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And the call will begin shortly. Please press star followed by one on your telephone keypad. If you change your mind, please press star followed by two. Thank you. At this time, all participants are in listen-only mode. Following the management's prepared remarks, we will hold a question and answer session. If you change your mind, please press star followed by two. 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 first 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. 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 Pharmaceuticals, Inc. website. In addition, a press release was issued earlier today and is also available on the corporate website. As a reminder, we will be making forward-looking statements, and I invite you to learn more about the risks and uncertainties associated with these statements as disclosed in our SEC filings. Such forward-looking statements are not a guarantee of performance and the company's actual results could differ materially from those stated or implied in such statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release, the company's other news releases, and Crinetics Pharmaceuticals, Inc.'s 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 the date of this live broadcast, 05/08/2025. Crinetics Pharmaceuticals, Inc. 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 good afternoon to everyone joining today's call. We are pleased to share our first quarter results and highlight the great progress we are making towards our mission of transforming the lives of patients with serious endocrine and endocrine-adjacent diseases. Turning to slide three, Crinetics Pharmaceuticals, Inc. has never been stronger, and I want to emphasize that. We are strategically positioned for long-term sustainable growth. Our immediate focus is on the anticipated commercial launch of our first product this year. This is a pivotal milestone for the company. We believe paltusotine has the potential to deliver meaningful improvements for people living with acromegaly. Backed by an experienced team deeply embedded in the community and driven by a strong commitment to patients and science, we are well on our way to becoming a fully integrated, global commercial organization. We are advancing a robust pipeline in parallel, including two late-stage candidates, one recently clearing IND, and three additional candidates in preclinical studies. With $1.3 billion on the balance sheet, we are able to continue to invest in our pipeline, support prospective launches, and thoughtfully pursue opportunities to enhance value across our portfolio. We have never been stronger. I'd like to take a moment to welcome Toby Schilke, who you'll be hearing from towards the end of today's call. Toby recently joined as Chief Financial Officer, and he brings over twenty-five years of global experience with a proven track record of guiding companies through the transition from R&D-focused ventures into fully integrated commercial organizations. Toby's extensive financial and operational experience will be invaluable as we accelerate our growth trajectory and position Crinetics Pharmaceuticals, Inc. for long-term success. I also wanted to reassure you that regulatory engagement with the FDA on the paltusotine NDA for acromegaly as well as our other clinical development activities have been proceeding on track. We are grateful for the ongoing professionalism and commitment of the staff at the FDA with whom we interact. We remain proactive in monitoring the evolving regulatory environment and maintain active dialogue with key stakeholders both in the administration and on Capitol Hill. As you'll hear from Isabel, we are laser-focused on preparing for the launch of paltusotine in September. This would be our first product approval and a defining milestone for our ambition to become a fully integrated pharmaceutical company. On today's call, we'll walk through some of the launch initiatives we are executing and reflect on the progress the team has made to date. Turning to SMLNIM, we remain very encouraged by its potential to establish an uncompromising treatment goal for people living with congenital adrenal hyperplasia. We are moving forward to the phase three study for adults with CAH, that Dana will describe in some detail. At a high level, this study is designed to redefine the standard of care as the achievement of normal adrenal androgen levels with only physiologic levels of glucocorticoid replacement. We believe that tamelanet should be used to treat the disease and glucocorticoid should only be used for physiologic replacement, not treatment. With that, I'll hand the call over to Isabel to update our acromegaly launch preparations. Isabel?

