients going to give us into the potential steroid reductions that we could expect in Phase 3?

Yes. Well, a couple of things. One, I'll just put some caveats. It's still relatively small numbers of patients. It allows the chance for physicians to begin to do steroid reductions in the actual treatment period of 12 weeks, that's pretty fast, right? I think that, together with the open-label extension data where there's a little more time.

Generally, I think it will give the directionality, but I wouldn't start doing power calculations or things based on it. That makes sense. I think there's been a lot of interest in this Cohort 4 data, and it's interesting, but again, it's relatively small numbers.

When should we expect the preliminary Phase 2 data for Atumelnant in peds?

I don't have exact timing on that, but that will come out in some phases because we're starting with older adolescents and then working our way down the age groups, right? We'll start expanding those populations into the Phase 3 portion as the age groups get the dose validation that we need.

We now turn to Alex Thompson with Stifel.

This is Patrick Ho on for Alex. I guess on the naive patients, are you guys seeing different dynamics here from payers? Or is it similar to the switch patients?

Similar dynamics. We had some reimbursed claims and some that we are processing through the Quick Start, so similar in both cases.

Again, early days.

We now turn to Joe Schwartz with Leerink Partners.

How does the traction you're getting at this early Phase 1n the PALSONIFY launch compared to the market research you've done in terms of willingness to prescribe or any other factors you consider important?

Thanks, Joe. I think we have not had any real pushback from prescribers about use of PALSONIFY, as was mentioned earlier by Isabel, who shouldn't get PALSONIFY. I think it's just the normal -- we're observing the things that are basically in line with our expectations. We're building momentum and working through a little bit of inertia in the system, but the patients are starting to come in. As they come in, I think they'll be best served with PALSONIFY. There's really not much pushback.

How much of a continuum is there in terms of running from inertia to excitement given providers are encountering a new treatment option, but they've been quite used to using legacy treatments for quite some time?

Maybe you want to take that, Isabel. I don't think it's the legacy of use that is anything that's really in the way. I think they see the benefits of PALSONIFY.

Go ahead, Isabel.

Yes. We see a lot of excitement in the prescriber community. When they look at the data, they really understand the value proposition with the efficacy, the fast and of action finally on a -- the inertia that Scott was referring to is more the normal cycle that takes place in rare diseases where appointments take place every 6 months to a year and physicians are not necessarily always having the support system to start calling the patients, but they will go with the flow of the appointments and wait to offer this new option to patients when the patients have their next appointment.

We see that narrowing down the story to a particular patient for that physician where urgency is higher is helping, but we know that there will be a cycle similar to all rare disease launches.

We now turn to Dennis Ding with Jefferies.

This is Anthea on for Dennis. Just 2 quick ones. On PALSONIFY, could you elaborate on just how many patients in the open label are now transitioning to commercial supply and the time lines there? Just curious if we would see all of that contribution in Q4 or later in 2026.

Then on the pipeline, any updates on the progress for the GLP programs? I think there was previous talk of candidate selection in '25, so just curious on progress there.

Yes. Just on the open-label extension patients, all 22 are in various stages of enrollment. They've all enrolled for commercial supplies, but they have to wait until their final follow-up visit as part of the open-label extension so that we can finish all the monitoring as part of that. I think most of those are through -- are completed by the end of the year, but I don't know the exact numbers at this point.

Then the GLP-1s, obviously and other obesity things we're working on, obviously, a very interesting space, especially today. I think we're going to stop talking as much about our early-stage programs now that we're really concentrated on the launch and our late-stage clinical development. I think it's just more appropriate that we -- when we're in the clinic, we'll let you guys know, but we're thinking hard about it, working hard on it, and you're going to see a lot of new things come out of the Discovery Group and not just soon, but for years to come.

Ladies and gentlemen, we have no further questions. This concludes our Q&A and today's conference call. We'd like to thank you for your participation. You may now disconnect your lines.

Welcome to the Crinetics Pharmaceuticals PALSONIFY FDA Approval Conference Call. [Operator Instructions]

I will now 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 FDA approval of PALSONIFY. Today on the call, we have Dr. Scott Struthers, Founder and Chief Executive Officer; Dr. Dana Pizzuti, Chief Medical and Development Officer; and Isabel Kalofonos, Chief Commercial Officer. In addition, Toby Schilke, Chief Financial Officer; and Dr. Alan Krasner, Chief Endocrinologist, will also be joining for the Q&A portion.

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.

Slide 2. 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 our commercialization plans as well as estimates relating to market size, future performance, growth 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 is 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 turn the call over to Scott. Scott?

Thank you, Gayathri. I'm very proud to share that PALSONIFY has been approved by the FDA for the treatment of adults living with acromegaly. This ushers in a new era in the acromegaly patient care and marks a truly transformative moment for both the acromegaly community and for Crinetics.

We founded Crinetics 17 years ago to build a company dedicated to transforming the lives of patients by carefully crafting therapeutics that intervene in endocrine pathways. But new drugs are only as impactful as the problems they solve for patients and their caregivers. That's why we began engaging with the acromegaly patient and caregiver community well before our clinical studies began. Through this, I've personally gotten to know dozens of people living with acromegaly. Their insights and those from many others have extensively shaped our discovery, development and now commercial distribution strategies. I'm extremely gratified to tell those patients living in the U.S. that PALSONIFY is now available.

As you can see on Slide 5, acromegaly is a serious chronic endocrine disorder caused by a benign tumor that secretes excess growth hormone. This leads to chronically elevated levels of insulin-like growth factor or IGF-1, which is the primary biomarker for the management of acromegaly. The consequences of chronically elevated growth hormone and IGF-1 can be severe, including changes in facial features, enlargement of the hands and feet, carpeted tunnel syndrome and enlargement of the heart that can lead to congestive heart failure. These excess hormones also induce insulin resistance, hypertension and there's more.

As I said, this is a serious disease. From the perspective of someone living with acromegaly, the physical changes in their parents, not to mention the sweating and skin changes can be alarming and socially isolating. Severe headaches, fatigue, joint pain and peripheral neuropathies can be debilitating. What's worse, these are relatively nonspecifics and acromegaly can it in plain sight for 5 to 10 years before diagnosis, even though diagnosis is relatively straightforward once the disease is suspected.

Based on the current treatment guidelines, the first step after diagnosis is typically surgery to try to excise the tumor. But remember, the pituitary gland is located behind the eyes right next to the optic chasma and the carotid arteries. Depending on how the tumor grew in this confined space, it's often difficult to safely remove it. Elevated levels of growth hormone and IGF-1 secretion from residual tumor fragments are unfortunately all too common. For these patients, for those who are ineligible for surgery, the standard pharmacotherapy has been peptide somatostatin receptor analogs. These are typically administered via monthly depot injections that are difficult to administer and painful to receive.

Importantly, these depots can take 6 to 9 months to titrate to the appropriate dose level and their symptom control can be inconsistent. Many patients experience troubling breakthrough symptoms each month. And despite well-established clinical practice guidelines, far too many people with acromegaly don't currently receive these depots or have given up and discontinued medical therapy altogether. We know that people living with acromegaly deserve better.

But it's one thing to talk about all the complications and symptoms of acromegaly. It is something completely different to sit down and talk with someone living with the disease like Dave, who I've gotten to know and is shown here on Slide 6. Dave told us how the pain and fatigue caused by acromegaly negatively affects his everyday life despite being on existing medications. Dave has a passion for music, but acromegaly caused his voice to change so he couldn't sing and the symptoms in his hands made it painful to play piano or guitar. Dave told us that some of the things that brought him joy were stolen by acromegaly.

We want to offer people like Dave the opportunity to regain their moments of joy to take control of their disease instead of letting their disease control them. One thing that came through loud and clear talking to Dave and many others living with acromegaly is the high level of unmet needs throughout their entire rare disease journeys. Our roots in the endocrinology community grow deep. We are 1,000% committed to being the partner of choice with the entire endocrine ecosystem and ensuring that people living with endocrine diseases get the care they deserve, starting with acromegaly.

Moving to Slide 7. We're very happy with PALSONIFY's broad label. It captures the breadth and depth of the work we put into its discovery and development and the impact it can have on patients for both biochemical and symptom control. Our experienced commercial and medical teams are ready to go, and we are well positioned to bring PALSONIFY to people living with acromegaly in the U.S.

Before I hand the call over to Dana, I want to take a moment to express our gratitude to the patients and their caregivers who participated in the clinical trials. I'd like to thank the investigators and their staff who conducted these clinical studies of PALSONIFY around the world. We also appreciate the FDA's constructive engagement throughout this process. Together, the contributions from all these stakeholders have helped shape a new era in acromegaly treatment, offering hope to patients who have long awaited a transformative oral therapeutic option.

With that, I'll hand the call over to Dana to review in more detail the clinical data that is now reflected in the approved label. Dana?

Thank you, Scott. Turning to Slide 9. We believe the broad label reflects the extensive clinical data supporting PALSONIFY's safety and efficacy profile. PALSONIFY is approved as first-line treatment of acromegaly in adult patients who have had an inadequate response to surgery or for whom surgery is not an option. The label for PALSONIFY allows a broad population of patients to potentially benefit without having to try other therapies first.

Notably, in addition to biochemical control, our label includes data showing improvement in symptoms for the subjects in both experienced and untreated populations. We believe this will resonate strongly with both health care professionals and patients and address an unmet need in acromegaly therapy. The favorable safety and tolerability language in our label is also significant as only expected class effects are listed in the warnings and precautions section. As I'll share in the next few slides, we believe this label provides a solid foundation for our team to educate health care professionals on how the use of PALSONIFY can benefit their patients.

Our clinical development program was carefully and intentionally designed to include 2 different but complementary pivotal Phase III studies, which have led directly to the broad indication reflected in the label. As Slide 10 shows, PATHFNDR-1 demonstrated PALSONIFY's ability to maintain disease control in patients who are already biochemically controlled on injectable somatostatin receptor ligands or SRLs.

Our PATHFNDR-2 study on Slide 11 demonstrated PALSONIFY's ability to reduce IGF-1 in 3 challenging patient populations, those who are treatment naive, those who were previously treated but uncontrolled and those who were previously treated and underwent a washout period. Furthermore, as shown in the label, 57% of patients who were uncontrolled on their prior therapy achieved biochemical control at week 24 with PALSONIFY.

The high response rates and durability of effect, as shown on Slide 12 by the OLE data across the Phase II study and both Phase III studies indicate that PALSONIFY can offer reliable long-term disease control for up to 4 years.

Turning to Slide 13. I'm also pleased to highlight PALSONIFY's impact on symptom management, which we evaluated using our novel acromegaly symptom diary or ASD. This innovative patient-reported outcomes tool allowed us to capture the real-world impact of PALSONIFY on patients' daily lives. This is a key differentiator in the approved label as it's the only one with symptoms as a prespecified endpoint. The ASD data revealed consistent evidence of PALSONIFY's ability to maintain comprehensive symptom control compared to placebo, and the results of the trial did show statistically significant improvements in symptoms for PALSONIFY versus placebo in prespecified key secondary endpoints.

The label explicitly notes lower severity across all 7 key acromegaly symptoms, headaches, joint pain, sweating, fatigue, weakness, swelling and numbness in both PATHFNDR-1 and PATHFNDR-2 studies. Again, this is one of the biggest differentiators in the label. Patients living with acromegaly often report uncontrolled acromegaly symptoms or breakthrough symptoms while on treatment with currently available injectable SRLs even when IGF-1 is normal. A post-hoc analysis from PATHFNDR-1 confirmed a high frequency of breakthrough symptom exacerbations in those patients. This frequency was significantly reduced after switching to PALSONIFY.

Turning to Slide 14. The comprehensive safety data from both PATHFNDR studies demonstrate that PALSONIFY was safe and well tolerated across our robust clinical program of over 500 study participants. There were no serious adverse events reported during the randomized control period in patients receiving PALSONIFY compared to 2.4% in placebo. While some gastrointestinal adverse events were observed, these were predominantly mild in nature, typically occurring within the first 2 months of treatment and resolved spontaneously without requiring discontinuation of therapy.

The discontinuation rate due to adverse events was remarkably low at less than 4% among PALSONIFY-treated patients. Importantly, our long-term safety monitoring showed tumor volume generally remained stable. The robust safety and efficacy data from our clinical program validate our conclusion that PALSONIFY represents an important advance in acromegaly care.

With that, I will now turn it over to Isabel to discuss our launch strategy. Isabel?

Thank you, Dana. Turning to Slide 16. We know that patients should not have to settle or make trade-offs between the burden of disease and the burden of treatment. And we believe that PALSONIFY represents a new era in acromegaly care. We have a transformative product, a very experienced team and the right strategy to successfully execute this launch in a dynamic competitive market.

First, activate. We must shift the treatment mindset. Through our engagement with the acromegaly community, we have learned that success for patients is more than IGF-1 control. It is about the impact symptoms have on their lives. Our patient activation initiatives are designed to accelerate appointments with health care providers and encourage conversations about disease control. Our educational initiatives with prescribers emphasize our differentiated profile and the start of a new era in acromegaly man.

Second, adopt. We plan to win on efficacy. Both treatment-naive and switch patients can benefit from a therapy that works rapidly, provides lasting results and consistently control symptoms. Our robust clinical data and broad label clearly demonstrate PALSONIFY's ability to deliver in all those fronts and will serve as a powerful foundation for our engagement with practitioners. I'm very pleased that our label will be uniquely differentiated within the class because it includes data on symptom control.

Third, access. We have implemented programs to ensure broad patient access and provide unprecedented support to ensure acromegaly patients can start and stay on therapy. We have been educating payers on the unmet need in acromegaly and the value proposition of PALSONIFY, and they have been receptive to our core med.

Finally, adhere, getting the prescription is just the first step, especially in a space where discontinuation rates are high. When patients stay on therapy, they see better outcomes. We believe PALSONIFY is a therapy that patients will want to stay on, and we remain committed to providing ongoing education and service to all stakeholders to support adherence and persistency.

I will now provide more detail about our specific launch preparations as it relates to our 3 key stakeholders. health care providers, patients and payers. Starting with our health care provider engagement strategy on Slide 17. The medical affairs team has prepared the foundation for our commercial organization to execute on the launch. They have been educating physicians about the PATHFNDR data and PALSONIFY's clinical profile as part of its speaker engagement, congresses and our CME series, all with meaningful engagement.

Our sales representatives are ready to get PALSONIFY to patients in need. The field team has extensive experience in rare disease and endocrinology and a shared passion for transforming patient care. They understand that physicians adoption will take time and persistent engagement because health care providers might default the treatment they are familiar with. Our field force will be armed with clear messages that will draft their attention to facilitate use, a first-line oral therapy that delivers rapid and sustained IL-1 control and allows consistent symptom management.

Our customer engagement model is designed so that our field force will be calling on both academic centers and community practices. Learning from our market research on this space, we recognize that success requires meaningful engagement from community practitioners who treat approximately 50% acromegaly patients. Given the profile of PALSONIFY, we believe it will achieve broad adoption, but we expect a gradual ramp considering the long tail of endocrinologists seeing only 1 or 2 acromegaly patients per year.

Our sales force will be focusing on the 5,400 targets. Their efforts will be supplemented with omnichannel nonpersonal promotion that will reinforce messages from the field and over time, expand the universe of potential prescribers to reach a much larger health care professional base. We believe our strategy will drive steady growth in the long term as health care providers and patients gain firsthand experience with PALSONIFY.

Moving to Slide 18. Before I discuss our patient engagement strategy, I would like to detail how we see the current addressable market and then explain how we plan to reach each segment. First, there are approximately 11,500 addressable acromegaly patients in the U.S. Our market research indicates that approximately 40% are medically treatment naive, 25% are currently on SRL treatment, 20% are using our therapeutic options and 15% have discontinued treatment. Additionally, there are approximately 1,500 newly diagnosed patients each year, of which 500 are likely to be candidates for pharmacotherapy. In the longer term, we intend to help drive diagnosis and treatment for the more than 17,000 undiagnosed patients.

Turning to Slide 19. Our patient engagement strategy seeks to refrain the narrative around acromegaly management. There hasn't been through innovation in acromegaly for over 20 years. This is the first time that the acromegaly community will have a treatment that offers unparalleled efficacy, favorable tolerability and safety and once-daily convenient dosing. The current treatment paradigm presents clear opportunities for PALSONIFY. Real-world data we published shows that 80% of patients on injectable SRL discontinue or switch their initial therapy within the follow-up period of up to 5 years, reflecting the inadequacy of these options.

In contrast, over 90% of PATHFNDR study participants actively chose to stay on therapy and transition into the open-label extension studies where the vast majority have now been on PALSONIFY for over 2 years. We will activate patients with an omnichannel strategy and a variety of tools to empower them to have more informed discussions with the providers. We're encouraged by the initial response to our disease state awareness campaign. We aim to mobilize patients regardless of whether they need to switch, initiate or resume treatment.

As you will expect, patients typically wait for the regularly scheduled appointment to talk to their health care providers and patients who are not actively on treatment might face a wait list of several months to see an endocrinologist. No matter the starting point, Crinetics is committed to helping people living with acromegaly get the care they deserve. We will also continue our decade-long partnership with the patient advocacy community at the corporate level to ensure we continue to be aligned with the needs and effectively address the challenges faced by people living with acromegaly. This collaborative approach has been essential in building trust as we make sure that patients' voices are heard and we support them in their treatment journey.

Moving to Slide 20. We have strategically developed our infrastructure and payer engagement plan in order to ensure broad access to PALSONIFY. First, we have controlled distribution model to provide the best patient and practice experience. We're also working with 2 specialty pharmacies and specialty distributor that can provide products directly to the pituitary treatment center pharmacies where many patients get care.

And second, for over a year, we have been educating payers on PALSONIFY's differentiation versus current standards of care. Unlike other treatments, PALSONIFY is the first and only once-daily oral SSP2 selective agonist that has the potential to achieve rapid biochemical and symptom control that is consistently maintained over time based on the Phase III data. Payers understand that this can contribute to better patient outcomes and lower overall cost due to the burden of uncontrolled acromegaly.

Importantly, the label reflects its efficacy, safety, tolerability and ability to address a broad population. We believe PALSONIFY delivers extraordinary value to patients, health care providers and the health care system. Based on our extensive research, we have set PALSONIFY's annual WACC price at approximately $290,000. This is within the price range of other products approved for acromegaly.

Importantly, we have implemented a sales pricing structure across both SKUs, ensuring that treatment decisions are based on clinical needs rather than on cost considerations. Payers indicate they accept very low barriers for access with typical prior authorization requirements linked to the indication on the label. Only a small number of payers are expected to require a [ stipend ]. We recognize the critical importance of making PALSONIFY accessible to appropriate patients, and we know that navigating insurance coverage can be complex.

That's why we're implementing several key programs within our customized patient support center, CrinetiCARE. In the short term, our Quick Start program ensures that eligible patients are [indiscernible] PALSONIFY within 48 hours of the prescription. This eliminates potential treatment delays as we work through our prior authorization and securing coverage during the initial review period.

Our payer team has been focused on ensuring access soon after launch. As with most new drug approvals, reimbursement at the outset will require prior authorization. We expect that it will take at least 6 to 9 months after launch, in line with other specialty pharmaceutical launches to be placed on formulary without [indiscernible]. We also want to ensure financial circumstances don't prevent access to therapy. For commercially insured patients, our co-pay assistance program will help minimize out-of-pocket expenses. Additionally, our patient assistance program will provide PALSONIFY at no cost to eligible patients. CrinetiCARE also connects patients to foundations that might be able to provide financial assistance.

Turning to Slide 21. We have worked closely with payers, pharmacists, patients and prescribers to design a unique patient support program to ensure every patient who is prescribed PALSONIFY can start and stay on treatment. Our patient support hub, CrinetiCARE, is designed to provide white glove service and personalized support throughout the entire treatment journey with PALSONIFY. Our experienced nurse team will provide ongoing education and support throughout the treatment journey to help patients understand their therapy, manage potential side effects and maintain adherence to treatment. This ensures that patients have consistent access to expert guidance and support as they begin and continue the treatment with PALSONIFY.

Moving to Slide 22. In conclusion, we are prepared to meet the needs of patients with our broad label, strong value proposition, experience team and clear strategy. We're excited to launch PALSONIFY and usher in a new era of acromegaly care with a potentially transformative treatment for patients.

With that, I will now turn the call over to Scott for his closing remarks.

Thank you, Isabel. With the great clinical data from PALSONIFY, Crinetics demonstrated that we can deliver world-class drug discovery and development. Now with the FDA approval of PALSONIFY, we intend to prove that we can broadly deliver a transformative therapy to people living with acromegaly and help improve their overall rare disease journey. The infrastructure and strong financial position that we've built will support PALSONIFY's launch and serve as the foundation to advance our entire pipeline of first-in-class small molecule therapeutics.

As we conclude today's call, I want to emphasize that while the upcoming launch of PALSONIFY represents a significant milestone for Crinetics, it's truly just the beginning of our journey to transform endocrine care. It's not often these days that a company conceives of an idea for a drug, discovers it, develops it and has the opportunity to launch it. I'm proud that we are now joining those rare few.