Thanks, Scott. As described on slide four, our mission with participants is to provide the next generation of care for people living with acromegaly. While we have a long-term global vision, and we are building out our infrastructure to support commercialization of our whole pipeline, we are currently focused on executing on the anticipated US launch. We are making significant progress in building our infrastructure, educating and driving awareness among healthcare professionals and patients, and engaging with payers. We also have strong, long-standing patient advocacy partnerships in place as we continue to engage with the broader acromegaly community. On the healthcare professional side, we have held advisory boards with nurses and endocrinologists, and they have provided positive feedback on the potential value proposition of paltusotine in both biochemical control of IGF-one and symptom control. We are working on the final Salesforce mapping, and we expect to have approximately 30 reps in place over the summer. We will cover healthcare professionals in pituitary treatment centers, academic centers of excellence, and in community endocrinology practices. We are making powerful strides in advancing awareness and visibility for paltusotine and our broader pipeline at conferences attended by academic endocrinologists, like Endo, and by community endocrinologists, like ACE. We will share exciting new scientific data that reinforce the long-term value of paltusotine and the need for innovation in acromegaly treatment. Notably, we'll present data from our four-year acrobat open-label extension for OLE study, demonstrating that patients on paltusotine maintain biochemical control in IGF-one over a ninety-six-week period. Equally important, eighty-seven percent of patients prefer paltusotine over prior injectable SRL therapy, highlighting the patient-centric benefits of our once-daily oral treatment. We will also share real-world evidence that current SRL therapies are associated with persistent breakthrough symptoms and low compliance and adherence. Patients experience symptom exacerbations more than one-third of days each month, and those days are not always concentrated in the week leading up to the next injection. Data from Pathfinder one demonstrate that patients treated with paltusotine experienced decreased symptoms exacerbation rate over time. Additionally, based on real-world data compiled over a four-year period, eighty percent of patients with acromegaly who are newly treated either discontinue or switch from their initial treatment within their first year. This data highlights paltusotine's scientific and clinical relevance in an area of significant unmet need to improve the lives of patients living with acromegaly. In slide five, education and awareness are critical elements of our plan to reach patients as part of our activate, adopt, access, adhere, launch strategy. We are focused on elevating awareness of the burden of disease experienced by patients, even those currently being treated. Our insights consistently show that while patients might achieve biochemical control, they often continue to experience persistent symptoms that impact quality of life. Our educational initiatives are designed to address both aspects of disease control to ensure patients are better informed, more empowered, and fully activated to advocate for treatment that addresses the unmet need of the current standard of care. We recently launched our CrinetiCare patient support service platform to act as a partner to patients on their treatment journey from the very beginning. We opened our hub before the approval because the acromegaly community faces significant unmet need in patient support. CrinetiCare connects patients with nurses to discuss their symptoms and offers interactive tools to help them locate experienced healthcare providers. The CrinetiCare platform will serve as a continuous connection between us and the patients we serve. Once paltusotine is approved, CrinetiCare will provide a white-glove experience for patients from the time they receive a prescription to initiation of therapy all the way to long-term maintenance. We also recently revealed our unbranded disease state education campaign. This campaign leverages our learnings from our ongoing engagement with healthcare professionals, patients, and acromegaly community partners to amplify patients' voices and provide educational materials. Turning to slide six, we continue our preapproval conversations with payers and we are encouraged by their feedback. In particular, we anticipate that prioritization for paltusotine will reflect the label, which will help us drive the success of reimbursement. Paltusotine's value proposition is resonating with payers because their main need with injectable SRL long titration times, incorrect injections, and inconsistent symptom control collectively result in higher cost overall. First, patients starting on SRLs typically have their dose titrated every three months. With three different dose strengths available, it might take patients up to nine months to get to the right dose where the disease is under control. Payers bear the cost of treatment for many months before the patient sees the benefit. In contrast, daily dosing of paltusotine will allow titration to the optimal levels within weeks if titration is needed. Second, SRLs are not always correctly delivered, which can lead to higher costs to manage the resulting symptoms and side effects. For context, SRL injections are given with a large 18, 19-gauge needle. The injections are unpleasant to receive and challenging to give. A research study conducted at MD Anderson, one of the leading centers, found that half of long-acting octreotide injections administered by experienced nurses were not injected into the intramuscular space. The depot of octreotide instead persisted in the subcutaneous layer where it formed nodules that sometimes became granulomas. It is important to note that if the drug is not administered properly, it might not achieve its intended effects. In addition, payers understand that injectable SRLs often do not provide adequate disease control for the duration of an injection cycle. According to our real-world data analysis, one-third of acromegaly patients on injectable SRLs receive more than the thirteen injections per year expected based on an approved dosing, which is every four weeks. Consequently, this increases costs substantially for payers. Furthermore, uncontrolled acromegaly is associated with comorbidities and additional procedures, which are costly for payers and very burdensome for patients. Lastly, paltusotine's once-daily oral dosing offers an opportunity to improve patient adherence for more consistent control. In sum, there remains a significant unmet need for safe, highly efficacious, easy-to-administer treatments that offer daily control. The economic and clinical value that an option like paltusotine could provide to all the stakeholders is clear. These and other market insights continue to highlight meaningful unmet need in acromegaly and strong enthusiasm for paltusotine. During early launch, we anticipate major uptake as we educate both healthcare providers and patient communities. As with any new therapy, we expect coverage to be progressive and we will work through the formulary review process with payers over the first six to nine months. Our team is highly prepared and confident in navigating these initial steps to unlock the full opportunity of paltusotine. As the value proposition continues to resonate with patients, healthcare professionals, and payers, we are optimistic that over time, paltusotine could become the new standard of care in acromegaly. And now Dana will share regulatory updates and additional detail on our CAH late-stage development strategy. Dana?