Lastly, I'd like to take a quick moment to thank my fantastic team at Crinetics. Their hard work and unwavering commitment to scientific excellence and patient care has been instrumental in bringing PALSONIFY to its first approval. Thank you all for your attention today.

With that, I'll turn the call over to the operator to begin our Q&A session. Operator?

[Operator Instructions] Our first question comes from Josh Schimmer with the company, Cantor Fitzgerald.

Congrats on the approval. I guess what do you think it may take to gain traction in surgically naive patients? Do you plan on running additional trials to expand the label? Do you think the current crafting of the label gives you some meaningful inroads into that population? And then separately, for those patients who are not diagnosed, how do you think about a targeted campaign to find them?

Thanks, Josh. Yes, I think there's already data in our trials and in the label supporting the use in patients who haven't received surgery. Some of the patients in Phase III were not surgical -- had not been in surgery. So it's already there. And in my conversations with various prescribers around the world, I think they see a new opportunity with the rapid onset of action to be able to give it to somebody and if they can't get the surgery or if they can't get the surgery for a while and get control relatively quickly, so 2 to 4 weeks.

So I think that's a really obvious population for people to go in. I mean the question isn't why would you use PALSONIFY there, it's why wouldn't you? And then as we get to thinking about finding more patients before the disease has more time to cause damage, I think there's a long history of new therapeutic options improving awareness. And we're going to be out there with awareness campaigns and both at the practitioner level, but also at the patient level. And I think that will help.

And then we're also starting some brainstorming sessions about how we can apply technology or communications or other routes to try and improve the diagnosis rate. The thing about the diagnosis is if you suspect it, it's really straightforward. You measure IGF levels and then you confirm that you can't suppress them and you do a look for a tumor with an MRI or CT. I mean you can find out within days whether somebody has acromegaly or not.

The problem is those things that have been bugging them for years are kind of nonspecific and nobody thinks to look. But we need to make sure that your dentists, your shoe salesmen, your primary care, maybe even somebody treating your diabetes. So a lot of patients who aren't being adequately controlled for their acromegaly have problems with insulin resistance because of the excess growth hormone in IGF. So there's a lot we can do, but that's going to take some time and some effort.

Josh, I was just going to add to what Scott said that those efforts had a target, and we had CME programs that also target primary care physicians, and we have significant participation on those. So it's something that is not an immediate group that we are targeting, but definitely, we want to make sure that we improve care and we accelerate diagnosis.

And the one -- just to follow on, on this because I'm super passionate about it is it's just so sad that people have given up on their treatments. We need to get them back into their physician offices. And then as Isabel's group has dug deeper and deeper into the claims data, we find these patients who -- we found 7,500 patients who've been clearly diagnosed with acromegaly and have no active follow-up. I don't know why. they don't understand that. So I think we can make a big contribution, not just to an improved therapeutic option, but to the overall management of the disease.

Looking forward to the launch updates.

Our next question comes from Yasmeen Rahimi with the company, Piper Sandler.

Congrats on an incredible accomplishment and what a wonderful label that you received. I guess the question, given that acromegaly questionnaire is part of the clinical section, it would be great if you could talk about how your sales team could speak to patients and physicians around a therapy that's available that really cuts through breakthrough therapies that is one of the challenging symptomologies of the disease to feel good for 3 weeks and allows in your fourth week. Could you maybe talk about how that could be utilized that that's going to be a big driver of utility of PALSONIFY beyond just being highly effective and safe in an oral option?

Yes. Thanks, Yas. I think it's important to step back a little bit and remember that the patient groups have been advocating for understanding symptoms and managing symptoms for a long time. I mean part of their motto has been they're more than just an IGF number, and they've been trying to educate the physician community about that. And they also had active listening sessions with the FDA. Our conversations with the FDA about exactly that, which is why we're glad to see that the FDA listen to that and included comments about symptom improvement in the label, which is something that's not all that common. But let me let Isabel answer a little more directly how the field force can use that to try and improve care.

Yes. As Scott said, it's highly uncommon in rare diseases to have a label that acknowledges symptom control or quality of life issues. So we're very pleased that we are able to use that. And of course, it will be in our sales materials. We're able to communicate symptom improvement, reduction in severity. We're able to talk about the core symptoms of the disease and how the worst symptom actually improves with PALSONIFY, which is very relevant to patients and physicians.

So the label is giving us the opportunity and the data that we collected in PATHFNDR-1 and PATHFNDR-2 to really make sure that patients are not only looking at IGF-1 control, but symptom control and that initiates a dialogue, a different kind of dialogue between physicians and patients that we think is very relevant and will really transform acromegaly in the future.

And if I may ask one question from Toby. Toby, moving forward into the upcoming quarters, what metrics do you hope to share with us as we are going to be monitoring the launch closely?

Yes. Thanks. I think that as we gain experience in the marketplace, we will share key performance metrics. They will be linked to our progress with patients, health care providers and payers. And we'll gain experience over the next few months. And then on the upcoming calls that we have and engagements publicly, we'll provide detailed metrics. So we look forward to providing those in the coming quarters.

Our next question comes from Gavin Gartner with the company Evercore.

On the approval. So just on the pricing side, I'm currently calculating that [ somatuline ] and [ zanostatin ] net price is probably in the $60,000 to $70,000 range, give or take, depending on dose after all the rebating and discounting. But the Signifor LAR WACC price is pretty closely aligned with what you noted, and it seems like without that much rebating. So I'm wondering what quality of access does Signifor have in acromegaly relative to the SRLs at a higher price? And what are your own expectations on gross to net?

Yes. Thanks, Gavin. And I think that's a great example on Signifor, which, as you know, also impairs insulin secretion. And so you end up having to add antidiabetic drugs as well for many of those patients. But look, we had quite a bit of time to think through that and talk to payers, as Isabel was describing. And I think that with the value that we're bringing, the rapid onset of action, the reliability, durability, consistent control of both the IGF and symptoms and a favorable safety profile and all this is reflected in the label, it's not that hard to communicate the value proposition to the payers. And I think they're getting it.

So -- and maybe what's more important is irrespective of that aspect of getting care to patients, we're really committed to making sure that everybody has access to PALSONIFY with a really unparalleled level of patient support, certainly in the acromegaly space. And as well said, that's called CrinetiCARE. But we expect most commercial patients to have 0 co-pay. We have a bridge program so that they get a script, they can get cut, they can get it in days. And we'll have a very generous patient assistance program so that they're not insured or underinsured, they'll get on drug. So I'm very confident that we'll have good access.

But Isabel, maybe you can elaborate on that.

Yes. We conducted extensive payer research, as you can imagine, to make sure what will be the appropriate price point that really demonstrated the value of our treatment as Scott outlined. And we found that basically, when they see the efficacy profile, the impact on symptoms, the safety profile, the once daily convenient dose that allows for patients to stay on therapy, that resonated very well with patients. Also, if you look at the space and you look at the data on IQVIA and different databases, many of these patients right now either are taking more injections per year or are taking less injections per year or are discontinuing. So basically, the disease is not managed.

So when we talk to payers in summary, most of them told us that they will expect to primarily cover the drug based on the prior authorization to label, and as you know, we have a first-line label, a minority of the patients might implement a single step edit primarily through NRL or potentially through [indiscernible]. And we expect that most of these patients actually at some point during their treatment has been on those medications, which will allow for immediate access to PALSONIFY.

They also highlighted for us that there are very few patients per plan that are in their programs, and it will make no sense for them to put too many barriers. So through all the discussions with them and considering the high value that we bring to patients, health care professionals and the health care system, we feel very confident that we'll get access very quickly. And as Scott highlighted, we also have to make sure that the patients we have access very fast. So our Quick Start program will allow for a 48-hour delivery of the treatment while we do benefit verification in the background, and we'll be very moving very fast through that process. So overall, we feel very confident that this is not going to be a variant and we will be in formulary within 6 to 9 months.

And then I think on the question around gross to net, I think it's early innings right now to guide on a gross to net ratio. However, Isabel has alluded to in the past about a 60-40 split between the commercial payers and the government payers of this product.

Next question comes from Jessica Fye with the company, JPMorgan.

This is [ Dillon ] for Jess. I just wanted to quickly double check if you said that most payers will acquire a step edit through an SRL. And then I have...

No. A minority of payers.

Most will not, sorry.

Yes. A minority of payers. The majority of payers will cover based on prior authorization to label.

Okay. And then recognizing that you're coming out of a very different price point, I just -- what do you estimate the injectable SRL sales are in acromegaly, both in the U.S. and worldwide?

Yes, that's been very difficult to dig out exactly. So you have to probably ask Gibson and Novartis. We've never had a number and we can really rely on the number of scripts, but sales is harder to get.

Got you. And it's okay if I ask one more. How long should we expect for coverage to come online?

How long for coverage to come online?

Yes. So we're expecting that as a new-to-market drug will take 6 to 9 months to be in most formularies.

Our next question comes from Joe Schwartz with the company, Leerink Partners.

Great. Let me add my congrats as well. First, I was just wondering, to what extent do you expect physicians to trial PALSONIFY in their own practices on a relatively limited basis so they can get experience with how it performs in their own hands? We see this dynamic play out sometimes, yet here, it seems like the decision could be relatively straightforward. So I was wondering if we could get your thoughts on potential adoption patterns in the real world.

Yes. Thanks, Joe, and I'm kind of an experimentalist at heart. And I think we're doing that experiment now in acromegaly. And like anything else in life, it's probably going to be a bell curve of different phenotypes. So the experienced pituitary centers, my guess, are going to be quite a bit more confident in prescribing an SRL. On the other hand, they have many more patients, so they may want to make sure and see how it works in the first Q.

Similarly, in the community, there's going to be physicians with 2, 3, 4, and there'll be some that want to switch everybody to keep it simple, and there'll be some that will try it out for one. And then when their next patient comes in 4 months later, they'll try it out again. So I don't know. I'm very curious to see how that plays out. Do you want to add to that, Isabel?

Yes. Our market research indicates that one of the key attributes that will help with adoption is the fast set of action. They will see very quickly how the patients respond, how they feel about their symptoms, and that will definitely be a motivation to move the drug. So if you remember, as of the label, the drug works as rapidly as 2 to 4 weeks. So they will see and they will be able to evaluate very different from SRS where you have to wait for several months before you titrate up and make further adjustments and decisions.

We are also very excited to see the significant interest from community doctors. Those community doctors tend to have 1 to 5 patients, the majority really 1 to 3 patients. But they had shared with us that if they have a positive experience with one, they will immediately switch the others because they really want to have a single way of managing in their practices. particularly because they have many other patients with diabetes and other conditions. So they want to standardize the way that they look at that. So we are expecting uptake from both PTC centers and community. And again, the onset of action and the rapid effect is going to be very important in that broader adoption over time.

But all that said, I think we're still going to have significant headwinds in just the core way medical access is these days. I don't know about you, but the last time I tried to get past my -- well, even my primary care, when you could get a reasonable appointment time on telehealth, but it was like 2 months to see my primary care and the specialist was 4, 5 months out. So we'll help where we can there, but that's going to be an intrinsic challenge in the system.

That actually anticipated my second question.

Our next question comes from Maxwell Skor with the company, Morgan Stanley.

This is [ Selena ] on for Max. Congratulations on the news. We wanted to ask what are your plans for sharing real-world data? And how might that help with uptake among patients well controlled on injectable?

So look, we have a big set of open-label extensions going. And there's emerging data from that. We showed some of it in the slides today and some will keep on going. But maybe Alan or Dana can comment a little further on our plans in the real world.

As Scott mentioned, we have long-term open-label extension data in patients who have been treated for up to 4 years now in our Phase II extension study and 1 to 1.5 years in our Phase III extension studies. And I'm sure as these long-term open-label extensions wind down, that will be converted into more kind of real-world experience kind of reports as well.

Our next question comes from Alex Thompson from the company, Stifel.

This is [ Patrick ] on for Alex. I guess, could you guys just talk about who you think your early adopters are here? I know the label is broad indication position this is first line, but do you expect to see mostly switch patients in the beginning? And then I guess on the OE, are those patients converting to drug? And maybe how many patients could we expect here?

Yes. So I mean, again, I'll say, I don't know who shouldn't be prescribed paltusotine or PALSONIFY, still getting used to the new name. But as you start thinking about the dynamics of the practice, it's probably going to depend a lot on who comes in first into that individual practice. I do think that the patients who are currently actively managed and coming in for their monthly injections are a kind of a prime area to -- you know when and where they're going to be or at least the office does.

The new patients are an obvious one for the newly diagnosed and untreated patients are an obvious one for the practitioner, but you never know when they're going to come into your practice. And of course, I think that these patients who are untreated who should be are a huge priority, but that's probably going to take some while to get to that depth of the potential opportunity. But did you want to comment, Isabel, on how you're thinking about deploying the efforts of our team?

Yes. Frankly, it's interesting. When we talk to patients, there are patients that are newly diagnosed that have been waiting to actually be in this therapy. So we are eager to see adoption in that segment. But as Scott alluded, the majority of the patients are currently in some sort of treatment, whether it's an SRL or [indiscernible]. And those already have appointments and doctors are already seeing some of the shortcomings of those therapies, whether it's breakthrough symptoms, whether it's lack of efficacy and IGF-1 control, whether it's the fact that the patients are not consistent in using the medication and are taking some sort of drug holidays.

So we are expecting that across the board, we will have an opportunity to have patients that are currently on treatment transitioning to PALSONIFY. So across the board, as Scott says, all patients should be benefiting for this treatment, but we see that a lot of that will also come from switching.

Our next question comes from Dennis Ding with the company Jefferies.

This is Anthea on for Dennis. Congrats on the approval. In terms of switch patients, I think you mentioned patients usually switch within the follow-up period of up to 5 years. So curious to see what that frequency of those follow-up appointments where docs are evaluating their progress is? And when do doctors typically start considering a switch in terms of moving away from their current treatment?

Well, I think kind of like I answered one of the earlier questions, it's a bit of an experiment in progress. Typically, patients see their endocrinologists once or twice a year, depending on the state of their disease control, maybe more rapidly if they've recently been diagnosed or have recently had surgery. So that's the natural cadence of the contact point. And then in terms of the -- just how docs think about switching, I think about it both from the patient and the physician point of view. I think there's some docs and some patients who can't wait for their next visit to talk about it. I think there's others who are going to be much slower. And I think momentum will build as patients talk to each other and as physicians talk to each other.

Do you want to add something, Isabel?

Yes. There are many patients today that are making trade-offs between the burden of the disease and the burden of the treatment. And they have shared with us many stories. For instance, the treatment doesn't allow them to travel. Treatment is very painful. The treatment is constraining them and allowing them to do their daily activities for periods of the month, long periods of the month. So those patients are very and many times, not only the prescribing doctors, but the nurses in the practice are aware of that and want to make sure that those patients have an alternative option. All the patients are in suboptimal treatments like cabergoline, and they are not really controlled.

And this is the opportunity to actually be in an oral that is effective and is well tolerated and will allow them to have the life that they deserve. So we see that there are different motivations to switch the patients and primarily is the disease under control, IGF-1 control, symptom control, but also the burden of the treatment will play into their decisions.

Our next question comes from Jon Wolleben with the company, JMP Securities.

This is Catherine on for Jon, Citizens. I just have a quick question about kind of the line of sight going into the October launch. Do you have any guidance on how many patients you guys kind of already know that might be coming on drug early in the launch? And also another quick question about the Quick Start program. How long does the initial prescription last? So how much drug do the patients get initially?

I have no idea how many patients are waiting, but I don't think you should expect any sort of a bolus because as much as you might want to call in and get an appointment, good luck. But I feel bad saying that, but it's just tough out there. Our Head of Medical Affairs was Chairman of the Department at Dartmouth before he came and joined us, and it took a year to get an appointment, more than a year, actually. So I hope we can improve that as a health care system. But maybe, Isabel, you want to comment on the second part of her question?

Yes. Our quick start program, the patients will receive a bottle with a treatment for 30 days. which we believe is sufficient time for us to do the benefit verification and move into a commercial paying customer.

Next question comes from Brian Skorney with the company Baird.

Congrats on PALSONIFY's approval big day. I'm sorry if I missed this on the 290,000 number, but you have 2 different NDCs. Are they both the same price? Or like is it $24,000 per tablet bottle for each? Or do they have 2 different prices? And if so, could you break out the list by NDC? And then on the 60/30/10 breakdown, for commercial Medicare, Medicaid payer mix. Is that in the active treatment segment or the actively managed segment? Just wondering if those injectables might have a higher commercial representation and treatment naive, maybe higher Medicaid representation or if you could just give some better on-the-ground insight there.

Yes. Thanks, Brian. I'm really glad you asked that because I guess we weren't as clear as we should have been. We're implementing a flat pricing. So it doesn't matter what dose, it's the same price. I don't think people should be making dosing decisions on what's best for their patient based on the price of the drug. It's just -- I mean, sometimes that has to be done, but not with PALSONIFY. And then maybe you want to comment on the different coverage groups then, Isabel?

Yes. As we had shared, 60% of the patients currently are in commercial. As you know, the onset of disease is later. That's why Medicare is about 30% of the patients and Medicaid is 10% of the patients. To your question of whether that's different, whether they are in an SRL or they are actively managed, this is basically the breakdown for patients on treatment.

Our next question comes from Richard Law with the company, Goldman Sachs.

This is Paxton on for Rich. Congrats on the approval. I guess a question for me is in regard to the step edits, do you expect that this would have a larger barrier to potentially new patients? What are your expectations for what that percent of payers requiring step edits could be? And what would the trial period be for the prior agents?

Yes. I think the -- really, I want to emphasize that our impressions is this should be few and far between. This should not be something that happens all the time. We expect it to be primarily just a prior authorization to make sure -- a simple prior authorization to make sure that patients are appropriate for the drug. And so in the case that, that happens and somebody might implement a step edit, it's way too early to predict what that may look like. And we do think that the bulk of the patients initially will be those who've already experienced that drug.

And again, it just doesn't make medical sense. So you've got a newly diagnosed patient. You know that they've had surgery, their IGF is not where you want it to be. You can choose between something that is going to be giving you the right answer in 2 to 4 weeks or you could go to one of the depots where you wait 3 months for the first dose, 3 months for the second dose.

And if they need the third dose, that's 9 months. And half the time, at least according to one study, half the time those injections are administered poorly. Why -- what's really in it for the -- any payer to want to impose that on a newly diagnosed patient. So I just don't think it makes sense, and it's not a very supportable physician.

Yes. We come back to the market research, as I mentioned. And for instance, when we're talking to the PBMs, they told us not many of our members have acromegaly. So there is even much more cost trying to implement a step edit than actually covering the drug. There is no much to gain there. So the response that we got is the vast majority will be covering our treatment based on label. Very few will have a single step edit, and we believe that we have everything ready to implement and get over that very quickly because the example that they gave us is potentially we'll put you to a step edit to SRS or cabergoline.

And as I mentioned before, the majority of the patients have been on those treatments. So we'll be able to process those fairly quickly. I mean you probably know in rare diseases, it's very, very hard to start implementing that. This is actually across rare diseases that most of the time, it doesn't make any sense to put the patients or the physicians to a step edit if the physician considers that that's the best treatment for the patient.

Our next question comes from Cory Jubinville with the company, LifeSci Capital.

On this really incredible update. One thing I noticed on the label, there's a section that flags potential ocular phototoxicity findings from nonclinical studies and it found some findings such as early-stage dry AMD and diabetic retinopathy. Since acromegaly patients tend to be older and more at risk for metabolic disease, can you walk us through some of those nonclinical findings as it relates to potential impact in the clinical setting?

Yes. Thanks, Cory. I'm really glad you brought that up because man, if you look through that label, it's so clean overall. I don't want to have any confusion. There -- in the general warnings and things are almost all class effects that you see with all SRLs. So for those of you who haven't had a chance to pour over the entire label yet, what Cory is referring to is a language related to a preclinical [ photo tox ] study where there were some findings in some of the animals. And so after discussions with the FDA, we implemented ocular assessments in our ongoing open-label extension studies. And as we follow these patients, some for over 2 years now, we've not seen any adverse events of phototoxicity as we're following it. And this is pretty extensive.

However, we don't have baseline assessments for those patients and the observations that you mentioned were included in the label. But these observations are conditions that you'd find commonly in any cohort of this age demographic, and none of them are related to the preclinical findings. So overall, I want to make sure there's no confusion there. I don't think this is an issue at all. But I just want to remind everybody what an excellent profile it is overall for PALSONIFY. And just on a personal level, this has been one of the cleanest drugs that any of us have ever worked on. So we're super happy about that. But then you add the clinical benefits on top of it and all of this in the label, the biochemical and symptom control. I think this is just a huge advance for people with acromegaly.

Our next question comes from Douglas Tsao with the company, H.C. Wainright.

On the approval. It's been a great journey for you, Scott. Just maybe a question for Isabel. I'm just curious, when we think about the launch, where do you expect to see the greatest adoption early going? I assume -- or where will you be focusing most of your efforts? Will it be largely on pituitary centers? And how long do you think it will take before you start to see adoption in the broader community setting?

Again, we're -- I'm an experimentalist, and I think Isabel too is too. And I'm eager to see. Of course, we're spending time in the pituitary centers. We've spent time with them for years anyway, both as part of our development of paltusotine, but also part of our development of [indiscernible] and talking to them about what else we should be doing. So I think the -- we've been at the scientific meetings. We've had high-profile talks at Endo and European endo. So I think that group knows about us.