Thank you, Isabel. Starting with paltusotine, we continue to make progress in both the US and EU where our regulatory reviews remain on track. We have not experienced any disruptions with our interactions with the FDA and continue to expect a decision by September 2025. As previously mentioned, we do not anticipate an advisory committee meeting as part of the NDA review. The European Medicines Agency has validated our MAA submission and granted orphan drug designation. We believe the orphan drug designation highlights the unmet need in acromegaly and the potential benefit that paltusotine can offer patients compared to existing therapies. Our team continues to work with regulatory authorities in the US and EU on all aspects of the review process. In preparation for launch, our growing medical affairs team has been connecting with the endocrinologist community. Our experienced endocrinologists at Crinetics Pharmaceuticals, Inc. have been making warm introductions for our medical science liaisons to all the top KOLs. We've hosted roundtable discussions to deepen our understanding of the patient journey and gaps in treatment. As Isabel highlighted, we have submitted multiple abstracts to upcoming endocrinology meetings that showcase paltusotine's differentiation. Moving to carcinoid syndrome, we expect to initiate the CareFinder phase three trial in the second half of 2025. Turning to adomelnet on Slide seven, we added a fourth cohort to our Phase II study due to the significant amount of enthusiasm and interest from sites and investigators. Cohort four is just one part of our larger development plan for adomelnet and CAH. It is an exploratory analysis in a small group of six to twelve patients to evaluate eighty milligrams with morning dosing as opposed to evening dosing in the prior cohorts and to allow for glucocorticoid reduction. As previously shared, we are also conducting an open-label extension study which will provide real-world insights into adomelnet's efficacy and safety over the long term. Investigators will have the opportunity to titrate both the dose of adomelnet and the dose of GCs as they see fit. Study participants from the phase two study are given the opportunity to enroll in the OLE. This study is ongoing and will eventually also include patients who complete phase three. Turning to slide eight, our phase three study for adomelnet in adult CAH patients builds on the strong top-line results we shared from cohorts one through three of the Phase II study. It is designed to provide a potential new therapeutic paradigm for patients. As Scott mentioned, there is a significant need for new treatments in CAH that not only allow patients to lower their GC dose to physiologic levels but also to control their androgens, which account for many of the signs and symptoms of the underlying disease. With this in mind, we are pursuing a novel primary endpoint that combines both goals: the proportion of participants with A4 levels less than or equal to the upper limit of normal, and who are on physiologic doses of GC replacement at week thirty-two. Patients should not have to sacrifice one or the other in treating CAH. In this study, we will enroll 150 participants who will be treated for thirty-two weeks. We will offer investigators two periods of time over which they can reduce GCs with four assessment visits in each period. Investigators are given additional flexibility for physician-guided reductions. We designed this individualized approach in response to feedback we received from investigators who prefer to use their discretion in titrating GCs as they would in a real-world scenario with the goal of reaching physiologic doses. Based on the early and profound decrease in A4C without adomelnet treatment in the Phase II study, we are measuring A4 at just two weeks after the study initiation and allowing investigators to assess glucocorticoid reduction immediately thereafter. Midway through the study, participants will be on stable GC doses for several weeks so their A4 can be measured. Investigators will then have the option to titrate patients up to a hundred and twenty milligram dose of adomelnet if the patient needs more A4 control. Otherwise, participants will continue on eighty milligrams. The key secondary and other endpoints are designed to demonstrate potential benefits beyond what has been achieved with existing standard of care for CAH patients. In addition to reductions in key disease biomarkers, such as A4 and seventeen OHP and other androgens, we will study improvement in the clinical signs and symptoms of CAH including, but not limited to, restoration of menses, testicular adrenal rest tumors or TARTs, and adrenal size. Our primary endpoint will use morning androgen measurement post-GC dosing consistent with the previous regulatory precedent. However, in our secondary endpoint, measuring these hormone levels pre-GC dosing is a rigorous test of efficacy because the androgen levels can be influenced by morning GC administration. Consistent with our patient-centric approach to drug development, we will include a novel disease-specific patient-reported outcomes tool as part of the study design. The last piece of our CAH development program is the combined phase two-three study in pediatric patients. We are finalizing our specific plans for integrating each age group into the registrational study, and we have already received helpful feedback from FDA and European authorities on our proposed study design. In summary, as illustrated on Slide nine, we believe adomelnet has the potential to establish uncompromising treatment goals for people living with CAH by addressing both elevated androgens and reducing the need for supraphysiologic glucocorticoid dosing, which could lead to negative side effects for patients. We believe glucocorticoids should ideally only be used to provide physiologic replacement, not to treat the underlying disease. Our phase three trial aims to provide a tailored approach to treatment for individual patients, enroll a broad patient population inclusive of patients who could benefit from GC normalization, androgen normalization, or both, and measure clinical outcomes that are paramount to both HCPs and patients. Our vision is to lower the burden of disease overall and provide a new standard of care for the seventeen thousand plus people living with CAH. Moving to slide ten, we are making steady progress on the rest of our pipeline and we are pleased to announce 9,682, the first candidate from our nonpeptide drug conjugate or NDC platform. Nine six eight two is being studied for SST2 positive tumors including neuroendocrine tumors or NETs, to complement our carcinoid syndrome indication with paltusotine. Additionally, our discovery team continues to identify new ways to leverage the NDC platform for novel targets to address unmet needs in endocrine oncology. As mentioned in our press release, IND enabling studies for the TSA antagonist are continuing as expected. Also, we continue to progress our SST3 agonist candidate. Based on emerging data from IND enabling studies, our PTH antagonist candidate preclinical development has been substituted with another candidate expected to exhibit an improved profile. This new candidate is in IND enabling studies which we intend to complete next year. This decision is reflective of the rigorous process we followed with paltusotine and adomelnet and that we applied to all our pipeline programs. We look forward to highlighting our early-stage pipeline in more detail at our upcoming R&D Day on June 26. Of note, we will cover NETs and beyond with nine six eight two for SST2 expressing tumors and paltusotine for carcinoid syndrome. We will also present our TSH antagonist for Graves' thyroid eye disease, and our SST3 agonist for ADPKD. These programs represent the next generation of Crinetics Pharmaceuticals, Inc. innovation and have the potential to positively impact the lives of patients and their caregivers across multiple communities. With that, Toby will now provide the financial update.

Thank you, Dana. Turning to Slide eleven, I am pleased to be participating in my first earnings call at Crinetics Pharmaceuticals, Inc. It is a privilege to join a team with a patient-centric mission and leading-edge science. We are poised for growth, and, importantly, well-capitalized to execute on our ambition. Now I will present the financial results for the first quarter of 2025. I will not read aloud the full results as they are available in our press release and on our Form 10-Q filing. Beginning with our income statement, we recognized $400,000 of revenue during the first quarter of 2025 compared to $600,000 during the same period in 2024. As a reminder, this revenue is non-cash and is based on amortization of payments we received in connection with our paltusotine licensing arrangement with our Japanese partner, SKK. Our research and development expenses in the first quarter of 2025 were $76.2 million, a 43% increase compared to the same period in 2024. Excluding depreciation, amortization, and stock-based compensation, R&D expense was $64.4 million. The increase in R&D expenses was primarily due to additional personnel, increased manufacturing costs, and higher outside services costs to advance our clinical programs and expand our preclinical portfolio. We expect quarterly R&D spend to increase sequentially through the remainder of the year, primarily driven by Phase III clinical trials for paltusotine and adomelnet. Our selling, general, and administrative expenses for the first quarter of 2025 were $35.5 million, a 71% increase compared to the same period in 2024. Excluding depreciation, amortization, and stock-based compensation, SG&A expense was $26.2 million. The increase in SG&A expense was primarily driven by growth to support our ongoing programs and the planned commercial launch of paltusotine. We expect quarterly SG&A investment to increase sequentially through the remainder of the year as we continue to build our commercial infrastructure and prepare for the anticipated launch of paltusotine. Our cash used in operations for the three months ending 03/31/2025 was $88.5 million compared to $52.9 million for the same period in 2024. For 2025, we continue to anticipate our cash used in operations to be between $340 and $380 million. This compares to $226 million in cash used in operations in 2024. Approximately 60% of the increase relative to 2024 is due to R&D investments, with the balance due to SG&A. Turning to slide twelve, we ended the first quarter of 2025 on strong financial footing with approximately $1.3 billion in cash, cash equivalents, and investments, which we continue to expect to fund our operations into 2029. As a reminder, we could potentially receive up to $250 million if Lilly exercises its option to acquire Radionetics. Crinetics Pharmaceuticals, Inc. has always been disciplined with capital allocation, and we continue to take a prudent approach to execute on the compelling opportunities ahead of us. We believe our strong balance sheet positions us to deliver on our near-term milestones, including the anticipated approval and launch of paltusotine, and advance our deep enriched pipeline in parallel. I'll now turn it over to Scott for closing remarks. Scott?