And we're collaborators and friends and part of that community. So I think we're doing well there. We do have more work to do in the community outside of the centers. But remember, those folks also work very closely with the centers. And we've already started some education programs hosted by top KOLs who are now talking to a broader set of people but it's really hard to predict how this will play out. So I'm just waiting to see.

Yes. So as you know, 40% of the patients are in the PTC centers and 60% of the patients are in community. And as a reminder, our sales team has been in the field for the last 2 months, making connections and educating the physicians on the disease on acromegaly. So we are now ready to go. What we can anticipate is that the PTC centers have more patients, but they also have a harder time making appointments. So we want to see how quickly they can move through that cycle for the adoption of paltusotine.

There is a potential benefit there is that some of them would like us to partner with them. So they had they dispense directly, and we have the capability to do that, not only to our specialty pharmacists. And in the community, there is an interest because for them having a nurse injecting the patient, it's actually a burden. And for them, having an oral agent that is easy to use and easy to dispense is important. So we are expecting adoption in both.

If you have followed the CrinetiCARE launch, you will see also common for endocrinologists in community and PTC centers to start prescribing therapies almost in parallel. We just want to see how the sequence and the volume will come. But for us, it's important to be in both settings, and we are ready to go on both.

Okay. Great. And just a follow-up in terms of your -- the program to get drug to patients within 48 hours, will you be able to complete benefit adjudication in that time? Or will there be some amount of being at risk in terms of shipping drug to patients?

Well, that's for the Quick Start program. So we will be able to shift the quickest program within 48 hours while we do benefit verification. So the patient will get treatment for 30 days, and we hope that benefit verification will be done relatively soon, but we are accounting for that amount of time to actually make sure that the net prescription will be covered by the insurance.

Yes. We don't want to lose the momentum. You go into your doc, you get a -- you have a conversation, you get a prescription, and then you wait and wait for prescription. That's not the user experience we want for the people we're trying to help. So they walk out, they get the script or the script goes through electronically. And one way or another, we get it to them as fast as we possibly can, and we'll worry about the money later.

I think the other thing to note is maybe I don't remember if we said it or not in the prepared remarks, but we've got a group right now out putting labels, printing labels and getting them on bottles so that we can get this drug shipped to people very early in October. So we may not make the 48 hours for the first few patients. But after that, we expect to be very quick.

Yes. We are in the process of getting drug in the channel and as pretty much the new drug, it will take a few days. But once drug is in the channel, we'll be able to supply to the quick start program, we think as 48 hours.

Isabel, should we think of that to some extent as sort of in lieu of the sampling program sort of like a starter path?

Yes. We can consider it that way. We are not going to do anything else. It's going to be a big event.

Our next question comes from Andy Chen with Company Wolfe Research.

This is Emma on for Andy. I guess how do you anticipate physician practice patterns will evolve over the next few years following launch? And do you expect PALSONIFY to eventually replace injectables with standard of care expected to remain complementary for certain patient subsets like switchers?

Thanks. This is an interesting debate between the CEO and the commercial leadership, right? So the CEO thinks and has always thought why would anybody stay on the depots? I mean, maybe if you have some -- I don't know. I can't think of a reason why you would stay on it. On the other hand, it's unreasonable to expect that anything would -- any one new drug would completely displace a well-established entry. And so I think the way to think about it is, again, about time. There may be people who are hesitant to make the change. It's working for them. They can tolerate the injections. They love seeing their nurse every month. they don't want to change. Eventually, the new patients will come in.

And as I said earlier, why wouldn't you start a new patient on PALSONIFY. So I think with time, we will shift practice patterns. But what I really hope -- honestly, I don't really think the big deal is to switch everybody to PALSONIFY. I think the most important thing we can do is get way more people on medical therapies that need to be on medical therapies, get their IGF levels down to where they should be and get their symptoms under control. And if we do that in a few years, you won't be asking me about how many patients are still on the injectable depots. You'll be asking us about how we really grew the market or improve care overall for these people living with acromegaly.

Yes. For me, there is no doubt that we will become the new standard of care in acromegaly. And that means we'll have the highest number of patients on treatment than any other drug in the market. So I'm fairly certain about that. That's just the future, but it will take some time to get there because right now, the appointments are slow. We are still -- we have very few patients in our clinical trials in the U.S. So we need to get people to have experience with the drug to really see how that benefits their patients before they adopt more broadly.

Yes. And maybe another clarification. It's not just switching from other SRLs, but there's a lot of people who are on dopamine agonists. And I think we know pretty clearly that the dopamine agonists are not as effective as for most patients as what they really need. So there's that group as well.

Our next question comes from Catherine Novack with Company Jones Trading.

Congrats to Scott and the team on just a really well-executed program from start to finish. My question is a little bit on -- so in doing my market research, one thing that I saw was that the number of patients controlled after surgery is variable from center to center. And I was wondering, a, is this what you've seen in your market research? And b, have there been advances in surgical techniques or anything that might then impact the number of patients who are not biochemically controlled after surgery and therefore, the market opportunity?

Thanks, Catherine. I think that's a great question and part of the overall problem in the care of acromegaly patients and their journeys, there is a great deal of variability in the skill of different surgeons and their ability to excise these tumors. And what's really been found is that in centers where they're high volume, where they're doing this day in and day out, obviously, you practice and you get good at it and your outcomes can be better. So that's an important thing we tell any patient that they should look at the number of surgeries their surgeon does before they choose a surgeon.

And some of that information is what we provide on our CrinetiCARE website as we help people with the physician finder. But what was told to me at one of the conferences I was at recently was that the majority of surgeries in the U.S. for pituitary are done by neurosurgeons who spend most of their days doing back surgery and things like that, and they don't do very many pituitary surgeries. And I think that's not a great choice for most patients.

And just to ask again, has it -- have you seen any trends in recent years or it kind of held steady across the board?

Well, I think if you go back a little further, people have gotten into the more careful robotic surgeries. But I'm not sure there's been any big leaps in the area. Alan, are you aware of any big leaps?

No, I think there's a movement towards increasing standardization and defining, for example, pituitary center of excellence and things like experiential caseloads for surgeons and also for the endocrinologists and other health care providers. So there is a movement toward more consistency in care. But even in the best of hands, it is difficult to remove these acromegaly causing tumors in their entirety in many, many cases.

Yes. And yes, that's a great point. It doesn't matter how experienced you are. If that tumor is kind of wrapped around in between the optic nerve and the carotid artery, you just can't risk it. And the angles, again, I'll encourage somebody. If you really want to understand how hard this is, go on YouTube and you can watch them. But it's really hard to get in there safely. And you don't want to mix the optic nerve or do something to the carotid artery, that's for sure.

Congrats again.

Thanks, Catherine. Really appreciate it.

Thank you so much. That will conclude today's conference call. Thank you for your participation, and enjoy the rest of your day.

Thank you.

Welcome to Crinetics Pharmaceuticals Second Quarter 2025 Financial Results Conference Call. [Operator Instructions]

I'd 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 second quarter 2025 results. Today on the call, we have Dr. Scott Struthers, Founder and Chief Executive Officer; Dr. Dana Pizzuti, Chief Medical and Development Officer; Isabel Kalofonos, Chief Commercial Officer; and Toby Schilke, Chief Financial Officer. In addition, Dr. Steve Betz, Founder and Chief Scientific Officer; and Dr. Alan Krasner, Chief Endocrinologist, will also be joining for the Q&A session.

Please note there is a slide deck for today's presentation, which is in the Events & 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. Slide 2: 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 our commercialization plans as well as estimates related to market size, growth and other data about the acromegaly market. Projections, assumptions and estimates of the future performance and the future performance of the markets in which we operate are 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 report 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, August 7, 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.

With that, I'll hand the call over to Scott.

Thank you, Gayatri, and good afternoon to everyone joining today's call. Turning to Slide 3. We are pleased to provide an update on our corporate progress and share our second quarter results. We continue to execute on our mission to develop innovative therapies for patients with endocrine diseases and endocrine related tumors. As we approach the pivotal moment of our pending approval of our first NDA, I'm pleased to report strong execution across all aspects of our business.

I want to begin by reaffirming that the paltusotine NDA review remains on track. We continue to work closely with the FDA towards an anticipated approval in September. We are grateful for the FDA's commitment to this important work and their collaborative approach throughout the process. Our regulatory team has maintained excellent momentum and remain confident in our timeline and preparations for what will be a transformational launch for Crinetics.

We've assembled an outstanding launch team of experienced professionals both in our headquarters and in the field who bring deep expertise in endocrinology and rare disease commercialization. The caliber of talent we've attracted speaks to the excitement around PALSONIFY and its potential impact on patient care. Recently, we hosted a group of more than 40 people living with acromegaly at our headquarters in San Diego as part of our ongoing engagement with the patient community.

We have worked with the acromegaly advocacy group since before paltusotine entered the clinic. We continue to seek their insights to shape our commercial strategy. At this most recent patient event, I heard directly about their experiences with their disease and their interactions with the health care systems around the country. After talking with them personally, I am more confident than ever that PALSONIFY's profile addresses a critical unmet need that will make a very positive impact on all these patients' daily lives.

Deeper in the pipeline, we continue to make progress towards initiating 4 additional pivotal programs. Trials of paltusotine for the treatment of carcinoid syndrome and atumelnant for the treatment of adult and pediatric congenital adrenal hyperplasia are ramping up now. We remain highly encouraged by the potential of atumelnant's novel mechanism of action in ACTH dependent Cushing's syndrome and following extensive conversations with multiple regulatory authorities, anticipate initiation of a Phase II/III study in the first half of 2026.

The enthusiasm for our earlier pipeline continues to build. The Phase I/II study of CRN09682 in SST2 expressing solid tumors is ramping up and our work towards IND submissions across multiple additional discovery stage programs continue. As you may have seen, we've been extremely active at several key endocrinology conferences over the last few months, including ENDO 2025 last month in San Francisco. We delivered 6 poster presentations and 2 oral presentations covering PALSONIFY in acromegaly, atumelnant in CAH and our thyroid stimulating hormone or TSH receptor antagonist program.

We also hosted product theaters and innovation sessions to highlight our pipeline's differentiation and met with key opinion leaders across the different indications we are pursuing. Among the presentations at ENDO was an update of CRN12755, our TSH receptor antagonist candidate, for the treatment of Graves' disease. We believe this novel mechanism of action has the potential to be a single oral therapy that addresses the core driver of Graves' disease in order to treat both Graves' hyperthyroidism and treat or prevent thyroid eye disease.

Turning back to the launch of PALSONIFY. I'm energized by the team we've built, the progress we've made, the strength of our financial position and the opportunity to really transform the lives of people with acromegaly.

With that, let me turn the call over to Isabel to tell you more.

Thank you, Scott. Turning to Slide 4. We are incredibly excited for the anticipated launch of PALSONIFY, our recently debuted brand name for paltusotine. This represents a combination of years of dedicated research and development to bring a new standard of care to patients with acromegaly. We have made meaningful progress in our interactions with health care professionals, patients and payers as we approach this milestone and complete our transition into a commercial stage company.

Moving on to Slide 5. As Scott mentioned, Crinetics had significant presence at several prestigious medical meetings over the last few months with global key opinion leaders as well as with community endocrinologists. Our presentations across theaters at ENDO were at standing room only and health care professionals were excited to engage with our team to learn more about PALSONIFY. They were impressed with the new data from the open-label PATHFNDR-1 extension, which showed that paltusotine maintained control of both IGF-1 levels and symptoms through 96 weeks.

Health care professionals were encouraged by this durability since many patients discontinue acromegaly treatment within a few years. They were also excited by the post-hoc analysis that demonstrated that treatment with paltusotine improved symptom stability over 3, 6 and 9 months time period relative to baseline treatments with injectable SRL. This data could present a compelling value proposition to patients improve both symptom control and ease of use.

In addition, health care professionals were reassured by the stability of reduction of tumor volumes in patients who had MRI data throughout the OLE period for both PATHFNDR-1 and PATHFNDR-2. We believe that this OLE data demonstrating a stable or decrease in tumor volume over a long period will allow health care professionals to feel confident that paltusotine offers tumor control as well as symptom control and disease control.

Turning to Slide 6. With that in mind, we have built out our commercial team and are in the process of onboarding our sales force ahead of launch. We will have approximately 30 sales representatives in the field supported by additional health care professional-facing roles, ensuring comprehensive coverage and support for our target prescriber base. We have been impressed by both the quantity and quality of candidates who have applied for our field roles and we are confident they represent the top talent in the industry with extensive experience in rare endocrinology and a high degree of motivation to bring PALSONIFY to patients.

Now on to Slide 7. Our market research suggests that health care professionals perceive PALSONIFY as the preferred therapy among newly diagnosed patients due to its rapid reduction of IGF-1 levels and its accelerated titration time frame relative to monthly injectables. We believe there are 500 newly diagnosed patients per year who are candidates for pharmaceutical therapy. In addition, we believe that there are 11,000 currently diagnosed patients who have high unmet need and are candidates for PALSONIFY.

We believe many of these patients might be unhappy with the current treatment options and will consider starting or restarting therapy if an effective, safe and convenient therapy were available. We are activating patients to demand more from their acromegaly therapy and believe many will want to switch to PALSONIFY over time. 90% of patients from our PATHFNDR-1 study who were previously on SRL treatment opted to continue on paltusotine treatment in the OLE study underscoring the unmet need for patients currently on injectable SRL.

Other patients are on oral therapies like cabergoline that are not indicated for acromegaly and they might not have effective control of the disease. Patients on oral octreotide might be managing cumbersome twice daily fasting periods. It is clear that even oral therapies leave room for improvement on both biochemical and symptom control as well as ease of administration. In addition, we shared novel data on injectable SRL discontinuation rate during our science and innovation session at ESO. Over a 5-year follow-up period, nearly 80% of patients on injectable SRL did not persist with the newly started treatment regimen. Of those, about 2/3 discontinued treatment altogether.

This data suggests that patients are dissatisfied with the current treatment options and highlight the need for expanded treatment options. Low persistence on injectable SRL when either discontinuing switching or carrying on represents an opportunity for providers and patients to select a therapy like PALSONIFY that can better serve patients' needs. These findings highlight the need for expanded treatment options. We hope that PALSONIFY can provide new option for patients who want a safe, effective and convenient treatment for their acromegaly. Lastly, we believe that there are at least 17,000 undiagnosed patients. Over time we believe we can help drive diagnosis and treatment for these patients.

Moving to Slide 8. Our commercial strategy is not just based on growing market share in the naive and switch patients. It's about growing the market itself by bringing in patients who might have discontinued therapy, those that couldn't tolerate injections and those who are suboptimally treated and over time helping undiagnosed patients accelerate their treatment journey. We know that patient activation will be a key driver of potential uptake and have consequently launched our disease state education campaign and patient support hub well in advance.

We are very pleased with the early results from this engagement initiative as this multichannel strategy will be essential. As we approach potential approval, our goal is to increase awareness, educate the community and ultimately empower patients to advocate for the best possible care.

Turning to Slide 9. At this stage in our launch preparations, we have had numerous pre-approval meetings with commercial payers. We are also grateful for our ongoing engagement with CMS regarding Medicare and Medicaid coverage, particularly given all the changes occurring in the health care landscape. Payer groups have been receptive to PALSONIFY's value proposition, which includes faster disease control, lower treatment burden, symptom control and improved patient adherence. We expect that prior authorization activity will closely mirror the label we received for PALSONIFY and we are actively working with payers to ensure appropriate access pathways.

Our extensive market research and Advisory Board feedback have revealed a strong demand among health care professionals for a new treatment option. Endocrinologists are eager to use PALSONIFY across multiple patient populations, treatment-naive patients, those currently on therapy and importantly, some patients who have been lost to follow up due to the burden of current injectable therapies. Based on our data and the feedback from health care professionals, patients and payers, we are more confident than ever in the long-term potential for PALSONIFY to become the preferred treatment for the acromegaly community and our commercial strategy is anchored in delivering on that promise. So we are deeply enthusiastic about the potential of PALSONIFY.

I want to offer a few reminders on the expected cadence of launch. In the near term, there are several factors that will affect uptake after potential approval. First, we anticipate formulary placement will take at least 6 to 9 months after launch, which is consistent with other specialty pharmaceutical launches. Second, acromegaly patients see their endocrinologists relatively infrequently approximately 2 to 4 times per year. Consequently, we do not expect a bolus of patients on drug shortly after approval and instead expect adoption to gradually ramp in line with our outreach and engagement initiatives. We are all hard at work preparing for U.S. launch and we continue to progress in our international expansion in anticipation for a launch in Europe in 2026.

With that, I will turn it over to Dana to provide regulatory and clinical update. Dana?

Thanks, Isabel. Turning to Slide 10. I'm pleased to provide an update on our regulatory progress across our pipeline, which continues to gain momentum on multiple fronts. Starting with paltusotine and acromegaly, our ongoing FDA review is progressing as expected through the review milestones reinforcing our confidence as we approach our September 25 PDUFA date. I'm particularly encouraged that the team we've been working with at FDA hasn't changed, which ensures important continuity throughout this critical review period.

Our interactions with the European regulatory authorities also remain on track. Our medical affairs team continues to work in the field educating HCPs about acromegaly and sharing the data we presented at AACE, IPC and ENDO. These conferences are an opportunity to highlight our clinical results as well as our health economics and outcomes research. These presentations and resulting publications, much of which are derived from our clinical studies, are part of a broader strategic plan to generate and disseminate evidence of the unmet need in acromegaly and the role paltusotine could play.

Turning to paltusotine in carcinoid syndrome. We're making steady progress with our Phase III program, currently have multiple sites up and running and continue to expect to enroll the first patient later this year. We are also making significant progress on atumelnant in CAH, which I will address in more detail shortly. We are revising our timelines for ACTH dependent Cushing's syndrome as we discuss with regulatory agencies how to best measure effective control given atumelnant's novel mechanism of action.

Moving to our earlier stage pipeline. We presented data on our TSH candidate at ENDO. The data suggests it has the potential to be a once-daily oral therapy that treats Graves' disease, including both manifestations; Graves' hyperthyroidism and Graves' orbitopathy also known as thyroid eye disease or TED. Our mechanism of action has the potential to avoid the risk associated with ATDs in anti-IGF-1 therapy, including liver injury as well as hearing impairment and hyperglycemia. Lastly, we continue to work towards an IND submission for TSH and SST3 this year and for PTH in 2026.

Turning to Slide 11. For atumelnant, we've achieved several important milestones in our CAH development program. As a reminder, we shared data on the first 3 cohorts of our Phase II study in January with the primary endpoint of reduction in androstenedione or A4. We added a fourth cohort earlier this year primarily to assess the effect of morning dosing of 80 milligrams of atumelnant and to study reduction of supraphysiologic glucocorticoid doses in addition to a reduction in A4. Cohort 4 is now fully enrolled with 10 patients and so far it continues to support the favorable benefit risk profile we've observed in our clinical trials to date.

We will of course continue to monitor these patients very closely and communicate anything necessary in a timely manner. We intend to share the full data from Cohort 4 in early 2026. We also presented data at ENDO from the Phase II study in CAH, including the full results from the first 3 cohorts, additional detail on observed reductions in adrenal volume and reductions in novel biomarkers.

Through these presentations, we continue to demonstrate our advancement of the understanding of the disease biology of CAH as exemplified by our data on the underrecognized role of 11 oxygenated androgens in CAH. We continue to expect to enroll our first participant in the Phase III trial in adult CAH by the end of this year. Additionally, our open-label extension study is actively enrolling, providing continued treatment access for patients.

Moving to Slide 12. We are also making progress on our registrational trial for atumelnant in pediatric CAH. When we debuted our Phase III adult design last quarter, we outlined our ambition to assess normalization of both androgens and glucocorticoids and we hope to achieve the same with our operationally seamless Phase II/III design for pediatric patients. I am pleased to share with you the pediatric design. The study will consist of 3 parts. Part A is the Phase II, which is an open-label dose-finding 8-week study that will evaluate safety, efficacy and reduction of A4 and PK/PD. Part B is the Phase III, which will be a double-blind, placebo-controlled study that will assess safety and efficacy, including the ability to taper GCs.

Part C is the open-label extension study for Parts A and B wherein patients from Part A will also have the opportunity to taper GCs. We believe our clinical trials are designed to demonstrate differentiation of atumelnant with an uncompromising endpoint and the goal of developing a new standard of care for patients with CAH. Overall, I am pleased with the significant progress we have made across our early and late-stage programs and we look forward to providing future updates on each.

With that, I will hand the call to Toby to provide a financial update. Toby?

Thank you, Dana. Turning to Slide 13. I'm pleased to review our financial results for the second quarter of 2025, which reflect our continued disciplined execution and strategic investment in advancing our pipeline and commercial capabilities. For the second quarter, we recognized $1 million in revenue from our licensing and supply agreements with our Japanese partner SKK. Our research and development expenses for the second quarter were $80.3 million compared to $76.2 million in the first quarter.