Thank you, Toby. Moving on to slide thirteen, at Crinetics Pharmaceuticals, Inc., our core mission is to improve patients' lives and transform the treatment paradigm in areas of serious unmet need like acromegaly. For over ten years, we have partnered with patients for their direct input on our discovery efforts, clinical designs, and patient resources. We design our therapies to allow patients to live their best lives instead of letting their disease define them. With our strong pipeline of late and early-stage candidates, and the support of our robust balance sheet, we are well-positioned to deliver on our clinical, regulatory, and commercial priorities in 2025 and beyond. With that, I'll hand the call back to the operator to begin the Q&A. Please limit yourselves to one question each in the interest of time. Operator?

Thank you, Scott. When preparing to ask your question, please ensure your device is unmuted locally. The first question comes from Yasmeen Rahimi with Piper Sandler. Your line is open. Please go ahead.

Good afternoon, team. Thank you so much for all the great updates. Two quick questions. The first question is, could you talk about the powering of your very innovative primary endpoint, which is a composite primary? And then a short question for cohort four, have you been able to collect any data from that cohort yet? And I'll jump back in the queue. Thank you again.

Thanks, Yasmeen. I'll hand that over to Dana to answer.

Well, hi, Yasmeen. So with regard to powering of the study, it is, I would say, very highly powered to detect statistically significant differences between the treatment arm and the placebo arm across a range of potential deltas between groups. And I think that adomelnet is well situated to achieve this endpoint that Dana discussed earlier, showing both normalization of A4 and physiologic dosing of glucocorticoid. With regard to cohort four, this is enrolling, and I can't speak yet to the timing of data. I think what we would do, of course, is show new data at scientific meetings. But the timing of that, I can't comment on quite yet. One other lexicon thing I'd like to mention is the kind of primary endpoint we're talking about. I think it's better described as a composite endpoint rather than a co-primary endpoint. There are two components to the endpoint. A co-primary, though, is something else where you kind of have to each component has to statistically stand by itself. Whereas a composite is basically a responder analysis where a responder is defined as having both normal glucocorticoid doses and normal A4 levels.

Our next question comes from Jessica Fye with JPMorgan. Your line is open. Please go ahead.

Hey, guys. Good afternoon. Is the Calm CAH design fully signed off on by FDA as a trial that could support registration? And what indication statement would you hope to secure assuming the trial is successful? Do you think you'd need one or two trials to get approved for CAH? Thank you.

Jess, I'll let Dana answer that one.

Yeah, sure, Jess. Thanks for the question. The protocol was put together based upon input from FDA as well as other health authorities, and they are aware of the final study design. I think that, you know, the other parts of your question are about the indication statement. It's hard to say right now an indication, but I think what and the data, of course, will define what we can talk with the agency about. But, you know, the basic difference that we have is what we are trying to develop here is a drug that will treat the disease, the CAH, right, and will only need glucocorticoids for prevention of adrenal insufficiency. Right? So you look at the chronicity indication, it's as an adjunct to glucocorticoids, for the control of androgens. And so that implies that glucocorticoids are necessary to control the androgens. In our situation, based upon our phase two data, it's the adomelnet that's really going to drive the reduction in androgens. And therefore, you don't need glucocorticoids to treat that part of the disease. And as I mentioned, you know, when we did the call, we really only expect that the glucocorticoids will be used for, you know, physiologic replacement. So we expect that that could, you know, result in a slight difference in how the indication is, you know, granted.

Our next question comes from Gavin Clark-Gartner with Evercore ISI. Your line is open. Please go ahead.

Hey, guys. Thanks for the update. First, just on the primary endpoint for the Phase III, what's the rationale to test the endpoint at a single point in time at thirty-two weeks as opposed to averaging across multiple time points? Is there any risk that A4 variability may lead to some non-responders who maybe shouldn't be non-responders?

Thanks for the question, Gavin. I think, generally, responder analyses are conducted at single points in time rather than averages. There is always variability with biochemical markers. A4, I think, of all the choices in this disease state, is one of the least variable. And again, there's a lot of confidence that this compound can achieve both components of the composite primary endpoint. And, therefore, the odds that variability might explain, you know, one of these endpoints hitting it once in a while on an occasional patient. But hitting both is quite, I think, specific. And I would anticipate, you know, pretty strong results that are clearly delineated from placebo.

Our next question comes from Tyler Van Buren with TD Securities. Your line is open. Please go ahead.

Hi. This is Frances on for Tyler. So just one question about the A4 attenuation cohort. So what is the rationale for looking at the morning dosing versus the evening dosing?

Yeah. Thanks for the question. This is Scott. I think for many of us, you know, it'd be more convenient to perhaps take the drug in the morning rather than in the evening. We just wanted to explore that to provide future optionality for patients. And maybe just to clarify a little bit, a reminder that there's a strong diurnal rhythm in this axis, including in the CAH patients. And so you just want to be sure that the timing of the drug in respect to the diurnal rhythm doesn't have a significant effect.

Our next question comes from Cory Jubinville with LifeSci Capital. Your line is open. Please go ahead.

Good afternoon. Thanks for taking our questions. So, you know, you folks have recently received acceptance for your application for paltusotine in Europe. Curious how you're thinking about launch strategy in these different geographies. You know, you previously discussed patient concentration in the US is largely at these pituitary centers of excellence. Is patient concentration similar to those in Europe and Latin America, and what, if any, are some of the material differences in the way that acromegaly patients might be treated in those geographies that might be important to consider for a launch?

Yeah. That's a great question, Cory. So yeah. I was gonna hand that off to Isabel who's on the line here. Go ahead, Isabel.

Sure, Cory. Hi, Cory. Yes. So we are very excited to have the filing approved, and we are preparing for the launch in Germany where also there is a significant unmet need for patients with acromegaly. So to your question, the European market tends to be more concentrated in terms of even more patients are part of the centers of excellence. There is a little bit more of a community in Germany than the rest of the market, but it's still, you know, a ratio of about seventy to thirty percent, seventy percent of key centers. We continue to research to confirm that. And so highly concentrated. We are working extensively on our market access strategy and in our discussions with TBA and the different markets. And we are gonna be very progressive and very thoughtful about how we continue to expand there. So right now, we have a footprint in

Our next question comes from Jonathan Wolleben with Citizens. Your line is open. Please go ahead.

Hi. This is Catherine on for Jonathan. I had a quick question about the 9,682 program and the phase one-two trial. It's about to, I guess, begin soon. Any details you could share on the trial design and kind of what you want to learn? And, also, any particular safety kind of issues that you're gonna be looking out for in this trial. Thank you.

Yeah. This is Dana, and, you know, we look forward to sharing a little bit more about this at the R&D Day that we're going to have in June. And so that'll be sort of, you know, front and center, you know, for those discussions. But our general approach is that it's going to be a fairly standard, you know, dose escalation design protocol for oncology. And, obviously, you know, when you're treating patients as opposed to healthy volunteers in your phase one, you have additional safeguards and, you know, sort of parameters that you're looking at, particularly around safety. But, you know, we'll be very excited to share more details on that later.

Our next question comes from Alex Thompson with Stifel. Your line is open. Please go ahead.

Great. Thanks for taking our question. Another on the CAH Phase III. Just wondering if you could talk a little about your design here in the context of glucocorticoid reduction and investigator discretion. Are there any overall guidelines for how to do this? Or how confident are you that you're not gonna see a significant amount of variability here in the study? Thanks.

Well, I think part of the sort of overall sort of mindset that we were trying to convey in the trial conduct here was that we wanted it to be as similar as possible to the real world in what, you know, investigators would want to do in terms of reducing glucocorticoids. Obviously, patients can come in with quite a range, and some may have quite a lot of differences in what their, you know, glucocorticoid level is. Very, very high levels. And so what we wanted to do was allow enough time in the first part and the second part of the trial so that that can be done judiciously and carefully with, you know, the investigator deciding what increments they want to use in, you know, decreasing that. We have some general guidances that we put in the protocol about, you know, what the limits on those increments should be. But in general, we'd like to leave it up to the, you know, the PIs to decide what's best for their patients that are in the trial.

Our next question comes from Maxwell Skor with Morgan Stanley. Your line is open. Please go ahead.

Great. Thank you for taking my question. I was just wondering, I recognize you're not interacting directly with CBER for paltusotine, but I was wondering if you'd comment on the evolving regulatory environment overall and how you're thinking about any potential implications for the rare disease space. Thank you.

Yes. You know, as you know, we're working with the CDER part of the FDA. And so far, we really haven't seen much of a difference in terms of how things are progressing. And across all of the programs, not just with paltusotine. So it's, you know, right now, it seems like regular order for the way that, you know, FDA is working, particularly with programs like ours. And most of our programs are rare disease programs. So, you know, we don't really see, you know, any differences at this point.

Our next question comes from Joseph Schwartz with Leerink Partners. Your line is open. Please go ahead.

Hey, all. This is Will on for Joseph. Thanks for taking our question. Congrats on the progress this quarter. One on paltusotine. Now that we're getting closer to the eventual commercial launch, could you provide any preliminary comments on how you might be thinking about pricing? And then with the recent MFN pricing headlines, does this change your thinking around the general strategy at all? And finally, can you just remind us of where the drug is manufactured? Thanks so much.