This increase reflects our continued investment in pursuing multiple clinical programs, including progression of paltusotine for carcinoid syndrome, atumelnant for late-stage development and advancement of our novel non-peptide drug conjugate platform into first-in-human studies. Selling, general and administrative expenses were $49.8 million for the second quarter compared to $35.5 million in the first quarter. This increase primarily reflects our strategic investment in building commercial capabilities, including our field sales force and our broader corporate infrastructure as we prepare for PALSONIFY's launch.

We used $77.8 million of cash on a net basis during the quarter reflecting continued clinical development and launch preparation activities. We ended the quarter with $1.2 billion in cash, cash equivalents and investments. As of July 29, 2025, we had approximately 94.2 million shares of common stock outstanding. On a fully diluted basis, we had 111.9 million shares outstanding.

Moving to Slide 14. Looking ahead, we are lowering the high end of our guidance for net cash used in operations in 2025 and now expect to use between $340 million to $370 million compared to our previous guidance of $340 million to $380 million. This guidance reflects greater precision on clinical timeline estimates and prudent measures we have taken on overhead growth. We expect net cash used in operations in the second half of the year to be higher than in the first half of the year as our late-stage trials gather momentum and our commercialization activities accelerate into an anticipated approval.

Based on our current operating plans and cash position, we maintain our guidance that our existing cash and investments will be sufficient to fund our operations into 2029. This provides us with significant runway to execute on multiple value-creating milestones, including the PALSONIFY U.S. launch and the advancement of our broader pipeline.

With that financial overview, I'll now turn the call back to Scott for some closing remarks.

Thank you, Toby. Now turning to Slide 15. I want to emphasize the strong execution we're demonstrating across all aspects of our business. Our NDA for paltusotine remains on track with continued collaborative engagement with the FDA. I remain very confident about our launch readiness supported by the outstanding team we've assembled and our comprehensive corporate readiness for the upcoming launch. We expect multiple Phase III and earlier stage readouts across various programs up and down our pipeline over the next several years.

We look forward to providing updates as our pipeline continues to mature. As we move through 2025, I'm excited about the opportunity ahead of us to introduce a potential new standard of care for acromegaly patients. We are well positioned to achieve multiple value-creating milestones that will transform Crinetics into the premier endocrine-focused global pharmaceutical company. Thank you all for your continued support.

And with that, I'll hand the call back to the operator to begin the Q&A. Please limit yourselves to 1 question, 1 question only, in the interest of time. Operator?

[Operator Instructions] Our first question comes from Joe Schwartz from Leerink Partners.

Congrats on all the progress. Neurocrine seems to be doing quite well with the CRENESSITY launch. I was just wondering how does that figure into your thinking about the pace of enrollment for your Phase III CAH studies now, if at all? And are there any particular kinds of patients who are more likely to go on to CRENESSITY commercial versus enroll in a clinical study for atumelnant? Does that sound like for any kinds of patients in your view?

Joe, thanks for the question. So look, I think that the launch from CRENESSITY  is a great thing for patients with CAH and the momentum of that launch shows some of the unmet need that's out there. And in terms of impact on our enrollment in our Phase III, either adult or pediatrics, actually I think it's a positive. In general it's raising awareness on multiple fronts of the disease. And I think that as another nuance, in general most of these studies, the bulk of our enrollment has been outside the U.S. not inside the U.S. just because of treatment patterns in the different regions. So generally I think it's all positive for patients. And maybe just ask Dana if she wants to comment or Alan on kind of the patient population that we're treating.

Yes. I think 1 interesting difference between their indicated population and what we're trying to achieve in our Phase III is that we're looking at a broader patient population because the way we look at it is it's sort of a spectrum and there are patients who have high A4 and high GCs. There are patients that have just high A4 and are not on GCs. And then there's others with normal A4 and high GCs. We think that all of those patients can benefit from atumelnant. So in one sense, it's a much broader population. So that is a big distinction and does sort of reflect how we view this particular mechanism of action as addressing sort of the full spectrum of the disease.

Our next question comes from Tyler Van Buren from TD Cowen.

This is Frances on for Tyler. So just curious if you could elaborate on the timelines for the IND submissions of the TSH and SST3 agonist. Are you still targeting 2025?

Maybe, Steve, you want to give some color on that.

Yes. Thanks for the question. Those IND-enabling work is all still in progress. We are targeting the end of the year. I don't have particular granularity past that, but that's certainly what we're aiming for for both molecules.

Our next question comes from Jessica Fye with JPMorgan.

This is Abdul on for Jess. Can you speak to your comfort level with current consensus numbers for the paltusotine launch?

I'll let Toby take that one.

It's not typical for companies at this stage or prudent to comment on consensus. We haven't given guidance. So that's where we are right now. We feel comfortable though on the launch preparation and the progress we're making with the FDA.

[Operator Instructions] Our next question comes from Maxwell Skor from Morgan Stanley.

This is [ Selina ] on for Max. For the global CAH Phase III study, what are your expectations around placebo response and any potential impacts from different geographies?

Dana or Alan, do you want to comment?

Yes, sure. I think that we have a pretty ambitious endpoint as we've talked about for the adult trial and we are not really expecting a very high placebo response rate at all. So again, we're setting it up so that you have to sort of address both the A4s and have a reduction in GCs to physiologic levels. So in our mind regardless of which part of the spectrum of CAH you're in, it will be very difficult for a placebo patient to meaningfully change where they are. So that's kind of the way we're looking at it.

Our next question comes from Yasmeen Rahimi from Piper Sandler.

This is Liam on for Yas. Just in regard to PALSONIFY, we were wondering if you plan to provide color on pricing at the time of approval? And then also with like your current payer work, how much do you understand about the level of flexibility you might have to price when compared to like current SSR injectables?

Yes. So obviously we'll be discussing price at the right time after what we hope will be an approval soon. But Isabel, maybe you want to talk a little bit about the payer side of things.

Yes. Thank you very much for the questions. So we have continued to make progress in our discussions with payers and the value proposition continues to resonate and is very positive the feedback that we are getting from them. They understand that current treatments, particularly SRLs had a high burden of treatment and there is significant waste with many of the patients, 1/3 of the patients exactly taking more than 13 injections a year. So we continue to partner with them. We continue to reinforce the clinical value of the treatment. And at this time, we are not commenting further on price.

Our next question comes from Josh Schimmer from Cantor.

I guess given how much scrutiny there was on the cases of LFT elevation that we're seeing with atumelnant, can you provide an update on the ongoing experience and whether that's been seen subsequently? And how do you plan on kind of maintaining updates going forward on that liver tox profile and whether it is turning into a meaningful signal or the opposite?

I think we've said before, we're kind of surprised at the scrutiny on that 1 patient we saw earlier and we're very comfortable with the emerging and growing experience that we're gaining with it. And in terms of updates on it, I think it warrants updates as the data matures and we have something meaningful to share. We should remind everybody that this is part of a much larger program. We're enrolling patients into the open-label extension from the Phase IIs. We're starting to activate sites and we'll be enrolling patients in the adult study and then the pediatric study. And so I think that kind of emerging experience will give people more and more comfort. And if there's a big problem, obviously we'd have to let people know. So I think no news is good news on that front.

Our next question comes from Alex Thompson from Stifel.

This is Seth on for Alex. We just had a question about PALSONIFY and just how many patients are on the OLE and how quickly do you expect them to transition to commercial treatment once approved and launched?

Yes. Maybe we'll let -- well, this could be anybody answering this one. But I will remind you that we have patients all around the world not just in the U.S. So maybe Isabel or Dana, you want to comment on that transition.

The open-label extension, as Scott mentioned, is ongoing in numerous countries. And with the U.S. approval, there will be -- we'll have to see what the outcome of the regulatory interactions are. But I think that once the company has reached a PDUFA date and we've had a successful outcome, we can make a decision about what happens with those patients. And it's really only a small number of the patients that are in the U.S. that would be sort of potentially enrolled on to commercial drug.

Our next question comes from Gavin Clark-Gartner from Evercore ISI.

This is Yash on for Gavin. Just a quick question from our end. You shared that Cohort 4 of the adult Phase II for CAH is going to read out in early 2026. We're wondering if we could also expect any OLE data with this update?

This is Scott again. But look, I think we'll have a broader update on the whole program. Remember, in addition to that cohort and the OLE, we should be getting deep into then the ramping up of the adult CAH study, the pediatric CAH study and we'll need to provide some clarity then on the Cushing's disease program as well. So I think there's going to be a ton of things to talk about around atumelnant in the not too distant future.

Our next question comes from Rich Law from Goldman Sachs.

How much do you think you can learn based on atumelnant's Cohort 4 with only 10 patients? And I assume there's going to be data variability. Is there a chance to adjust the Phase III protocol based on what you learn in that cohort 4 since you're starting the Phase III study before you see the Phase II data?

Yes. I think that's a good point. As a reminder, it's only 10 patients and we've got quite a few more patients hopefully going into the OLE. But maybe, Dana, you want to talk about just the process around protocols?

Well, sure. As we mentioned Cohort 4, one of the interesting questions that we were trying to understand better is the difference between AM and PM dosing. We've already decided in the Phase III that it's going to be PM dosing. I think the information for that will be useful afterwards, right, in terms of eventually potentially trying to understand whether patients need that kind of flexibility going forward. But we are really locked and loaded for the Phase III. As Scott and we have mentioned before, the sites are already getting started and we expect the first patients in soon. So we really aren't planning on making any changes in the protocol right now.

[Operator Instructions] Our next question comes from Cory Jubinville from LifeSci Capital.

When we look to some of the competitive readouts in CAH, the criteria for GC dose reductions were a reflection of maintaining A4 levels within that 120% of baseline values. However, that was based on the pre-GC dose A4 levels. And when we look to the A4 component and the primary endpoint that you're using for [indiscernible] in BALANCE studies, that's based off of post GC dose A4. Obviously A4 is expected to be lower after a patient takes their morning GC dose. But can you just provide a bit of context as to why specifically you selected post-GC A4 as part of the primary endpoint and how should we be thinking about the clinical relevance of assessing efficacy pre-GC versus post-GC on androstenedione?

Yes. I think that's a good question, Cory. Just a reminder that I don't think that keeping A4 levels at 120% of what might be a very high baseline is all that great of a treatment goal for the person dealing with their CAH and we believe they should be getting down to normal or very close to it. But Alan, maybe you want to talk about some of those nuances in post and pre-GC dosing. And I'll remind you, Cory, that between the primary and the secondary endpoints, we're looking at both. And just as I always encourage everybody, it's the overall profile of the drug that's really important in addition to the primary endpoint.

Yes. So it is true that when you administer glucocorticoid, you would expect in this patient population for the A4 level to go down and that is kind of what the regulatory precedent that was set in the CRENESSITY trials established. That is the optimal time to measure A4 with respect to looking at the trough level of androgen exposure with the treatment regimen to include the drug plus the glucocorticoid. We use that partly because it's a precedent, but also because it helps to facilitate variability assumptions for sample size calculations. With those assumptions, we know we have a very well-powered trial here in Phase III.

Our next question comes from Brian Skorney from Baird.

This is Charlie on for Brian. We just kind of wanted to dig in a little bit into what you anticipate distribution looking like? And along those lines, if you anticipate PALSONIFY getting captured in data services like IQVIA for example?

Isabel, you want to respond?

Sorry, I couldn't hear the question well.

Yes. So I was wondering just what you anticipate distribution looking like for PALSONIFY and if you anticipate it getting captured in data services like IQVIA for example?

Thanks for the question. Yes, we had created our distribution system and it's going to be a closed distribution system at this point. So we are not planning to make that data available. It will be blocked. We want to make sure that we are able to track the launch and see the uptake in different segments that is not going to be widely available.

Our next question comes from Jon Wolleben from Citizens.

This is Catherine on for John. I have a quick question about Cushing's disease. And just if you could provide a little bit more color on kind of discussions on what potential endpoints you're looking at and kind of how the endpoint would differ for your mechanism versus kind of some of the other drugs that have been approved in the indication.

Alan, do you want to take that?

Yes. So the primary endpoint for Cushing's disease trials generally is normalization of 24-hour urine-free cortisol excretion. This is a measure of integrated cortisol exposure over a 24-hour period of time and approvals are usually based on the proportion of patients who achieve normal urine free cortisol. I mean I think atumelnant is uniquely situated here in several ways. One is in our trials to date, again we're running a single center trial at the NIH and we will be starting larger trials soon.

But what we're seeing so far is a very rapid normalization of urine-free cortisol in pretty much all of the patients tested so far. The rapidity I think is unprecedented and the treatment duration at the NIH is 10 days and within less than 10 days, we are seeing normalization of urine free. So I'm very excited to expand these trials to increase the duration of treatment and to enroll more patients to hopefully see this as a consistent finding. And if so, I think we have kind of a real new level of treatment for Cushing's disease here.

Our next question comes from Andy Chen from Wolfe Research.

Brandon on for Andy. You stated earlier that acromegaly patients see endos 2 to 4 times a year, which could lead to a slower start to the launch. But should this approval draw patients to see their docs regardless of their cadence throughout the year? And further, when do you expect patients to start flowing in?

Yes. I think this is almost something we can answer for ourselves just based on personal experience in most health care systems how long it takes to get to see a specialist, which is unfortunate but true. But Isabel, maybe you want to comment more specifically on the question.

Yes. Most patients are visiting their doctor every 6 months or once a year. Of course we are working actively in our engagement with advocacy and our activities in patient activation, as I mentioned it before, to get patients to proactively search for those appointments and move them. But we know that that will take time and that's why we are cautious that at the beginning it will take some regular rhythm of patients going to the providers and our goal is to accelerate it, but we recognize that that will be one of the barriers early on.

[Operator Instructions] Our next question comes from David Lebowitz from Citi.

It's Ross on for David. I guess I had a question on Graves' disease. It seems like a TSH agonist or antagonist is an obvious disease modifying mechanism yet other people are pursuing other targets. I guess why do you think there hasn't been a TSH antagonist successfully developed? And what do you guys think you're doing differently now with that in mind?

Well, this is Scott. I think that this is right in our sweet spot and you could ask that same question about almost any of our programs. So these are very difficult targets to address. We've built a capability for this over now 17 years at Crinetics. But Steve, maybe you want to comment a little bit on what it's taken us to manage to crack this one as well as some of the other programs.

Yes. Thanks for the question. I do think this is -- if you look at TSH antagonism for the treatment of Graves and the treatment of thyroid eye disease and you know that from a mechanistic standpoint, blocking the action of the receptor is the right thing to do if you can make the right molecules. But I think as Scott said, this is what we do for CAH and for Cushing's, the right thing to do is block the action of the ACTH receptor. So the right thing for hyperparathyroidism is to block the PTH receptor. And so rather than find kind of an end around to try and get an effect, we work to find the right molecules at the right receptors that will produce the right pharmacology that these patients need. And we have everything from the medicinal chemistry skills and the drug development skills and the understanding of biology and receptor pharmacology to kind of put all those pieces together to find the right molecules.

Our next question comes from Douglas Tsao from H.C. Wainwright.

Congrats on the progress. I'm just curious in terms of the BALANCE CAH study, in terms of Part B for the GC tapering, I'm just curious will that replicate what we see or the same protocol that will be used in [ COM CH ] because I believe there's sort of glucocorticoids reduction periods followed by sort of GC stable periods and I think it takes place over 2 sort of periods. Is that what you're going to be doing in the BALANCE CAH study as well?

Yes. Dana or Alan, do you want to take that on study design?

Yes. So I think what you were asking, Douglas, about the pediatric Phase III part, right? And what we're trying to do, it's not exactly the same, but we're trying to demonstrate both efficacy at reduction in A4 and getting GCs tapered, right? But I think in the pediatric space, you're always a little bit more cautious with the kids. And so we have a little bit more flexibility in terms of how the GC reductions take place. And I think that that is kind of going to be a little bit reflected in the mechanisms of how the investigators carefully titrate them down. But what we're looking for is to get patients to normal A4 and then keep trying to titrate them down.

And is it set in the protocol for investigators to titrate down or is that investigator discretion?

Well, that is the objective of the protocol is to get them to reduce the GCs as much as they can.

But there's no time when they have to achieve it or by 25 weeks or something of that order?

Yes, there is an endpoint to the trial. And so they're expected to be on stable GCs for a 4-week period before the end of the trial. 28 weeks. So from 24 to 28 weeks, it's stable.

Our next question comes from Rohan Mathur from Oppenheimer.

This is Rohan. At the moment, just given the timelines for the adult and pediatric trials, how does Crinetics plan to manage the progression towards NDA submission and labeling discussions while incorporating the data from both of those studies down the line?

Dana, do you want to take that one?

Well, yes, thanks for the question. And the way that we look at it is we're looking at each one of those as a distinct submission and so I don't think that we'll necessarily hold one until the other one gets done. So whatever gets done first, which the Phase III for the adults is definitely almost begun in Phase III. So that should be done before the pediatric one. And so the way that we look at it is we will submit that. Hopefully, it will be successful and then we'll do an amendment or a supplement to add the pediatrics.

Our next question comes from Catherine Novack from Jones.

I'm just curious on your thoughts on paltusotine in surgically naive patients based on the AAC presentation. Is there a market here? Is there a significant number of patients who do forego surgical resection?

Let me let Isabel answer that one.

Well, as you know, we have a label that based on PATHFNDR-1 and PATHFNDR-2 pending the FDA review look at naive and also switching patients. When it comes to presurgical patients, we are very excited about the data that we were able to present at ENDO and we also believe that there is an unmet need. But at this time, we are actively considering that segment. We believe that if physicians see that there is an opportunity and pending our label, that might be an opportunity in the future.

Thank you very much. That was our final question and that concludes today's call. We'd like to thank everyone for joining. You may now disconnect your lines.

Good morning, everyone. Welcome to Crinetics first R&D Day. For those of you joining us in person, I'm so glad the weather has calmed down a little bit, so you're not swelltering on your way here. And for those of you joining virtually, welcome you to the webcast.

So we'll be making forward-looking statements today. So I'll pause for a few seconds on the slide if we absorb all of the fine tech print.

Let's see. So now the speakers today, you all know Scott Struthers and Dr. Stephen Betz, the Co-Founders and CEO and Chief Scientific Officer. But I think the real superstars of today's presentation are global product leaders, our GPLs. So the GPLs are the CEO of their molecule, and they oversee the process from, a chaperone the molecule from discovery all the way through clinical development to commercialization. So really responsible for the strategy and execution and know everything there is to know about the molecule.

Today, we have Rick Grimes here covering TSH and Stacey Harte for the NDC-9682. Providing a clinical perspective, we have Dr. David Metz, a neuroendocrinologist. He was the President of the North American Neuroendocrine Tumor Society and received the Lifetime Achievement Award from NANETS. He's been involved in a lot of prominent clinical trials and has published over 200 papers.

Also, we have Tobin Schilke, our new CFO. He'll be joining for Q&A. And we have Jackie Kirby, our Chief Corporate Affairs Officer. We also have other people from Crinetics. So during the break and during lunch, we invite you to get to know the deeper bench of talent we have here.

In terms of agenda, we will have Steve kick off with a strategic focus and discovery overview. The first session, when we were talking about what molecules we wanted to share, the feedback that we got from all of you was that we wanted to talk about every molecule, every indication. And unless you want to come for a week of Crinetics summer camp, we thought we had to be efficient in what we actually cover.

So first, we'll be going through CRN-12755, which is the TSH molecule in development for Graves disease. We also have CRN-10329, which is SST3 agonist for autosomal dominant polycystic kidney disorder or ADPKD. We'll have a brief break. And when we regroup, we'll have the NDC or non-peptide drug conjugate platform as well as the first candidate from that platform, CRN-9682, and we'll go through the first indication, neuroendocrine tumors and other SST2 positive tumors as well as talking about how we position that with carcinoid syndrome.

After closing, we'll open the floor for Q&A. For those of you here in person, will have people running around with mics, and we invite those of you on the webcast to submit questions from the Q&A function. We ask that you hold your questions until the end. We'll have plenty of time for Q&A. And with that, please welcome to the stage, Dr. Steve Betz.

I hope everybody can hear me. Welcome to everybody here. Thanks for coming out. My name is Steve Betz. I am not Scott Struthers, but I am one of the co-founders of Crinetics and its CSO, which most days is a pretty great job, and you'll see some of the reasons why today. I have to make -- let you guys know that Scott was kind of laid up by a little GI flu this morning and was unable to make it here in person. So I get to cover his duties a little bit here today. Hopefully, I can be a good stand in for him.

As Gayathri was saying, we wanted to give you guys a bit of an idea about Crinetics, give us an overview. And I'll spend a little time talking about how kind of our philosophy around discovery and how we approach it. And honestly, I mean, it's kind of an easy thing to say, but we've founded the company around endocrinology and the mechanisms of endocrinology to serve patients that we thought were very kind of underserved by the pharma community and kind of needed a 21st century medicines for the diseases that they had. And this seemed like a pretty tall order back in 2010 when we opened our first lab, but I think you're seeing some of the fruits of that labor over the last decade or so.

And we're not going to spend a lot of time talking about acromegaly. This is more about the stuff that's earlier in the pipeline. But I want to point out like Tracy in this slide, she's an acromegaly patient, she's talked to us about her disease and about her journey as a patient and about the needs that the acromegaly community has. And this is something that we do all the time is get to know our patients, get to know the people who are -- who have these diseases and the people that are treating these diseases. And it's one of the core fundamental things, I think, as we've grown the company that we've tried to incorporate in everything that we do, and you'll see some of that today.