So I'll answer the manufacturing and then leave it to Isabel to not answer your question on pricing directly. But, you know, give you some thoughts about how we're thinking. In terms of manufacturing, the final tablets are made here in the US. And packaging here in the US. Although we get precursors and final API from Europe and, originally in India. So that answers that part. But maybe, Isabel, can you talk just a little bit about the value we're hoping to deliver?

Yes, of course. As I mentioned before, the value proposition of paltusotine is resonating really well with payers, you know. Fast onset of action, durable effect, easy to use, one daily dosage for patients. And also, the fact that they don't have to deal with the breakthrough symptoms and the wastes currently associated with injectables. At this time, we're not commenting on price. Of course, it's something that we're looking at very closely with conducting market research, advisory boards with payers, and as I mentioned, what is very positive for us is that the value proposition is resonating very well and we are tracking on that. We don't see at this point, to answer your second question, any impact in our strategy based on the recent dynamics, but, of course, we're closely monitoring that with our government affairs group as well. And we'll continue to do so. Considering that about 40% of the population is in Medicare and Medicaid, 30% Medicare, 10% Medicaid, and we want to continue to monitor the potential impact in the future. But for now, there are no changes.

Our next question is from Dennis Ding with Jefferies. Your line is open. Please go ahead.

Hi. This is Anthea on for Dennis. Thank you for taking our questions. On CAH, the long-term extension, can you give an update on enrollment and follow-up there? And what is the critical mass that you need to give another update to investors? Thank you.

Well, enrollment is proceeding and we will, of course, once we have a critical mass, we would present to the scientific meeting. I can't really comment on numbers and exact timing at this time. But, again, the OLE is another way for us to assess how the compound performs in sort of a more real-world setting, where the doctors have control over the dosing of the compound as well as over the dosing of the glucocorticoids. It's always very valuable data for us, and we look forward to reporting that when we can.

Our next question is from David Lebowitz with Citi. Your line is open. Please go ahead.

Thank you very much for taking my question. The new primary endpoint seems to be a higher bar. And I am curious. Do you reserve the ability to maintain all the same primary endpoint as Chronocort to potentially use if needed for FDA approval?

So I think you're right. It is a higher bar. We're asking the study to see if adomelnet can really be the treatment for CAH. And give patients an option so that they don't have to compromise on either glucocorticoid levels or the adrenal precursors that are being produced. And so it's intentionally a high bar, but I think it's designed specifically for adomelnet because that's the type of study that this drug deserves. And maybe I'll let Dana talk about the endpoint cascade.

Well, yeah. And I think, you know, just along the lines of what Scott was just saying, the patient population is also different from what Chronocort studied. In that we have a broader patient population. And as you recall in their study, basically, what they were looking at was trying to reduce GCs. And A4 was sort of a, you know, sort of a side issue. Had to be roughly where it started. Okay? Which could have been normal, could have been, you know, sort of above normal. And so what we'd like to do is be able to address the full population of patients who have CAH, may have high A4s and not so high GCs, high GCs, and normal A4, and high both. Right? And so in order to do that, you really can't have the same endpoint as Chronocort had. Okay? So now we also have a cascade, as I mentioned, and in the call, of secondary endpoints. And some of those are looking at certain aspects of how quickly we work and then, you know, sort of other combinations of particular, you know, sort of endpoints of interest. But we also will look in the same way that they did at, you know, somewhat, you know, similar, you know, endpoint for theirs too. But that's not what we, you know, intend to use for the FDA. And you can't, you know, so if we make the primary endpoint this broader endpoint, that's what it is required to have to get approved.

So we can't change the endpoint. And I think it's maybe important to remind all of us that we're building a study that measures a variety of different parameters of the impact of adomelnet on the lives of CAH patients. And it's that whole package that'll be the basis for guiding physicians about how this might be used should it be approved. And so we're interested in developing a broad profile, and that's the primary endpoint is one thing, and I know we'll all focus on that. But also getting to how much do we reduce the A4 levels or 17 OHP, which are a couple of our first secondary endpoints, because those lowering is important too even if you only get to, you know, slightly above the upper limit of normal. So the goal of the study is to capture all of this, provide the ability to guide physicians, and then eventually to use in our commercialization efforts. And we also intend to look closely at the other clinical endpoints and, you know, adrenal size as well.

Our next question comes from Brian Skorney with Baird. Your line is open. Please go ahead.

Good afternoon. Thanks for taking the question. Just also on the CAH study. In terms of enrollment criteria, how do you kind of compare exclusion inclusion criteria to the Chronocort study? Are there differences, and criteria around, GC dose, A4, 17 OHP to consider? And the pediatric plan, you have billed as a phase two-three. Is this just nomenclature? Is there a dose-finding portion for the PEEP study that proceeds full three enrollment?