Again, we're not going to talk about paltusotine, but I'll just answer the question because I'm sure it's one that everybody has. So far, so good on the NDA and its PDUFA date on September 25. Our interactions with the agencies have been routine. And so far, everything is going as planned.

I wanted to share a little bit of Crinetics with you. We did -- we -- actually, when we first thought about having R&D Day, we thought, oh, we just bring everybody into San Diego and we opened a new facility last year. And -- but we wanted to get as many people as we could in person, so we thought we would come here to New York. And we've kind of highlighted here what goes on in the building on a daily basis. And we've got -- you can always come and probably find a couple of dogs in the building always -- well, willing to stay high and be friendly. The dog wall is there for perusal. But really, it's the scientists doing the work in the lab that are the real stars here. They're absolutely killing it, and they -- I am so grateful for the people that's been able to work in our labs. They are really remarkable.

I wanted to spend a little time talking about Crinetics in the history in case some folks haven't heard this story before. We actually -- we incorporated the company in 2008, but we started raising money on grants and contracts. We opened our first lab in 2010 in January. It was the 4 of us as co-founders, myself and Scott, Frank and Anna, and our 2 dogs, Penny and Princess. We've always been a dog-friendly company. When you start a company, you have to do a lot of jobs that you're not trained to do, and so I was Head of HR, which is terrifying to the people who work for Crinetics right now. But we decided like, well, we can bring -- why can't we bring our dogs into work. They'll do fine. And so it's been something that has remained part of our culture ever since. And I think people really like that.

We really did bootstrap our way. I don't know if you guys remember what it was like in 2008, 2009, 2010, it was a really tough economic time, and it seemed like a crazy idea to start a company in that environment, but it was actually, in some ways, kind of a good time to start a company, and we were able to raise enough money to keep the company going and get these ideas of how we can make molecules that work at these endocrine receptors and do the things that we need them to do for the patients who need them.

And we've got a bunch of ideas, the fruition of which you'll see later in this talk. And we actually -- one of the ones that took hold earliest was the somatostatin 2 program, which ultimately led to paltusotine. And based on the data we had earlier, and I'll actually share a little bit of this data with you later, we raised a Series A in -- in the last part of 2015, that really catalyzed the company into a different status. We were able to move the program forward. We eventually came up with paltusotine. Paltusotine, we started our Phase I at the end of 2017. And that Phase I and the SAD and MAD data from that Phase I propelled us to a crossover round at the beginning of 2018. Some of you guys actually participated in that, and then the IPO in the summer of 2018. And that really was quite a remarkable run for us in terms of growing the company in terms of -- we went from kind of being a discovery company to being a development company, and we started taking paltusotine into the clinic.

Now as earlier, we've always wanted to be a pipeline company, and we started developing the pipeline, the next compound that we went into the clinic with was atumelnant. This is another first-in-class molecule ACTH receptor antagonist for CAH and Cushing's disease. That compound went into the clinic in 2021. And we've -- we used to have this -- we had this saying that I think a lot of folks at Crinetics -- we like this idea of like no good idea left behind. And we've been talking -- as we think about how we make molecules and what we want them to do. One of the ideas that we came up with was, can we use what we know about making molecules and GPCRs and find ways to deliver payloads to tumors.

And so we had this idea around could we use this to make radionucleides and deliver radionuclides both for imaging and for therapy. And that program, that project was actually so successful, we decided in the fall of 2021 to actually spin that out as Radionetics. Frank and Anna from the lower part of -- from that original picture. They went off and were part of the founding team of Radionetics. Scott's still on the Board of Radionetics, and they are off and running. And you'll see some of the fruition of that idea kind of in the story around 9682 and our non-peptide drug conjugate, Stacey Harte will tell you that story.

And then over the last couple of years, we've -- the PATHFNDR studies for acromegaly, both PATHFNDR 1 and PATHFNDR 2 have been completed. They were the basis of our NDA, which we submitted at the fall of last year, and as well as the atumelnant data, which we showed at Endo last year and showed some more at the beginning of this year, I think, has really set us up for kind of the next stage of the company as we went from discovery to the clinic. Now we're going from clinic to commercial. We're -- the company continues to grow. And I think fulfill this idea that Scott and I had when we started the company of making company that makes its own molecules, can get them into the clinic, can commercialize them and bring them to patients. This was the vision at the start and it is -- I can't tell you how exciting it is to see it come to fruition.

And that's us today. So starting from 4, we're now over 500, and that's our new facility. And even though we're not there today, if you guys are ever in Southern California, I want you to stop in and say, "Hi, see the lab, see the dog wall, I'll bring Enzo in, it will be good.

And thinking about where we are as a company, this is a tough couple of years for biotech. And I feel very fortunate that Crinetics is in such a good position as it is. We're in a really good spot. The pipeline is doing really well. We're starting Phase IIIs in CAH and carcinoid syndrome. But today, we're going to talk about the pipeline. Some of the stuff is kind of below the fold, if you're in journalism. And this combination of kind of our understanding of endocrinology and we're rooted in endocrinology, and we understand the mechanisms of endocrinology and how that might affect diseases that maybe most -- some people don't think of as endocrinological diseases. And we'll talk -- hopefully highlight a little of the science that most investors don't get to see until compounds are pretty further along in development. And we've got a good balance sheet. We can -- we've got a really good buffer to take us to 2029 and beyond.

This is a slide that I think we actually started showing versions of it at JPMorgan this year, and this is kind of our idea around what we're thinking about for Crinetics. And where it was founded in kind of pituitary science. So you see like paltusotine for acromegaly and originally for Cushing's disease atumelnant, but you can see how we've sort of taken those ideas and now we're growing them into new areas. Carcinoid syndrome for paltusotine, other SST targeted therapies, right, NDC for oncology and net an SST3 agonist for ADPKD and atumelnant of course, for CAH because it's the right molecule for that disease. And then you see some of the other things that we're thinking about in terms of other areas of endocrinology, other areas of oncology that we are pointing the company towards over the next several years.

But today, we're going to talk about the things that are here, that are probably closest to clinical development for us. Well, actually, one of them is already in clinical development. But we're going to talk about -- as Gayathri said, we're going to talk about our approach to grades and the TSH receptor antagonist. We're going to talk about ADPKD, and then we're going to talk about our NDC program. All these I'm very excited for you guys to hear about today.

With that, I will turn it over to me. And I'll tell you a little bit about what we do in the labs because this is something I don't think we get to talk about that often in this sort of setting. I won't spend a lot of time talking about GPCRs. I think everybody knows there's such an important family for biology first of all, and certainly for disease modification in endocrinology. A lot of endocrinology was laid down hundreds of millions of years ago in the way that cells and tissues communicate with each other through hormones. And too much, too little of a certain hormone or too much or too little of activity of a certain receptor can cause disease. And so this is what we have dedicated ourselves to, Scott, myself, others in the company, we've spent decades working in endocrinology and GPCRs. We spent decades making molecules and testing them against targets.

This is what we do, and this is our expertise. And we are particularly good. I'd like to think at making these small molecule drugs that interact with these peptide receptors. And there was a long time when -- we actually had to answer the question of like how do you do this? I mean I think we've done it enough to suggest that we kind of have this. And the current indications, I kind of showed that on, I think, what I think of as the solar system chart. But these are a lot of important indications where patients need really, they need new therapies. But I think the point here that I want to make is that this is just really scratching the surface of what we think we can do as a company and our approach to discovery. There's a ton of GPCRs and a ton of hormones out there where you can imagine that regulating their activity either up or down will make a difference for a patient.

Now one of the things about endocrinology, I don't know how to put this quite right, is that I like working in endocrinology, especially as a discovery scientist, because as I said, endocrinology was laid down a long time ago. And the endocrinology in our preclinical models in rodents often mirrors the endocrinology that you see in a healthy volunteer study in a Phase I study that mirrors the endocrinology that's going to [ride] in a patient. And so one of the things that we've been able to enjoy or derisk or however you want to put it, is that when we have molecules that do what we think -- that have the pharmacology that we think they need to have in preclinical models, we know that they're going to do that in healthy volunteers, and we know that they're going to do what they need to do in patients.

So it's one of the things like people say, "Oh, like when paltusotine worked in acromegaly, how excited were you? And I'm like, well, I knew it was going to work, right? There was no doubt that it was going to work. There's always a doubt of like, oh, are you going to get the PK you want, you are going to have some weird thing -- idiosyncratic thing that pops up. That's what I worried about. I never worried about whether it's going to work or not.

And so let's spend a little time talking about GPCRs. And I'll nerd out a little bit here because most people think, oh, you make an agonist, you turn a GPCR on, you make an antagonist, you turn it off. And I guess at a certain level, that's basically what you're trying to do. But what I want to show here is that GPCRs actually are incredibly dynamic in the way that they operate, and they're incredibly dynamic in the responses that they can have. And we have programs where we have agonists and antagonists. You can see them, I've listed them here. And sometimes you're looking for the primary signaling that you might want out of out of G-protein coupling that's cyclic AMP or an osteo phosphate. But most GPCRs, when they are activated by an agonist, a lot of times, they will become internalized and I show that on the right-hand side. Sometimes that internalization into the endosome can have its own signaling. Sometimes the receptor gets degraded. Sometimes it gets recirculated to the -- back to the self service.

And this dynamism in GPCR activity actually has -- it defines what we look for in a drug because what are you looking for? Are you looking for something that's a slow off-rate antagonist? Are you looking for something that is biased for G protein signaling versus beta rested recruitment and internalization. We'll talk about 9682 or NDC, that's actually -- we've designed that to get internalized because we want to be -- we want that process to pull the payload we want into the cell. And so thinking about -- we think about this from the start of every program. It's like what are we trying to do? What do we think this molecule needs to do, both from -- for patients in the end. But how do we get there? What does that look like?

And I'll show you a little bit of the data from the SST2 agonist program that led to paltusotine. And part of the reason here, I don't want to take any thunder away from Rick or Stacey or any of the other programs that we're going to talk about today. But -- and this is a complicated slide because honestly, discovery is a complicated business. And the one thing here, there's all a bunch of stuff here for in vitro pharmacology and vivo pharmacology for safety, for drug-like properties. And Frank, one of our co-founders from that picture of the 4 of us and our 2 dogs, he used to call this a water balloon. So Frank, you say, like making the right molecule is like a water balloon. Like you're always squeezing the water balloon, trying to get the right thing. Sometimes if you squeeze on bioavailability, selectivity goes wrong. And so you're always trying to optimize all these things all at the same time in probably 10 or 11 dimensions.

And the other thing here is this is the assay cascade for SST2. It doesn't look like any of the other assay cascade for any of the other programs that we have. Everything that we do is customized for that GPCR biology that we are trying to elicit with the molecules that we make. And this goes back to -- so this is it was actually kind of fun putting this slide together because I have got to go back and look at some of the really old data that we had from the bootstrapping era.

So one of the first really good compounds that we made that kind of told us we were on the right track to making a non-peptide somatostatin 2 agonist was this compound 351. And the structure 351 is shown there. 351, we do, like I said, the biology in a rat is going to mimic what we did in healthy volunteers and patients. We do a growth hormone releasing hormone challenge, and we see if our somatostatin agonist can suppress that. And you can see from the graph in the middle, 351 did a great job of that, just like it should, if you are a somatostatin agonist. The issue with 351 was that it also came along -- it was a really very good SST2 agonist, but it was also a really good SST4 agonist.

And as we think about making molecules, I guess there's a point like, well, do we take that one forward? Do we not take that one forward? But we actually -- our philosophy is you've got to make -- you got to have the right target, you got to have the right molecule that's going to solve for what we're trying to do here. And 351 was close, but it wasn't quite right. We needed -- we wanted to really dial out that SST4 activity. But 351 was actually good enough. This was the molecule and the data that actually prompted our Series A because we were able to convince folks in the investor community that we are on the track to making a non-peptide somatostatin agonist that was probably a good investment from our Series A folks.

So we went on, we churned the wheel a couple more times trying to figure out what to make. We came up with 808. The healthy volunteer challenge is there for 808, it looks amazingly just like you, the one that we did in rodents. And if you go on the data in Acrobat and the data in PATHFNDR especially speaks for itself, 808 did in patients exactly what it was designed to do, which is very gratifying to see. And so I wanted to show this here, and this kind of goes to Frank's water balloon. So there -- this is -- so this is fun for me because I get to go into the database and pull the stuff out of the database, and I don't get to do that as much as I used to. But I made a chart here of every molecule we made for our SST 2 program, and I highlighted 808 there in Crinetics green. And you can see that it's potent. It's somewhere -- it is the 808th molecule that we made. It came out of this cascade.

But 808 in terms of the water balloon, it's not the most potent molecule we ever made. It's not the most bioavailable molecule we ever made. It's not the most selective molecule we ever made. But in terms of the water balloon, it's solved just about everything. And so that was the one that we moved on. But I think that's something that I think a lot of people who don't work in discovery probably don't appreciate.

And this is a molecule -- this is actually paltusotine 808. This is sort of an encapsulation of what we would call that water balloon. Every atom here tells a story, every atom was poked and prodded and tested to look at in vitro, in vivo, drug-like properties. And you could have a whole course on how this molecule came to be, and it does exactly kind of what we were hoping for it to do.

And I think one of the other things that I wanted to get across here because a lot of times when we're talking about development, you're talking about a specific compound, right. 808, 12755, whatever we're going to talk about. But the thing is when we find those molecules, we know we're not quite done because when you make something that's going to be a development candidate, you're never 100% short, right? And you're always like, okay, I'm going to push this forward because I think it's worth the investment to push this forward. But what if something happens? And sometimes things happen. And so this is -- I brought up 2 examples here for -- and this is the program we're not talking about today. In the paltusotine program, -- we actually -- we decided we needed to make a backup because, a, it was the company's lead program at the time. And we wanted to under -- we were -- we knew that if 808 failed for some reason, that we needed a backup for the company, right? It was an existential threat of the company to lose its lead assets. We actually came up with 1941, which is another molecule that we made and it was ready to go.

We actually took it all the way through the end of Phase 1 because we wanted to make sure we had something ready in case something happened to the lead molecule. And paltusotine performed and it performed and it performed and now it's in registration. And so we had a clinical class compound sitting on the shelf. And a couple of years ago, we got together with some folks that we used to work with back in the bootstrapping era and they're like, "Oh, talk to these guys who are working on the endocrinology of aging, and they're using dogs as a test -- as a model species for that. And so we actually licensed out 1941 to this company called Loyal for Dogs. And it's been a real pleasure to work with them. And if you ever want to hear about that story, it's a great story I'll talk about that. We can talk about that at the break. But this is a great opportunity.

We had a backup. We didn't need it. Now we're going to use it for something else, and we're going to probe endocrinology, we're going to probe biology in a way that I think is meaningful and is going to be super interesting to see the answers out of that. And if it helps dogs live longer, I am 100% behind that.

In our ACTH antagonist program, our first development candidate was a compound called 4599. And 4599 looked great until it was -- it had a problem -- a developability problem around stability in a solid form, and we don't need to go into that part. But we had 4894, which became atumelnant right behind it. And so we probably lost, I don't know, a month or 2 in that development program for Cushing's and CAH. So having these backups ready to go is part of what we do. And in fact, it's kind of its own little water balloon is how far do you push these backup molecules. Do you take them all the way to the clinic, do you take them to an IND -- and so that's one of the things that we always talk about, how many backups do you have, how far do you take them? And then what do you do with them once the lead molecule is off and running. So that's a little behind the curtain there.

The last thing I want to come back to is patience. And I think it's easy to say that we're a patient-focused company, but I remember going to the Endocrine Society Meeting in 2015 and meeting Gilsisco and the members of the Acromegaly community for the first time. And this is before we ever had -- we had data from like compound 351 that I showed you. We weren't going into the clinic yet, but we wanted to understand patients because I'll tell you, one of the things I've learned in this -- in my journey at Crinetics is you know a lot about biology. You talk to really good doctors, you understand about the practice of medicine, you can get a lot of data out of prescription databases about how medicine is practiced.

But if you want to understand medical need, talk to patients, because they have -- they live it every day. They understand their disease differently and better than anybody. And we actually -- we incorporate by talking to the folks in the acromegaly community and, of course, in the Cushing's community and of course, the other communities. We actually -- it actually helps us decide what we want that molecule to look like. What's going to be the right molecule for these patients because there's sometimes a discrepancy between what doctors say they are doing and what they need and what patients are experiencing. And -- that's something that we try to incorporate. That's a vision and a view that we incorporate from the get-go.

I'm going to pause there. I think that is a little look behind the curtain, both of the history of the company, and as part of how we do discovery. We'll be happy to answer any questions at the end of the thing, of course, catch me at the break. I'm always happy to talk about this stuff. But for now, we're going to get on the main events. We're going to talk about TSH receptor antagonists and going to bring up the Global Product Lead, Rick Grimes for that.

Thank you, Steve, and good morning, everybody. I really appreciate this opportunity to come here today and talk to you about our TSH receptor antagonist program at Crinetics. It's one of the early programs in our portfolio and one of our exciting programs, too. So over the next 30 minutes, I'm going to share with you a little bit about our scientific rationale behind the program and some of our preclinical data that gives us a really strong reason to believe that this could be a really important new medicine for patients with Graves disease.

So, as I'm sure many of you in this room know, Graves disease is one of the most common endocrine diseases. It affects approximately 1% of people in the United States are about 3 million people. And it has 2 main manifestations. That's hyperthyroidism and Graves' orbitopathy, also known as thyroid eye disease. For Graves' hyperthyroidism has a number of significant symptoms, irritability, tremors, fatigue and can cause major complications, including atrial fibrillation, heart failure and thyroid storm, and this has significantly negative impact on patients. Firstly, not only emotional, mental and physical fatigue, but can cause significant anxiety. It can also create what's called difficulty concentrating due to what's known as brain fog. And all of this can come together and make it really difficult for patients to just complete daily tasks and conduct work.

The second manifestation of Graves disease is orbitopathy, like thyroid eye disease. It affects about 30% to 50% of patients with Graves disease. And it results in a lot of inflammation and damage to the tissue around the eye and a lot of pressure around the eye, including the muscles and fatty acid, fatty tissue and connective tissue. And in severe cases, can lead to vision impairment and vision loss and blindness. And again, it has a lot of impact on a patient's quality of life, not only with the physical discomfort, the pain, the impaired vision such as double vision or Graves' orbitopathy, but also bulging of the eye also known as proptosis. And this can lead to a significant anxiety and depression and can lead to social withdrawal.

The vision impairment can also impact this daily task such as reading and driving. So for great hyperthyroidism, there hasn't been a new therapy for these patients since the middle of the last century. And the standard of care has been stagnant for decades. And although it is relatively effective, it has imperfections and significant limitations. Recently, the oral antithyroid drugs have become the highly preferred standard of care in first-line treatment for Graves hyperthyroidism accounting for about 90% of first-line therapy. And this is due to the risk associated with the ablative therapies. The ablative therapy, this is where you were -- there was ablation of the thyroid function either through dosing with radioactive iodine, which destroys the thyroid cells or surgical removal of the thyroid known as thyroidectomy. Although it is definitive treatment, has limitations, such as it renders the patient permanently hyperthyroid, which leads to the need for lifelong thyroid hormone replacement therapy.

As you can see here on the slide, there's a number of other risks associated with these procedures, including with radioiodine there's an increased risk of incidents and exacerbation of underlying thyroid eye disease.

Now turning to antithyroid drugs. These oral antithyroid drugs work by inhibiting thyroid hormone synthesis. And although they are effective, especially if the patient is compliant, they have a number of significant limitations. Firstly, they don't -- although they do not exacerbate thyroid eye disease. They do not treat or prevent orbitopathy. And as I mentioned, this affects 30% to 50% of patients, and that typically occurs and presents itself within the first 18 months.

They also have a number of serious adverse effects, including liver injury and potentially fatal agranulocytosis and other adverse effects such as itching rash and hives. And so a new therapy that's able to control the hyperthyroidism, while also co-treating and preventing orbitopathy that doesn't have the adverse effects associated with antithyroid drugs and it would be hugely -- well and also well [indiscernible] potential as a really important new therapy for Graves patients.

Turning attention to Graves orbitopathy. With the approval of tepezza, the anti-IGF1 therapy in 2021, this really changed the treatment paradigm and is the first and only approved treatment for thyroid eye disease. And it is relatively effective. It does improve symptoms associated with thyroid eye disease, and it has a response rate of proptosis of up to 80% with a proptosis response being defined as a greater than or equal to 2-millimeter reduction in proptosis. However, many patients do experience a relapse and a recurrence of the disease within 18 months of therapy. Although it is effective, it comes with significant risks, including on-target risk of hearing impairment, which is experienced by 10% to 20% of patients some of which is permanent and secondly, hypoglycemia. There are a number of other safety risks that I've noted here, and it's also not suitable for all patients, including those that have irritable bowel syndrome, diabetes or any preexisting hearing impairment.

So there's really a need here for a treatment that's as effective as these first-generation products or anti-IGF1s, but with much improved safety.

So as I'm sure many of you know, Graves disease is an autoimmune disease that's characterized by the production of thyroid stimulating autoantibodies also known as TSABs. And it is 2 major manifestations, which is hyperthyroidism and orbitopathy. The core driver of these manifestations is the overstimulation of the TSH receptor by the stimulating auto antibodies. And just turning your attention here to the middle panel. In the thyroid, these thyroid stimulating autoantibodies bind to and stimulate the TSH receptor, which leads to overproduction of thyroid hormones and therefore, leading to hyperthyroidism.

In the eye, in the orbital fibroblast, these TSABs also bind to and stimulate the TSH receptor. And by crosstalk, they also stimulate the IGF-1 receptor. This leads to a number of downstream effects, including increased cytokine production, including IL-6, an increase in production of hyaluronic acid and cellular differentiation and proliferation of adipocytes into myofibroblasts. This results in a significant inflammation of tissue expansion and fibrosis and a number of symptoms that I alluded to earlier in the presentation.

None of the current therapies for Graves hyperthyroidism or for orbitopathy actually block this core driver of disease. Antithyroid drugs, as I mentioned, work downstream of the TSH receptor blocking thyroid hormone synthesis and therefore, have no effect on the orbitopathy. Anti-IGF1 therapy block only the activation through the IGF-1 receptor, an IGF-1 activation is not required for thyroid hormone synthesis and therefore, it has no effect for hypothyroidsm.

So the TSH block -- directly blocking the TSH receptor can have some significant advantages and potentially be able to block the activation and the manifestation of Graves disease regardless of location within the body. And that changes as to our approach. So TSH receptor antagonism. So TSH receptor antagonism as a potential as a targeted novel mechanism to treat all of the manifestations of Graves disease, including hyperthyroidism and orbitopathy. On the left panel here, the key aspects of this mechanism is that a TSH receptor antagonist would bind to the TSH receptor and block the activation of the receptor by these thyroid stimulating auto antibodies. In the middle panel, in hyperthyroidism, in the thyroid, it would block the activation of a TSH receptor leading to suppression of the overproduction of thyroid hormone and resolution of the thyroid symptoms.

In the eye, it would also block to the TSH receptor, it would block the activation of the TSH receptor by the thyroid stimulating auto antibodies. And by that cross-stock it would also inhibit at the same time, the IGF-1 signaling. This would then shut down those downstream processes, reducing inflammation, mitigate that tissue expansion and decrease the formation of fibrosis and resolution of all the symptoms that I spoke to earlier.

So essentially, one therapy to treat all manifestations of Graves disease. So at Crinetics, we are developing small potent, small molecule TSH receptor antagonist. We have developed a number of these antagonists in our discovery labs that are structurally diverse. They're potent and selective for the TSH receptor with good pharmacokinetic properties. Our leading candidate is 12755 and as predicted human PK to support once daily dosing. And as I'll show you in a moment, it's demonstrated efficacy in a preclinical model of Graves hyperthyroidism, and also we demonstrated ability to inhibit the activation of the TSH receptor in Graves patient orbital fibroblast. It's currently going through IND-enabling studies, which are in progress.

And as you can see here on the right panel, 12755 is a potent antagonist of the human TSH receptor with -- of approximately 8 nanomolar and it's also slightly less potent as an antagonist of the rat TSH receptor, which is great because it enables us to put this and study this in our preferred Graves model.

So at Crinetics, we have studied 12755 in our in-house rat model graves hyperthyroidism. In this model, as you can see here on the right panel, the rats are dosed with a human thyroid-stimulating autoantibody known as M22. And you can see here on that right panel that following dosing of M22, you see a rapid increase in thyroid hormone T4, as you would see in a Graves patient. The rats are then dosed with either vehicle or an ascending dose of 12755 orally. And you can see here we get a rapid dose-dependent response and reduction of the T4 thyroid hormone levels. And you can see at the higher doses within that first day, there's a return to baseline. I mean as Steve was alluding to earlier, with these models being so translatable in the endocrine area, this provides very strong proof of concept that 12755 will perform equally in Graves hyperthyroidism in the clinic.

We've also studied the ability of 12755 to not only inhibit the TSH receptor in the thyroid, but also its ability to block with the stimulation in the eye. Just as a reminder, one of the effects of TSH stimulation by these antibody -- autoantibodies in the eye is production of hyaluronic acid. Hyaluronic acid attracts and bind water and therefore, contributes to the increasing of the volume of the orbital tissue.

In this model, we have obtained orbital fibroblasts from TED patients that have undergone orbital decompression surgery and differentiated those into adipocytes. They are then stimulated with a human T-cell. And you can see here in the center panel, that 12755 is able to dose dependently suppress the production of hyaluronic acid when stimulated by the human stimulating antibody. Not only is it able to block the stimulation by this isolated antibody, it also able to block stimulation by autoantibodies to a number of patient samples shown here on the right.

Another effect of the stimulation of the TSH receptor in the eye is production of IL-6. IL-6 plays a number of roles in the pathophysiology of Graves orbitopathy. Firstly, it increases cytokine production. It also increases production to the TSABs themselves. And finally, it leads to increased cellular proliferation, differentiation and differ genesis. And as you can see here in the middle panel, 12755, is also able and we've demonstrated that it's able to dose dependently suppress production of IL-6 in these same orbital fibroblast from patients as an isolated antibody in the middle and from the autoantibodies for a number of patient samples on the right panel.

So we've generated preclinical proof-of-concept data that's given us a very strong reason to believe that this has potential as a really important new therapy for Graves patients, addressing the key -- potentially addressing the limitations of the current standard of care. Our vision for this product -- is for it to be a single oral therapy that will treat both manifestations of Graves disease, be that hyperthyroidism and while treating and preventing great orbitopathy. Our vision for the product is it has potential to put for the hyperthyroidism as a once-daily therapy that will achieve rapid control of hypothyroidism symptoms while simultaneously treating and preventing orbitopathy. With none of those risks associated with antithyroid drugs and it will preserve the thyroid and spare the need for ablative therapy.

For orbitopathy, again, it will be an oral once-daily therapy. And because it blocks that same access, the TSH receptor IGF-1 complex, we have a strong reason to believe that has potential for equivalent or better efficacy than the currently approved IGF-1 for thyroid eye disease. But more importantly, with that improved safety. None of those on-target hearing impairment or hypoglycemia and this improved safety could enable longer treatment duration and therefore, improve durability.

So it has very much potential as a single therapy to address limitations in current standard of care for both hyperthyroidism and orbitopathy. As I'm sure many of you in this room are aware, there is a number of emerging new; therapies in the clinic for Graves disease, either for thyroid eye disease or for hyperthyroidism. And we still believe that a TSH receptor antagonist has still -- has potential advantages over these emerging new products. As you've heard me go through the profile. So one of the major classes that's in development is the second-generation and anti-IGF-1s. These are other subcutaneous monoclonals or oral small molecules.

As I touched on earlier, because of their mechanism, they will only treat thyroid eye disease. Early data from the clinic is suggesting that the subcutaneous injectables have the efficacy of the current standard of care. The question still remains though whether they will be able to thread that needle and overcome the on-target side effects of the anti-IGF-1 inhibitions such as hearing impairment and hypoglycemia.

The second major emerging class is the IgG degraders. These come in 2 major forms. Firstly, the anti-FcRn monoclonal antibodies and small molecule bispecific degraders. These work by reducing the levels of these circulating thyroid stimulating auto antibodies by promoting their degradation. However, they are not specific to the thyroid -- they're stimulating auto antibodies. They broadly degrade IgGs. And data is suggesting that they may require large and sustained and deep IgG reductions to maintain efficacy. And finally, they are all high dose once weekly subcutaneous injections.

So the population itself, so switching to how big is this population and our opportunity here is, as you can see here, and I think many of you know, there's a very large patient population in both Graves, hyperthyroidism and orbitopathy. Hyperthyroidism affects approximately 1% of the population, which is approximately 3 million people. And recent studies have shown that there's up to about 1.2 million people who actively have Graves hyperthyroidism. And we see this as a potential addressable patient population for the right new therapy for Graves disease that addresses limitations of standard of care. And it has an annual incidence of new diagnosis of upto 170,000.

For Graves orbitopathy or thyroid eye disease, we really see the addressable patient population as those with moderate-to-severe disease, which is the population of which tepezza is mainly used. As I mentioned, it affects about 30% to 50% of patients with Graves disease. And that's approximately 150,000 patients with moderate to severe to prevalence, and about 9,000 to 10,000 of moderate to severe incidents per year. So a very large population with a high unmet need.

So what's next for this program that we're excited about at Crinetics. So next month, we will -- we have a poster presentation at the Endo Conference in San Francisco, where we'll share this and more data on 12755. As I mentioned, we are progressing through IND-enabling activities, and we'll have IND submission. What we're really looking forward to is the Phase I healthy volunteer study. And as Steve touched on earlier, with this being an endocrine target, we do expect to see the modulation of a thyroid hormones in healthy volunteers. So not only will we establish safety, tolerability and pharmacokinetics, but we'll also get initial proof of concept in terms of thyroid biomarker modulation of the TSH, T4 and T3 thyroid hormones, which actually will be our Phase III endpoints for Graves disease.

So thank you for your time, and let me share an overview of our exciting TSH program, and I'm going to hand back to Steve to talk about and share with you our ADPKD program.

Thanks, Rick. And I did -- actually, I was in all my free time yesterday, I was reviewing that 755 poster for Endo, and I think it looks -- I think it looks great. So I'm excited to see that look.

We're going to spend a little time talking about ADPKD. And this is one where I think of as kind of endocrinologically adjacent, but this is one where kind of as I was talking about before, the infrastructure of endocrinology can play a big role here.

So ADPKD is actually the most common inherited renal disease affects nearly about 150,000 people in the U.S. And it's actually quite incredibly debilitating here on the graph, I show you, as the disease progresses, you get these large increases in cysts in the kidney. And over time, you actually lose kidney function and kind of -- it has a very rapid drop off at the end. In other words, early in the disease, kidney kind of chugs along and manage it to get by and then later in the disease progression, it really falls off and that leads to patients requiring dialysis and kidney -- ultimately, kidney transplant, incredibly burdensome disease, especially as it comes to the end of its run.

The only approved therapy for ADPKD is a compound called tolvaptan. We'll talk about that a little bit later. And it is only used in about 10% of patients. And the reason for that is some on target pharmacology from -- as a mechanism tolvaptan, to go into this a little bit, that causes frequent -- frequent urination for patients so much the fact it becomes actually debilitating for them. And so there is not -- this is a disease with a lot of people that need a good option and just don't have one.

I'll spend -- let's talk about the kidney a little bit, especially in the cilia. This is a disease of disrupted signaling within the cilia of the kidney, and I've got a little diagram of it here. On the left-hand side is a healthy kidney doing all the things it needs to do. And really, what happens here is there's a balance within the cilia in the kidney of the concentrations of calcium and the concentrations of cyclic AMP. And that homeostasis is maintained for healthy kidney function. What happens in ADPKD, there's mutation either in this protein called PC-1 or PC-2, and what that does is those mutant proteins do not allow the influx of calcium. And so what happens is then you start to get this disproportionate ratio of cyclic AMP to calcium. And this has downstream effects of turning on cystogenic signals within the kidney, and this leads to the development of cyst, which leads to bad renal function in the end.

And so our hypothesis about this disease, and thinking about this from kind of a disease burden and pathophysiological sense is if we could restore that cyclic AMP and calcium ratio, you would alleviate the disease and be able to treat these patients.

So let's spend a little bit talking about tolvaptan. So tolvaptan is a vasopressin receptor antagonist. The -- and vasopressin is found on the kidneys. And the thing is if vasopressin causes -- vasopressin receptor activity causes an increase in [indiscernible]. And so the answer here is if you block the action of vasopressin, you actually lower cyclic AMP, which is what you would want to do for an ADPKD patient. The problem with vasopressin is it's also known as antidiuretic hormone. And so if you block the effect of antidiuretic hormone, what happens, you're no longer able to reabsorb water from the kidney into the system. And so you end up having frequent urination, very high-volume urination and very high urgency of urination. And this can be 3x or more frequently than healthy individuals can have. And this ends up being so debilitating, I think people would rather not be on therapy than to have to put up with this.

So in some ways, tolvaptan -- and this is exactly -- this is not a side effect. This is actually the pharmacology of vasopressin in action. And so this is -- this is not an unexpected outcome for this drug. And so as we thought about it, and so in some ways, the right idea was lower cyclic AMP, right? -- but not have these side effects. And so the right way to -- as we think about it, the right way to lower cyclic AMP here is to turn on somatostatin 3, which is also found in the kidney and specifically found in the cilia in the region where the mutations in PC1 and PC2 occur. And we did some work here -- as we were characterizing this idea, we went back and we characterized the expression of site -- of SST3 within the kidney, and I won't go into it for purposes of time, but essentially SST3 is expressed in the cilia and in the kidney, exactly where you need it to be to normalize this cyclic AMP to calcium ratio.

So actually -- so somatostatin agonist have been looked at in ADPKD before because it's a good idea, it's a lower cyclic AMP. The thing -- so SST2, SST3 and SST5 are all found in the kidney. So why SST3. And this is kind of one of the main underpinnings of our idea about developing a selective somatostatin 3 agonists. So SST2, what I have here is some staining that we've done and looked at for mice in -- for ADPKD mice and also tissues from ADPKD patients. And what they show is that in healthy individuals and normal mice, you get nice expression of both 2, 3 and 5. But when you go to disease mice or patients with ADPKD, you can see that SST2 expression goes down. And the manifestation of that in treating disease is that an SST2 agonist likeoctreotide and lanreotide has been used in the past, will often have some activity. They will work a little bit and they will help kidney volume or EGFR. And -- but that activity will wane as the disease continues to progress a little bit. And so SST2 good, but not the right one.

SST5 activity and expression remains high in both -- both mice and patients with ADPKD. But the problem there is if you treat -- SST5 is an incredibly potent suppressor of insulin secretion and so if you do that, you end up having -- you end up raising glucose, you end up raising people's HbA1c, you can turn them into diabetics, and that is not what you want to do for an ADPKD patient at all.

And so -- in the middle there is the expression of SST3, also highly expressed in the ADPKD mouse model and as well in ADPKD patients. We think that this consistent expression in the ability to lower cyclic AMP levels with SST3 gives all the benefit of restoring that ratio of calcium and cyclic AMP, hopefully without the safety -- the on-target side effects that you would find with an SST5.

I went back in here, I just wanted to show you a little bit more in the -- from the discovery that we did. We've run a lot of compounds in our SST2 and SST3 assays. And what I did is I went back and I pulled out all of them just to show you kind of the selectivity of SST2 versus SST3. And here, I've highlighted both paltusotine in 1941, the molecule we sent to -- we license to loyal. You can see that they're very potent for SST2, very weak at SST3, For 10329, 10329 is very, very potent at SST3 activation, not much activity at SST2.

And so like all our molecules, we've got a bunch of different scaffolds that we're interested in. These are potent selective for SST3. They've got all the ADME properties that we want that once a day and the whole thing. And 10329 is our leading candidate, it is predicted to have once-a-day human dosing. I'll show you some data in an ADPKD model, and it's currently in IND-enabling studies.

So the model that we used for ADPKD and you go back and when I was talking about 25 minutes ago. And I said how everything was translatable in endocrinology from preclinical models to healthy volunteers to patients. We don't quite enjoy that with ADPKD, and this has been something that's been known in this arena for a while, but there's not a great model and then the mouse doesn't quite recapitulate what happens in patients. But the best model that we know out there is one where we can induce cyst formation by knocking out PC1 in mice. And you can see we have this model, which takes about 3 weeks, return on cyst formation with tamoxifen, you can see in the lower right -- lower left-hand corner, you can see a healthy -- a slice from a healthy kidney to one where we've started to form cyst. This is an incredibly fast, aggressive model. And you can see kidney weight increases and cystic index increases.

And one of the things we've done is we've co-localized where these cysts are in the mouse model, and these go exactly in the same places in the kidney that they do in ADPKD patients. So this is a pretty reasonable model of cyst formation, even though the cyst formation is incredibly, incredibly rapid.

And so because we don't quite have the biomarkers like we did for growth hormone or insulin or thyroid hormone that we've enjoyed for other programs, we've really taken the approach to characterize this model at several levels, starting from just the macro kidney, look at the kidney and the biology of the kidney, look at the histology and tissues, look at cellular proliferation and even look kind of down at the molecular level for what's happening in the kidney. And I'll walk you through just a little bit of this data so that you can see what we've been able to do.

In the upper left-hand corner is a moldy experiment there where we did -- when we dosed mice with 10329, and we're able to do a moldy experiment where we can image the concentration of 10329 within the kidney. And there's a nice overlap here with cystic kidney there in the right-hand picture. And you can see that 10329 is co-localized exactly where you would need it to be throughout the kidney to affect cyclic AMP level. So this is exactly what we would hope for in this model. And you can see here some of the data when you treat these ADPKD mice with 10329, you get a decrease in kidney weight, you get a decrease in cystic index, both in the proximal tubular and collecting DUCs. And then we looked at cellular proliferation in both those -- in both highly -- highly proliferative cells in the course of the whole kidney as well. And that's in the right-hand side of the graphs. And so 10329 is affecting all these things in the direction that you would want.

One of the other things that we've looked at is a couple of markers, kind of at the RNA level. And one of these is -- so when you knock out -- when you knock out -- when you create these PKD knockout mice, one of the things that happens is you get an increase in a marker called periostin. Periostin is known as a modulator of growth within the cell. And you also get a decrease of this microRNA30a. And so what happens here is if you have an increase in periostin, you get increased cellular proliferation, you get increased cyst formation and the microRNA30a -- it's job is, it blocks that it inhibits that. So really, you've got a kind of a double whammy in these mice because periostin is going up, the thing that stops periostin is going down, so you get this really rapid growth assists.

And after 10329 treatment, you can see that periostin levels go down to baseline, and you get a very nice increase in microRNA30. So this is what you would hope to see in a molecule that could normalize this disease and bring the kidneys back to kind of a healthy state.

And so we think that this actually has a chance to be -- an SST3 agonist has a chance to be a kind of a new standard of care, and this goes back to what I was talking about a little bit earlier, a lot of what we think about is how can the molecules that we make change the practice of medicine. This is one where if we had the right molecule that could normalized cyclic AMP and calcium levels within the kidney, retard the progression of disease and not have the side effects that kind of the current therapy tolvaptan does, I think this would be an incredible win for patients.

So we think this 10329 is capable of treating patients at any stage of the disease, including earlier in the disease to help halt disease progression, that would be fantastic. We have every reason to expect based on what we know that this should be an efficacious in patients. We think that SST3 presents a really compelling case for being well tolerated and should not have -- some of the data that we have suggests that you're not going to see the hypernatremia that you see in what you can manifest in rodents and is what keeps people from taking tolvaptan. And of course, it would be everything that we always do kind of target oral once a day dosing, take it, forget it in the morning kind of thing.

So this is the hope for this SST3 program and ADPKD is super excited about this opportunity.

And the vision here, I've kind of gone into this, so I won't spend a ton of time talking about the vision. But we think this is -- this could be a new standard of care for this patient population. We've learned some of the things that are being done in this arena and ADPKD, there are new endpoints that are being used, including total kidney volume, an eGFR that the agency seems to be willing to work with. We can go into patients who are earlier in their disease than patients who are typically getting treated, especially those who are getting on tolvaptan.

And I think here, the one that's also important is ADPKD is a ciliopathy, right? And there's a lot of -- and what happens at the cellular level and the molecular level in ciliopathies is somewhat similar. And so ADPKD is a ciliopathy. There's other ciliopathies out there that we might be able to treat. And one of the other ones is polycystic liver disease. And so we're curious to see and excited to see how SST3 agonist might perform in PLD as well as ADPKD.

And so what's coming up next for us in this program. We are in the midst of our IND-enabling studies and getting that package together to submit to start a Phase I. We're hopeful for IND clearance in the near future. And we'll be doing a Phase I study. This will be done in healthy volunteers and we're thinking about what we might be able to see in healthy volunteers that convince us that an SST3 agonist is doing what we want it to do. That's all I have for the SST3 program at the time. Thank you for your attention. I think we have a break. I'm going to turn it over to Gayathri for a little bit of housekeeping here.

We're going to take a brief break now until 10:25. So for those of you here in person, we still have coffee and snacks, there's a terrace out if you want to go around and talk to management. For those of you on the webcast, please be back online at 10:25, we'll continue with the presentation at that time. Restrooms are out that way as well if you need.

[Break]

Hi, everybody. Thanks. We're going to continue with the program here and the second half of our programs that we're going to talk about today is 9682, our non-peptide drug conjugate program. I'm going to kick us off kind of with a little bit of the concept behind it and the idea of how we got to the molecules we got to.

So one of the things that prompted this idea around creating non-peptide drug conjugates was a synthesis of 2 ideas that we had seen evolve in the oncology space over the last decade or so. And one of these was the use of dotatate scans for patients who have SST2 expressing tumors. And so here on the left-hand side, I've got an image of a NETs patient who using a copper dotatate scan and you can see that the NETs are clearly indicated as well as, unfortunately, some metastasis as well. But this is pretty -- this is getting to be more standard. And then, of course, the growth of PRRT in oncology also kind of stems from this. And so that was one of the things as we were thinking about these conjugate ideas of delivering payloads to tumors.