Okay. Just to make sure that I understand, like, you asked about the entry criteria for our trial, right, first for the adult trial. And, you know, I think that, you know, as I mentioned before, what we're trying to do is capture a broader population than, you know, the previous trial, you know, from Chronocort. So now in terms of our, you know, pediatric, you know, program, we've also received, you know, feedback from, you know, health authorities on that. And we're going to try to achieve the same things that we're doing for the adult program, and we just need to make sure that we have the doses right for the right size kids. And so we'll be gradually working through that. But, you know, we don't plan to do it differently. And as you recall in, you know, the Chronocort trial, they didn't, they held it. The GC is constant. Right? In that one. So there was no GC reduction. So that's, you know, sort of one of the big differences.

Our next question comes from Douglas Tsao with H. C. Wainwright. Your line is open. Please go ahead.

Hi, good afternoon. Thanks for taking the questions. And, you know, welcome to Toby to the call. It's great to hear him on a recent call. But maybe just as a follow-up, on CAH and the pediatric study, I'm just curious how you think about that program moving forward. Do you anticipate sort of, you know, Dana, you referred to sort of needing to do some dose exploration. Would you anticipate needing potentially to do two studies there, or think there's an opportunity to do an adaptive design which would enable you to only run one study? And, you know, again, would you anticipate, you know, you just said that you anticipate sort of having the same goal as with the Calm CAH study. Does that imply that you would think about the same endpoint in terms of normalization A4 and physiologic GC, or is there some other potential sort of similar endpoint, but perhaps a slightly different one for targeted for the pediatric population? Thank you.

Well, I think, you know, to answer your first part of your question, and maybe Alan can comment on the, you know, sort of treatment objectives. As far as the first question, the way we've designed this study is to be sort of a seamless design. Right, as opposed to two separate trials. And so the way that it will work is the phase two part will guide the phase three part. And so we don't, you know, plan on doing separate trials on that. I think, you know, maybe if Alan could comment on, you know, the treatment objectives or the pediatrician's office.

Yeah. Second, the reason I'm really excited and very supportive of this endpoint that we're talking about, normal GCs and normal A4s, is because this really is the treatment goal for this disease. And by the way, it's the same for pediatric patients and adult patients. This is what you want to achieve in clinic. It's very hard to do that these days with available treatments. I really think adomelnet has a lot to offer here to achieve that two-part goal. So, yeah, I think it would be very similar in pediatric patients ultimately.

Our next question comes from Andy Chen with Wolfe Research. Your line is open. Please go ahead.

Hey. Thank you for taking the call. And back to your phase three trial design, so I understand that the speed of reduction is individualized. But is it mandatory reduction at each stage of GC reduction, or is it optional reduction for patients? If it's optional, does that make the primary endpoint very wonky and highly dependent on baseline characteristics of patients? Like, is that a worry here or no? Thank you.

Well, maybe just to, this is Scott. Just as a quick reminder, we may have patients in who have physiologic replacement but their A4 levels are already high. So they don't need a glucocorticoid reduction. So you have to account for that in the way you design the protocol. But maybe you want to explain a little bit more.

Right. It's a good point, Scott. And those who do come in on high glucocorticoid doses, I want to be clear that, yes, this is not optional. The protocol requires, particularly at certain predefined visits, glucocorticoid dose reductions. Of course, the investigator has to make the individualized dose based on toleration and safety. But these dose reductions are expected and would be very carefully monitored and followed. And I agree. It's important to reduce the doses of glucocorticoid in those who come in on high doses in order to achieve this endpoint and also to achieve the goal in clinic, which is the same. So yeah.

As a reminder, to ask a question, please press star followed by one. Our next question comes from Catherine Novack with Jones. Your line is open. Please go ahead.

Hi. Afternoon, everyone. I just wanted to ask one question about paltusotine. Based on Pathfinder two, we know you can go into treatment-naive patients, but do you anticipate any possible step-through requirements for payers based on price? How are you thinking about that? Thank you.

Thank you for the question. Well, as you know, we have Pathfinder two. I was looking at naive patients, also washout patients, and patients that have discontinued therapy. Our current discussions with payers don't anticipate any step therapy. And so far, the feedback is that they will really just hold us to the label in terms of prioritization, which in general is a very positive sign for us. And at this point, we don't anticipate that.

We currently have no further questions. So I'll now hand back to Scott Struthers for closing remarks.

Thank you, everybody, for being with us today, and maybe I'll just take a brief moment to also thank our colleagues at the FDA for their hard work on multiple different programs we're working on and keeping up the normal course of business, at least as far as we've seen. So thank you all, and have a great afternoon and weekend.