One of the first things we started with was this idea around creating non-peptide compounds that were delivering radio nucleides either for imaging or for therapy. And this idea -- this program actually works so well, and I said this a little bit earlier, we started Radionetics, and spun that out in the fall of 2021, and that is off and running and doing its thing. But as we were thinking about it, we're like, well, radio nucleide, isn't the only thing that you need to deliver or that you might want to deliver. And so we had thought about, well, what if you could -- radiotherapy, PRRT has some limitations, and we'll talk about that in a little bit. But one of the things that we thought, well, what if you could deliver like kind of like a successful ADC. What if you could deliver a payload that was toxin to the tumor, but without some of the hassles of ADCs.

And so this is where this idea of a non-peptide drug conjugate sort of arose from in us. And we thought that an SST2 targeted payload with a toxin would be a great way to kind of integrate ourselves, a, we've been working in carcinoid syndrome and neuroendocrine tumors. We knew this space. We knew that there is still a need for better treatments there especially if you could deliver something because one of the things about GPCRs is they're very difficult to raise an antibody too. And so they're very difficult to drug with ADCs. But we, of course, have lots of ways to make molecules that will go to the receptors that we want to be selective for the receptors that we want. And we try to think about how we could get them to deliver payloads to the tumor cells specifically. And we opted to go with MMAE as our first one because it's been used in ADCs very effectively. And we've done enough in vitro work to know that MMAE was effective at killing at least in vitro cells derived from neuroendocrine tumors in SST2 expressing tumor cells. So a combination of an SST2 agonist MMAE seem like a great first thing to go for.

Of course, we're starting in NETs because we know this area really well. There's still a real unmet need here. But the figure on the right is supposed to indicate there's a lot of tumors out there that express SST2 and an incredible amount of unmet need in a large population that could really probably benefit from a very specific and targeted therapy.

So NDCs are designed. So I'm not showing you the atomic level structure of our NDCs, but this is actually a space-filling model of what one of our NDCs looks like. And they're comprised of 3 components. One is the targeting ligand. One is a linker. And the linker is not just a spacer between the targeting ligand and the payload. It actually has a lot of purpose as well. And then, of course, the payload. And we think that this configuration had a lot of benefit compared to some of the therapies that are out there. Now, of course, chemotherapeutics aren't going to be -- it's not very hard to think of something working better than many of the chemotherapeutics. They're not tumor specific. They've got a low therapeutic window. They are across the whole system of the body.

But we think about antibody drug conjugates, which have been, I think, vexing and waning in interest over the last couple of decades. And they can be effective in a lot of areas, but they have a couple of liabilities, a, they're biologics, so they're hard to make. They don't get very good tumor penetration in solid tumors. The other thing is they last for a long time and in the circulating plasma circulation. And this can actually help -- it actually lowers their therapeutic window as well because as they get chewed up in the plasma, all your releasing is the toxic payload into the system, which is what you don't want.

And of course, we talked a little bit about the radiotherapy, radio imaging and PRRT. Again, I think some incredible data coming out of some of these things. But there are limitations even as we were starting NETs, we knew there were some limitations here, which is one of the things that spurred this idea of NDCs. And it really comes around, a, difficult to manufacture. You got a really difficult supply chain sometimes with some of these radio nucleides, you've got to create them in situ in the place of -- in the clinic. And then, of course, patients are limited in their -- how much radiation they can absorb over the course of their lifetime. So we thought that NDCs sort of took the best aspects of radiotherapy, took some of the best aspects of ADCs, combine them together to get something that we think can be pretty transformative for patients.

9682, which Stacey Harte is going to tell you more about is the first of what I hope will be many NDCs to come out of Crinetics. It is an SST2 agonist with a linker and then the payload. The agonist, we've talked a lot about SST agonists. This one is specifically designed to go to the receptor, get internalized by the receptor in that kind of -- remember that cartoon I shared with the endosomal signaling is designed to do that and get the payload released. And here, the payload is MMAE, which we had shown in preclinical or in vitro experiments should be effective against tumor cells.

The thing about the linker, I want to make sure and impress upon you guys, it's not just the spacer between the 2 active parts of the molecule. The linker actually has a lot of craft behind it in terms of how we make them, and these are synthetic, right? So unlike a biologic, we are not limited by how you can attach payload to an antibody or a peptide or anything like that. So we get to make these by chemical synthesis in the way we make all of our molecules, but they're designed to be stable in plasma. They're designed to be cleaved specifically in the endosome. And then we can also use them to modify the physical chemical properties of molecules so that they're soluble, so that they have the tissue distribution that you want. All the things that you -- the -- I guess I'd say NDCs have their own little water balloon that we work on to make sure that they do the things that we need them to do.

But I don't want to go out into the future, but I do want to talk a little bit about the future before we go back to 9682, because I do think of all the things that we've been able to create, I think of this -- I don't love to use the word platform, but I am going to use the word platform because this gives us an opportunity to really think about from a targeting standpoint, what receptors are we targeting, how do we make the small molecules to target them. We have a lot of experience there. We understand these receptors as we talked about. So we can make a lot of -- we can make a lot of NDCs that target different GPCRs.

The payloads, I think, are a fascinating thing. You can think about how you might deliver either different payloads, a different toxin than MMAE, maybe more than one different toxin. And you might not even think about this in terms of delivering toxins. There could be other things that you might want to deliver to a tissue of interest. And of course, we've got a whole group back in San Diego, thinking about this and making these different constructs and seeing what they can do in the lab. And then of course, the linker, of course, as I was talking about, gets really optimized so that it's stable in plasma so that the overall molecule has the properties that we're looking for, and so that it's this whole combo of activity, payload, biophysical properties that is going to make an NDC kind of the best drug that it can be. And these are optimized in the same way that we optimize every atom for every molecule that we make.

And so I'm super excited about these. I think there's going to be next generation of these and sometimes it's almost like what do you want to make next is almost the hardest question because there's so many opportunities here. We could probably spend a whole R&D day just talking about NDCs. But I will turn it over to David Metz, neuroendocrinologist who we've worked with from time to time. And as Gayathri said, have been President of North American Neuroendocrine Tumor Society. He's going to talk to us a little bit about NETs and why this is still an unmet need in oncology.

Great. Thanks, Steve. Thank you, everybody. It's a pleasure to be here today. I want to be giving sort of a background on the status of neuroendocrine tumors and neuroendocrine neoplasms, just so that you can get an idea of the landscape that Crinetics is addressing.

So neuroendocrine neoplasms. They are rare tumors arising from neuroendocrine cells throughout the body, and the correct term these days is neuroendocrine neoplasm. That's because the neoplasm consists of 2 different subgroups, neuroendocrine carcinomas or NEX and neuroendocrine tumors, or NETs. As I suggested, they originate in a wide range of organs, most them, about 80% plus have somatostatin 2 receptors that can be identified with imaging so that they help towards the [indiscernible] approaches that we've been talking about. And the spectrum of disease, as I've just mentioned, spreads from well-differentiated indolent slow-growing tumors that are there for a long time that are incurable in many cases, to the very poorly differentiated, rapidly growing tumors that behave just like a cancer. So that would be neuroendocrine carcinomas as opposed to the neuroendocrine tumors, the so-called carcinoid was an old term used to describe like carcinoma, but not quite as aggressive.

These tumors often present, as I've suggested, at a very advanced stage. And in fact, about 50%, 58% of patients with neuroendocrine tumors present with widely metastatic disease. This is in contrast to normal carcinomas that you could think of normal solid tumors where you have a primary that is relatively large grows, develops lymphadenopathy and then spreads to other organs into the bones.

In neuroendocrine tumors, it's an upside down kind of picture. You have a very small primary tumor. You have a conglomerate of lymph nodes around it, but the bulk of the tumor actually is metastatic, often in the liver. And that is what ultimately causes the mice for these patients. So that liver-directed therapies are reasonable approaches.

These tumors can be functional or nonfunctional. Here, we mean functional in terms of tumors that produce products that give you hormonal syndromes, various different kinds in various different locations. And in that situation, there's a potential to diagnose this early if you have an astute physician who thinks about the syndrome, but even in that situation, often, tumors are already metastatic.

On the right-hand side, I've given a figure here of the more traditional approach as we talk about [indiscernible], gastroenteropancreatic neuroendocrine tumors, the GI tumors on the left and the pancreatic ones are on the right. The pancreatic ones can be functional and -- or nonfunctional, many different functional syndromes. The GI NETs, if they functional tend to cause the carcinoid syndrome, carcinoid syndrome, which you know from related to paltusotine being the most common of all the functional neuroendocrine tumors and therefore, a good one to go for first.

The GI elementary [indiscernible] are traditionally divided into forgot, midgut and hindgut, and that does have some relevance in terms of their clinical behavior. And sometimes you worry about the primary side more than the actual tumor. But as I'll show you in the next couple of slides, it's really the biological behavior of these tumors that is important. The lungs are an interesting offshoot. You can think embryologically as the lungs as being a derivative of the foregut. So that would fit into the foregut group or you can talk about pulmonary neuroendocrine tumors and thimic neuroendocrine tumors as being in a separate group.

So at the bottom, I've listed there, the 3 most common sites, the pancreas, the GI tract, the elementary track, the so-called carcinoids bad term or the lungs. And depending on what grade of tumor you're talking about, you might be separating those out in terms of extra pulmonary or extra pancreatic. And the reason I've said that -- made that distinction for you is that the extra pulmonary neuroendocrine tumors in terms of the NETs are very important because there's a different treatment paradigm for small cell lung cancer and NETs that are not in the lungs. And on the other side of the coin, you talk about the extra pancreatic and the pancreatic neuroendocrine tumors because in the lower-grade tumors or the well differentiated tumors, there are different chemotherapeutic approaches depending on if it's a pancreatic primary or non-pancreatic primary.

So with that background, it is important to recognize that neuroendocrine tumors are increasing rapidly and they're becoming really a prominent cause of patients seeking help. On the left is an example of the incidents and how it has increased over other malignancies in time. And you can see in this figure that the increase of neuroendocrine neoplasms is outpacing the development of standard solid tumors. And we don't really know 100% why this is. It's partly just because of improved imaging. It's partly because of increased endoscopy procedures, but it's also just because we don't understand why this is happening.

On the right-hand side, I want to point out that although the biggest increase is in early-stage disease based on imaging and endoscopy, it's not limited to this. And the increases in localized, regional, distant disease as well as the various grades of severity. And this is sergrading, not the grading I'm going to be talking about in a minute.

Let me just also mention that this study is from Arvind Desari at MD Anderson from 2017. And yesterday, he republished the entire analysis updating it to the modern era was published yesterday showing that these trends have continued.

So I've alluded to the difference here between NEX and NETs. So I just want to go into that a little bit more so that you can get an idea of where Crinetics is trying to pigeon hole or use the NDCs going forward and finding the various possibilities without leaving opportunities on the table. So on the left, we've got the neuroendocrine tumors. They are all well differentiated tumors. If you look at them under microscope, they won't look like malignancies and such. So I'll have a few mitotic figures. They'lll be very uniform, have pale cytoplasm with a nice little nuclei and they don't look like they're going to really be an ugly sort of tumor, but they are and they do grow. And they can be graded as Grade 1, Grade 2 and Grade 3. And these gradings depending on mitotic figures or what's called the KI-67 index.

And the reason for that distinction was determined post hoc because GI Grade 1 tumors tend to behave quite nicely and slowly, and you don't need to get too excited about it. And in the older days physicians would say, don't worry about it, you'll live with this tumor, which is not true. On the other hand, you have the G2s, which are relatively more aggressive. They have a higher KI-67 and those are going to grow and will need therapy. And more recently, this is really a new update is the G3 well differentiated group that we know are the highly aggressive, well-differentiated neuroendocrine tumors that often have somatostatin receptor positivity quite densely and would be a good target for a somatostatin directed drug.

The neuroendocrine carcinomas on the other hand, are all poorly differentiated. So when you look at these under a microscope, you'll see [indiscernible] cells. They're not all the same size. Some of them are dark, some of them are light. They look like a malignancy and they all are high grade. And there, you need to think of 2 kinds. There's a small cell and a large cell. That in itself is not much of a distinction, large cell neuroendocrine carcinomas are really rare. But the small cell lung cancer would be in the lung and small cell NEX can be extrapulmonary and the current therapy differs between those 2 groups.

As I've mentioned, as you can see in the purple arrow there, as you go from left to right, the aggressiveness increases, your likelihood to get a response with therapy is going to be easier to show. But on the other hand, as you can see in 2 lines down, the more frequent patients are those that have relatively lower grade tumors. Again, 58% with metastatic disease, they're ultimately going to succumb to the disease. When are you going to intervene? So you have to sort of decide where you want to pitch your product over here.

The SSTR expression, the somatostatin receptive expression also is highest in the lower-grade tumors, less in the poorly differentiated patients, but you don't want to leave that opportunity on the table until you've had a look at it. And in terms of long-term outcomes, the NEX do poorly and the NETs do better and it's dependent on grade.

So this is how I think about treatment for neuroendocrine tumors. No 2 patients are the same. I think that's something we really stress in the field. Everybody needs their own sort of thoughtful tumor board approach treatments. But it's based on what is going to make a difference in the long term. A recent study out of Europe suggested that there are 4 major predictors of outcome. First of all, the stage and extent of disease and whether that depends on tumor bulk greater than 25% or 50% in the liver is sort of still being studied, but the amount of disease makes a difference. The grade certainly makes a difference. There have been many studies showing that. And the differentiation, obviously, will make a difference with poorly differentiated NEX, definitely doing worse than well-differentiated NETs.

Does the primary tumor site make a difference? It certainly does in terms of some of the approaches to therapy. And it may, but it may also be in part related to the KI-67 and the behavior of that particular patient. So we don't really know that completely, but it has been shown to be an independent variable. And finally, the last issue is age of the patient, something that you obviously cannot change when they walk in the door to see you.

So the algorithm that I've tried to summarize over here on the right-hand side is as follows. You diagnosed with a neuroendocrine neoplasm, a NET or a NEC. If it's locally resectable or regional disease, you can take out the tumor, you can remove as much as possible. You can potentially cure somebody if you catch them early enough, even if they have lymphadenopathy. That is still a potentially curable situation. And you might do that and then sit and wait and see what happens after surgery or you might want to put them on to some kind of a maintenance treatment, which we'll get on to in a little while.

However, if you can't remove all of the tumor, but you can debulk, it is also an opportunity, and we now are starting to believe that if we can reduce the tumor bulk by 70% or more. 70% is not that much, right? You can leave a lot of potential tumor behind, but make a significant impact. So that there will be a large population of patients who go to surgery have their tumors resected. And I'm talking more about the lower grade group here. And it will have tumor left behind that you then can watch or treat with a product that isn't going to be too onerous for the patient to take.

Once you've decided the surgeries are done deal, your next step is to determine is this a fully differentiation or well-differentiated tumor. If it's fully differentiated, the standard of therapy or certain types of chemotherapies and there are different types of chemotherapies depending on if it's a neck or a NET. And that's an important distinction to make. So there are different studies -- sorry, a pulmonary or extra pulmonary neck. So the [indiscernible], they're using different therapies like FOLFOX and FOLFIRI and in the pulmonary small cell lung cancer, there's now immunotherapy being utilized. That's the IO therapy.

For the well differentiated tumors, you get the slow-growing patients with metastatic disease that's rolling along the might be have comorbidities. You don't necessarily want to do anything. A large population are just being observed. Many of them are going on to somatostatin receptor ligand therapy and those that are receiving that in a recent paper that's just come out suggests that actually SRL therapy is better than watch and wait, even in small tumors, and that was a study limited to the pancreas specifically.

On the right-hand side, what happens about the tumor has got progressive disease that's growing, that's symptomatic that you think you need to get on top of and control quickly. Well, if it's -- since a liver bulking deliver dominant disease often in these patients, there is a role for liver-directed therapy and hence, multidisciplinary discussion. But as far as systemic therapy is concerned, the traditional approach for NETs is to separate into pancreatic and non-pancreatic, and the reason for that is that chemotherapy regimens with Cap TAM are felt to be better in the pancreatic group than in the non-pancreatic group, that's still open to some debate.

And then you have a bunch of different treatments. You can use the somatostatin receptor ligands. If it's low growing and slow and not a big worry for now. PRRT, as I'm sure you all know, has grown, and there are going to be lots of new PRRT molecules coming to clinic in due course. It has a tremendous advantage of being the best odds -- best duration of response, but there are issues with PRRT, as was alluded to by Steve earlier on. The kinase inhibitors and the mTOR inhibitors will block specific therapies and they have a lesser duration of efficacy. They have some side effects, but there certainly is a role for those. And cabozantinib, as you all know, is something that is coming to fruition soon.

And finally, there are various types of chemotherapies that can be considered here. The cap TAM regimen specifically, but then there's all the FOLFOX, FOLFIRI [indiscernible] group for the GI NETs. And then there's all the combination therapies with immunotherapies and PD-L1 inhibitors and all sorts of other treatments.

So there's still a lot of space to sort of improve on this. And there is no consensus about appropriate sequencing of treatment and when one treatment ultimately fails what's your next approach?

So to end off here, I've listed on the left-hand side, the expected outcome, as you would hope for with the various classes of systemic treatments that are available. These tumors, as we've suggested, are incurable when we had a static regardless of the grade and it's just a matter of inexorable time. But you don't want to use up all your therapies too soon and cause too much in the way of adverse events. So the somatostatin receptor ligands are favored early on because they cause stability potentially of tumors, they're very well tolerated. They have a variable duration of response in patients. Some do well for many, many years. some change quite quickly and you need to go into the next treatment.

When you go into the next treatment, you've got your options of PRRT, the kinase inhibitors with -- the mTOR inhibitors as well or cytotoxic chemotherapies of various kinds. Those 3 lines of treatment, you would potentially expect some kind of response and the frequency or the rapidity with which you want to response may also impact on your choices of therapy.

They all have their potential issues with side effects, some more severe than others. The best duration of response at the moment is PRRTs. We're not sure what's going to happen with the future PRRTs that seem to be potentially more affected, but may not be as well tolerated. The kinase inhibitors have a defined response time and the cytotoxic chemotherapies also ultimately are going to have issues related to side effects and ultimately, other issues limiting their use.

So there is a significant opportunity in the neuroendocrine neoplasm space, both NETs and potential NEX to find drugs that will kill tumor cells rapidly and effectively, that will improve the efficacy, especially in these rapidly growing aggressive tumors, that will address the limitations of PRRT which is excellent, but not the be all and end all, namely the fact that you can't take it forever, and you're going to get limitations with radiotherapy, radio activity. That will provide a better risk-benefit ratios after patients have moved on from SRLs and ultimately improve the quality of life and survival. I tell my patients, well I told my patients when I was in practice that we would grow old together. And hopefully, my aim is to keep them with the neuroendocrine tumor until I retired and they carried on living and hopefully, that was achieved with many of the patients.

So with that background, let me now pass it on to Stacey Harte, who is the global product lead for this very exciting molecule that we're going to hear about next.

Hi, I'm Stacey Harte. I'm the global product leader for 9682. I'm really excited to be here today to talk you about -- to talk to you about all the great progress that we've made so far in the program.

So 9682 is a first-in-class novel non-peptide drug conjugate. As Steve discussed, it's designed to selectively target and deliver payload to SST2 expressing tumor cells. So let me walk you through how it works quickly.

So we have 9682 binds to overexpress SST2 cells on the surface of the -- on-cell surface. It's been internalized where the linker is cleaved by lysosomal enzyme specific to the tumor, releasing that MMAE payload, that payload MMAE is a tubulin inhibitor that stops cell division and eventually leads to cell death.

Here, we use in vitro data to show that 9682 was purposely designed to be selective for and internalized by SST2. Using cyclic AMP production assay, we show that -- if you look at the blue line, we show that 9682 is both highly potent and selective for SST2 in comparison to the other somatostatin subtypes. Using the endosomal trafficking assay, we show that SST2 is trafficked into cells in a very similar fashion to the native somatostatin agonist SS14. These data give us confidence that 9682 has desirable pharmacology and trafficking properties for bringing -- for delivering payload into SST2 expressing tumors.

The data on this slide really demonstrate that we design 9682 to do exactly what we want it to do, which is to deliver that payload into these SST2 expressing tumors with overall minimal systemic exposure to free unconjugated payload. In the left, you can see intact 9682 has both rapid uptake and clearance from the tumor and the plasma. And on the right, we see that free MMAE has rapid uptake into the tumor, peaking at about 24 hours and then it's retained in tumor out to 10 days, or longer. In contrast, we can see that the free MMAE in the plasma has a low concentration and is rapidly cleared, thereby minimizing that overall systemic toxicity that we would expect from unconjugated payload.

Here, we're showing that 9682 inhibited tumor growth in 2 small cell lung cancer xenograft mouse models typically used in NETs in a dose-dependent manner. So we first studied lower doses in H52 tumor model, and we show antitumor activity in a dose-dependent manner with the highest dose showing some kind of tumor inhibition. On the right side, we show in the 869 model that we took higher doses in and we show induced tumor regression across all dose levels with higher doses.

Here, this data got us really excited. Here we grew up large tumors in the xenograft mouse model, and we're showing that we have demonstrated significant antitumor activity with tumor inhibition at all dose levels and complete regression seen at the 2 highest dose levels, 1 mg and 3 mg per kg with no impacts to body weight. So these data are just a small subset of data that we have that gave us confidence in the 9682 molecule to bring it forward into the clinic and into patients.

Our first-in-human Phase I/II basket study is named [BRAVESST2]. It's a dose escalation followed by a dose expansion. And the dose escalation, we'll evaluate escalating doses until we reach the maximum tolerated dose, then we'll select the best dose that we'll take into the expansion phase, where we'll study that dose across different types of tumor types by cohorts. Our eligibility criteria allow for the inclusion of patients with neuroendocrine tumors, neuroendocrine carcinomas or other SST2 expressing tumors. We'll be using the somatostatin Dotatate scan to confirm that patients have the right level or adequate level of SST2 expression in their tumors.

We know that SST2 is a well-validated target for neuroendocrine tumors, and we look forward to the opportunity of how we can expand 9682 into other SST2 targeting tumors like you see here on this slide, metastatic breast, glioblastoma, et cetera.

So we've talked a lot about 9682 today and NDC platform, and we want to remind you that we have paltusotine, which I shouldn't have to remind you, but we have paltusotine in the clinic for carcinoid syndrome. And we believe that both paltusotine and 9682 really have the potential to offer distinct and complementary treatment options for patients with neuroendocrine tumors. 9682 can really address those metastatic patients that have progressive disease, really eliciting that true antitumor response needed in that patient set, where paltusotine is really addressing carcinoid syndrome or patients with functional tumors providing that rapid and consistent symptom control with an oral therapy. And together, in the future, potentially, there's an opportunity for combination use where we can broaden the therapeutic approach with both therapies together.

We believe our strategy with 9682 and paltusotine really unlocks the full potential for addressing patients for improving outcomes and enhancing quality of life in the broadest set of NETs patients possible. David mentioned that the incidence and prevalence of neuroendocrine neoplasms continues to rise. The latest data from the -- 10-year prevalence data from the analysis that we did in 2024 with the SEER data shows there's approximately 200,000 patients diagnosed with neuroendocrine neoplasms. Of those, a majority of them are really not treated with medical management. They are in the -- that kind of addressed by surgery, as David also mentioned, or they're really those patients that physicians are doing watch and wait. They have those lower-grade tumors or they have really nonfunctional tumors.

On the other side, we have a smaller percentage of about 28,000 to 51,000 that are undergoing various types of medical management. And this is what we see as our first -- as our real initial opportunity for both paltusotine and 9682, with paltusotine really addressing the population of patients that are on SRL therapies and 9682, really addressing the population of patients that need that antitumor agents.

So I'm really excited today for the future for us to share this program with you and to think about the future of where the program is going. We announced earlier this quarter that we cleared the IND. So we're on our way to the clinic. We're looking forward to enrolling patients in our Phase I/II BRAVESST2 study, then taking insights from this dose escalation to really determine the best tumor cohorts to expand into and what other tumor types we work in. And then looking to Steve and his team to see what kind of new indices this Discovery Group is going to bring forward from our pipeline.

And with that, I want to thank you, and I think I'm turning it back over to Steve at this point.

Thanks, Stacey. I got to say I'm not allowed to have favorite children, but I really actually do love 9682 a lot. So again, apologies for those who weren't here a little earlier, Scott's laid up a little bit with a GI bug and wasn't able to make it today, which I know will infuriate him because he's been looking forward to this for a long time. So again, I'll do the closing remarks here in his stead, hopefully, do a good job.

So you've heard today kind of what's coming next for the company and for the compounds that are either in the clinic or about to go into the clinic. But I wanted to take a minute and remind everybody here of the pipeline that we've been able to create over the last 10 years, and think about the upcoming milestones that are coming up for everything that's going on. Of course, the biggest one for us is the PDUFA date for paltusotine and acromegaly in September. But we've got carcinoid syndrome coming up. We've got all the work going on in atumelnant. And then, of course, the molecules and programs that we talked about today.

And of course, in the Discovery Kitchen, we're always cooking up something new, and we're always thinking about what the programs are that are going to be behind that and maybe those are going to be the Tobi's told me, I probably had to do another one of these in the future. So maybe that will be for the next R&D day. But we really do think that, like I said at the beginning, we always had this idea that we could create a sustainable company that grew its own pipeline, that brought meaningful therapeutics to patients that really needed them, not just the next me-too things, but things that can meaningfully impact patients lives and maybe even change the practice of medicine.

And that's been -- that -- the continuing fruition of that vision has been incredibly gratifying to me. And I'm excited as we transition hopefully into a commercial company, we're transitioning into even a larger pipeline company. I'm excited to see that and see what this company becomes over the last part of this decade and beyond. And really, this is kind of sets up the stage for the future. We've done a lot of transitions at Crinetics. And you saw some of those in the time line slide that I showed you. And we're coming up on another big one. And I do foresee the things that aren't going to change. We've got the -- I think I'm -- like I said, I'm incredibly proud of the people who do the discovery work in our -- in our labs. We've grown an incredibly effective and knowledgeable development team in terms of both the way we design our clinical trials and the way we execute them. I think that was crystal clear in the PATHFNDR studies and the way that they came out, just a remarkable achievement.

So we've got R&D going really well. We're going to do very well as a commercial company. And we're well capitalized right now, and I look forward to having the revenue that we hope to generate to start funding -- funneling back into the company and funding the future. And I -- like early -- all of our IP stretches out to 2040 and beyond. So I think one of the real -- as a founder, one of the things that's probably the most exciting thing is the long-term plans -- when we were -- when we were small, the long-term plans we were making were like, what are we going to -- like how are you going to survive next quarter or next year? And now the long-term plans we're making are into the 2030s and beyond. And I'm super excited about that, and I hope -- I hope -- I hope I can convey that excitement to everybody here in the room and everybody at home.

That's where I'll leave it. Thank you all for coming here today. I am -- I will invite the other speakers up here to the stage so that we can answer your questions that we might have left for you.

Doug Tsao, H.C. Wainwright. I guess on the TSH antagonist program, obviously, one of the attractive attributes of the molecule is its ability to potentially address both graves disease as well as Ted. I'm just curious how you're thinking at this point in terms of the development program and the sort of maybe is one of those indications sort of prioritized over the other. And I know you sort of alluded and in conversations with Scott in the past, you sort of alluded to the potential value being the opportunity to prevent the development of Ted. And I'm just curious if you have thoughts in terms of the practicality of running a clinical development program that would be able to demonstrate that?

Thanks, Doug. Yes, I'll answer briefly, and then I'll turn it over to Rick, who I think spends a lot of time thinking about this. I don't really see them as 2 different indications. It's the same mechanism that's manifesting in different ways for Graves. And so I think by the right TSH antagonist is going to be able to treat both of those indications. So I don't really see them as 2 indications. But we're in the process, as we approach Phase 1, of course, we're always thinking about like what happens in Phase II, and I'll let Rick answer that.

Yes. I think you touched on it really well, Steve. I think if 12755 works as we expect, you see it's got a potential to be a really important new therapy for both all aspects of Graves disease. I think the first step for us is to really get this into the clinic and really establish efficacy in both of those and then take it from there. I think as you mentioned, it has potential to only treat hypothyroidism, but prevent incidents of thyroid eye disease, too. And we'll love to see that in the clinic.

Alex Thompson from Stifel. I guess another question on TSH. As you're thinking about what you're going to be dosing, how to think about the therapeutic next year, do you think you're going to need to drive patients to full hypothyroidism by blocking the receptor completely and the signaling there? Or is there going to be a sweet spot? How do you think about that in the context versus ablation therapy?

Thanks, Alex. That -- it's an insightful biological question. And it's one that we've considered, I think one of the difficulties in treating thyroid patients is the fluctuation in thyroid patients. And so you can imagine a world where it might be easier to block and replace, but we're thinking about that a lot. Rick, you can probably speak to that as well.

Yes. I think obviously, this is a new mechanism of action. And I think this certainly benefits of a titration approach and potentially, there could be upside of a block and replace. And I think that's something that we'll look to establish as we move into the clinic, and we really understand the treatment effect and how this mechanism works in patients. So I think it's something that will really define what's the optimal approach as we move into -- as we go through the clinic.

Joe Schwartz from Leerink Partners. So it doesn't seem like a lot of dose ranging work was done in teprotumumab development. They might have just selected a dose that was safe and well tolerated. How -- another question on your TSH program, Steve, since you talked about how the SST3 receptor distribution might be advantageous relative to vasopressin V2. How high of a concentration do you need to achieve in the kidney to have adequate target engagement there versus how do you think about the therapeutic index of inadvertently targeting SST3 extra-renally?

Yes. Thanks, Joe. That's a good question. I think about this, one of the things that's been interesting is -- one of the things I really like about the study that we did that showed how we got into the kidney is seeing the levels -- the concentrations that we were able to achieve in the kidney with kind of the doses that we were using. I will say that one of the things we're thinking about is in comparison to -- we use a lot of the work we've done on other somatostatin agonist to know how much we need to have on board. So we're thinking about that pretty actively. But I don't have a dose range or anything like that as a number that I'm looking for. But looking at the data we have and the data we expect to see in Phase I studies, I'm pretty sure we'll be able to cover that.

Now you think about what the on-target effects of SST3 activation in other parts of the body might be it's interesting to think about SST3 because it's found in the pituitary, it's found in the pancreas. But we don't have a lot of data that would suggest that there's going to be any deleterious on target effects that we've been able to manifest in any of our safety studies so far. But we are definitely keeping an eye on that, but I feel pretty good about that margin.

Max Skor with Morgan Stanley. So I have a question around the neuroendocrine neoplasia's SST2 expression through the different lines of treatment. And the potential for, let's say, a selection for resistant subclone if you are targeting SST2 and it's being internalized, just thinking about how it changes over time through the course of treatment?

David, I'll let you speak to that or Stacey, you guys are probably best.

So yes, that's a very good question. And I think what's being done currently with patients who receive PRRT is if you receive your PRRT, you respond, you go another year, you get another scan, you look like you're stable and then you grow later. The current approach is to get another data at scale before you determine whether you're going to be able to use PRRT again. Eventually, you run out of it, the repeated PRRT does have some effect, but not as durable and not as responsive as the first time around.

The possibility of selecting clones, I think, is a real issue. And as you get to the higher grade tumors, you will start thinking about getting FDG pets as well as getting Dotatate PET scans because the higher grade lesions may be selected whether it's from prior treatment or just naturally occurring, I don't think it's been established. But that is a legitimate concern.

On the other hand, you don't want to leave the possibility behind that you may well have an SST or responsive disease. And here, you've got a drug. So this Phase I trial, I think, is appropriately as broad as it can be. And ultimately, it might narrow down, and that's the subsequent cohorts in the expansion phase. But Stacey can comment about how they're going to move forward there.

Well, I think I described it when I presented, and I think the data will drive what tumors we enroll in kind of in this escalation phase, what kind of PK and efficacy, early antitumor effects we see. And then really, that will help us inform what exact tumor types to take into the expansion phase.

First, first of all, great presentation all of you. So that was very, very helpful. I guess as we -- first question is for Rick. So Rick, are you envisioning the clinical development to be in Graves patients who have been refractory to antithyroid medications? Or would you be just looking patients who are just naive coming in with Graves. Second one is, I think the regulatory path has been paved with the anti-Fc, anti-FcRns. I'm wondering if that's sort of the thought process for a future Phase III would be? Or would it be slightly different, and I know it's a little tough to ask. And then maybe a question for Tobi. Based on the modeling that you're doing, what assumptions are you making for these 3 programs that are in early stage, how far the cash could take you to sort of development, and then I'll pass the mic back to Megan.

So thank you -- that's a really great question. I think on your first question around uncontrolled ATDs, I think that -- as a clinical development option, that's a potential for us as maybe a first in-human proof-of-concept study as it enables a placebo-controlled trial, as you can see. I think as you sort of heard from the presentation, we see this as a really important new therapy potentially addressing standard of care for Graves disease. So ultimately, our hope is that we can bring this with many patients as we can -- and obviously, exactly what the late-stage development program looks like and obviously exactly how we proceed for the clinic. We're still evaluating.

I'm just trying to remember the second part of your question, the pivotal trials was it? Yes, that's really going to depend on obviously, exactly what we go after and how we're going to sequence things. But we're not envisaging focusing just on controls on ATDs at this point.

Yes. And thanks, Yas. we're in a very fortunate position in this business right now to have over $1.3 billion of cash. And the company has really demonstrated over its entire history to be very well disciplined on the allocation of that capital. And as we've said, we've guided that cash will take us into 2029. And that's what puts and takes. There's obviously things that happen in an earlier stage that are exciting developments, and there are setbacks as well. But we think that when you balance all those puts and takes, balance the future commercial potential of paltusotine, both in acromegaly and carcinoids. The investments we're making in our Phase III programs in carcinoid and CAH, in Cushing's disease, we feel like we're really well capitalized to get us through 2029.

Brian Skorney for Baird. Maybe sticking with the TSH program. I'm just wondering -- I was a little surprised to see I think you showed slides showing autoantibody reductions preclinically. I was just wondering what would be the mechanistic rationale for why TSHR antagonist would result in reduction of autoantibodies. And then on the ADPKD program, -- just the tachyphylaxis of SST2 agonist, I'm just wondering, is there a redundancy between 2 and 3? And if maybe SST2 can get down regulated if you operate [indiscernible] SST3?

Okay. So Rick, why don't you address the auto antibody question for TSH first?

Sure. Thank you for the question. I think -- I don't think we didn't show any data, I don't think, on reduction of thyroid stimulating auto antibodies. Obviously, clearly, that's not something we can directly expect with this kind of mechanism. But it's certainly going to be something that we're going to be monitoring in the clinic, especially as we think about -- as we move through, that's going to be one of the important endpoints or measurement look to see the effects on those circulating antibodies from this mechanism as we move forward.

Can we listen to your second question again?

[indiscernible] So I was just wondering if you could -- is there any concern you can see a similar effect that both tumor-related [indiscernible]?

Yes. So what we know so far in ADPKD and somewhat in PLD is that SST2 highly expressed and healthy wanes with progression of disease. SST3, highly expressed and healthy doesn't seem to wane with the progression of disease. And that's why we think an SST2-based agonist like some of the ones like some of the peptide agonists some of the depots kind of work early and then their efficacy wanes. But we don't foresee that with SST3. We -- we'll obviously watch it, but there's nothing from a receptor biology's perspective that we know right now that's going to -- that suggests that, that's going to be the case.

Tyler Van Buren from TD Cowen. A couple of questions. Maybe I'll start with Steve's favorite child, 9682. Can you talk about the starting dose that was approved by the FDA? Is it an abnormally low dose like we've seen with some of the novel bispecific platforms because it's a new technology? Or is it possible that it could be higher and closer to the therapeutic range?

And then the second question is related to the ADPKD program. So other than the advantage of being once-daily oral with no titration, how would you expect 10329 to compare to the miRNA 17 inhibitor by Regulus, now Novartis in terms of efficacy and safety?

So I'll start with the ADPKD question first. That data is so young. I want to see more data there before I can weigh in on what I expect there. I mean I'm intrigued by their data, but I want to see it play out over time. I want to see what their safety looks like over time. But -- Yes. So I don't think there's a comparison. There's honestly not a comparison to make there. I think we feel that SST3 is going to be beneficial period there.

To your question about the dose, I don't think we're going to talk about specific doses in the Phase I, but I'll let Stacey talk about this is a -- these are fairly prescribed ways that these starting doses get started. So I'll let in Phase I in oncology. So I'll let Stacey speak to that.

I would just comment that we have an FDA-cleared starting dose, and it has potential to be within the therapeutic range. But with most dose escalations in oncology, you start with lower doses and you escalate up really until that maximum tolerated dose. So the FDA does take a more conservative approach with wanting you to start with lower dose levels in patients.

Jon Wolleben with Citizens. A follow-up on 682. You showed a graphic about tumors with presentation of SST2. And I'm wondering, do you have a sense if there is a threshold necessary for effectiveness or if it's a binary present or not. And would that be kind of the best predictor of efficacy? Or is there anything else along grade or tissue targeting that could factor in as well?

Thanks, Jon. Yes. So I mean we sort of have a little bit of a slang in the lab. It's like if you can see it, you can treat it, -- but certainly, SST2 expression is that level of SST2 expression as much as you can get a quantitative versus a qualitative feel, I think, could be instructive for how the therapy might be effective in patients. But I don't think of it in a quantitative way. I do think from a clinical practice standpoint, it is -- it's a well-accepted method now. And I think we would feel very confident going to the patients with positive images from Dotatate scan. David, do you want to add any color to that?

Yes. I would say that the -- you're talking about the [indiscernible] score from the old the PRRT trials. Those were based on Octrea scans, which aren't done any longer. So in terms of the Dotatate scans or the PET CT scans, there is some suggestion that maybe higher SUV counts imply a better receptor density and more efficacy. But I don't think that has really been shown. The idea is that you have to -- we would have in this trial, a density greater than liver sort of like [indiscernible] and that way, you'll know that there's enough density there to get a response.

In the higher grades, where you may find some heterogeneity the issue is going to be to actually look at known lesions that are higher than liver and to compare those, whereas your point is well taken, that it might be the marker is actually the density of the response not studied.

Cory?

So you've obviously taken an extensive iterative approach to molecule design across the pipeline. Thinking about this as it relates to the options available for cytotoxic payloads for the NDC program. How did you specifically land on MMAE as a match for 9682. And is there any -- coming back to your water balloon analogy? Is there anything specific about MMAE that pairs well with either the NDC approach or specifically in SST2 expressing tumors? And I guess as a follow-up, can you walk us through the rationale of not including symptomatic carcinoid syndrome patients in those initial studies?

So I can answer the question about 9682 and the choice for MMAE. Like we were kind of saying earlier, this is our first NDC we wanted to use a targeting mechanism moiety we were very comfortable with. And we knew that MME -- as something that has been widely used in ADCs, we knew it was -- we knew what to look for from a safety standpoint, which I think was really important for us and specifically for this first molecule. And then in our in vitro program, we went and made sure that MMAE itself would be cytotoxic to the cells and tissues that we were -- tumor types that we were targeting. So that combo gave us confidence that this was the right thing to go for as a first NDC to make because it gave us -- we would be able to understand them targeting, we'd be able to understand the toxicity. And as the first NDC out of the gate, that seemed like a great choice to us.

Stacey, I'll let you talk to the inclusion of carcinoid.

Yes. So for our first in-human study, we decided to not include patients with carcinoid syndrome because we really wanted to get the cleanest profile that we can with 9682. As you know, carcinoid syndrome patients have a lot of complications. And we just -- we wanted to kind of make sure that we don't have that noise in the first-in-human trial. But we do anticipate that later -- in later studies enrolling patients that have carcinoid syndrome once we know the profile of 9682 in patients.

Catherine Novack from Jones. I have a question on the ADPKD program. When you mentioned polycystic liver disease, are these patients who have concurrent liver sets with ADPKD? Or is this a complete label expansion opportunity?

So the question is around PLD versus ADPKD. So a lot of patients who have PLD arise from having PKD. So we look -- I look at this as sort of a specific subset of ADPKD patients not entirely separate.

Thinking about other, I guess, ex renal manifestations of ADPKD I know that CNS manifestations are also common. And I know thinking about the locations of SST3 that may not have a direct impact, but do you think there could be any indirect benefit on -- such as aneurysms that occur?

That's a super fascinating question. So I think -- so the question is, is does the effect arise from the mutation? Or does the effect arise from the disease? That I honestly don't know the answer to and is probably worth looking -- it is worth looking into.

Another question at the back.

Brandon Frith with Wolfe Research on behalf of Andy Chen. In regard to the Graves and Ted opportunity, I believe you commented on being equal to or better than Tepezza. Does that confidence stem from primarily the mechanism? Or is there a quantitative piece of that in the clinical -- in the mouse models that you can point to that you think will translate well to in the clinic?

No. This comes from an understanding of the mechanism, right? So if you think of what happens in thyroid eye disease, right? So that cost that is an activation of TSH, which causes downstream activation of a TSH or IGF-1 or complex, right? So the underlying mechanism, the first thing that happens is activation of TSH, right? Everything after that comes after. In Graves, of course, having an antibody IGF-1 doesn't do anything for Graves, right? And so it is the -- mechanistically, it's the right thing for Ted. It's the right thing for Graves. And if we get it right, you should be able to prevent the development of Ted in the presence of Graves. So it is definitely about the mechanism.

[indiscernible], JPMorgan. Can you just talk about the anticipated time lines for IND submission in Phase I trials for CRN-12755?

Yes. So I think everything that we have guided to since our last call still is in place. We are driving towards IND, hopefully, by the end of the year. And as that gets closer, I'm sure we will give you a refined timing on that.

Anything else? Okay. No, going once, going twice. I will invite everybody to have a little bit of lunch out on the patio. Thank you all for coming and for your participation. This was very exciting for us. It was super glad to be here. And as always, feel free to stop and ask us any other questions, especially ones about nerdy science. Happy to talk about that. All right. Thank you very much.