Crinetics Pharmaceuticals Inc Aktie

Good day, and welcome to the Vertex Pharmaceuticals conference call to announce the acquisition of Crinetics Pharmaceuticals.

[Operator Instructions]

Please note this event is being recorded. I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead.

Thanks, Chuck. Good afternoon, everyone, and thank you for joining us on short notice for this exciting announcement. I'm Susie Lisa, and as Senior Vice President of Investor Relations, it's my pleasure to welcome you to this conference call to discuss Vertex's acquisition of Crinetics Pharmaceuticals.

Making prepared remarks on today's call, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Duncan McKechnie, Chief Commercial Officer; and Charlie Wagner, Chief Operating and Financial Officer. We recommend that you access the webcast slides as you listen to this call. The call is being recorded, and a replay will be available on our website. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed medicines for cystic fibrosis, sickle cell disease, beta thalassemia and acute pain, the proposed acquisition of Crinetics and the expected benefits of the transaction.

The commercial potential of PALSONIFY and the clinical potential of Atumelnant and Crinetics' other pipeline assets, the expected timing of closing and associated financing and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial guidance we discussed this evening is presented on a non-GAAP basis. Please consult our forward-looking statement on Slide 2 and see our filings for more information.

I'll now turn the call over to Reshma.

Thank you, Susie, and good afternoon, everyone. We are excited to announce that we've entered into a definitive agreement to acquire Crinetics Pharmaceuticals for $85 per share in cash in a transaction with a total equity value of about $10 billion or $8.8 billion net of estimated cash acquired. Crinetics is an excellent strategic fit for Vertex with its focus on serious diseases in specialty markets with significant unmet need, well-understood causal human biology and potentially best-in-class medicines that could deliver transformative benefit to patients. Crinetics has 2 compelling derisked potential best-in-class specialty endocrine assets, PALSONIFY in the early days of its U.S. commercial launch and Atumelnant in pivotal development for congenital adrenal hyperplasia, or CAH, and in Phase II for Cushing's syndrome.

There are additional preclinical and clinical programs in the Crinetics pipeline that we won't highlight today, but we will discuss post closing. We believe that these assets have a combined peak sales potential of more than $5 billion. PALSONIFY is the first and only once-daily oral therapy for adults with acromegaly. PALSONIFY is already FDA approved and generating strong early momentum in the U.S. post an October 2025 launch. More recently, it was approved by the EMA. We see blockbuster potential for PALSONIFY. Atumelnant is a once-daily oral ACTH receptor antagonist currently in Phase III development for CAH. Atumelnant has additional potential in ACTH-dependent Cushing's syndrome, another rare endocrinology disease. It is currently in Phase II development for this indication. Across the indications for Atumelnant, we see multibillion-dollar potential.

Given the significant unmet medical need in acromegaly, CAH and Cushing's along with the best-in-class potential of both PALSONIFY and Atumelnant for the treatment of these conditions, we see the Crinetics acquisition accelerating Vertex's revenue growth and diversification as well as enhancing our long-term earnings profile. We are truly excited by what the Crinetics team has built in the endocrinology space over the last 18 years. Their world-class R&D capabilities are focused on their G-protein coupled receptor drug discovery platform and differentiated small molecules.

Crinetics has uniquely and successfully discovered and/or developed multiple small molecule drug candidates for rare endocrine diseases where the natural ligand is a peptide. This is a capital-efficient model, focused in rare endocrine conditions with high unmet need, where achievement of proof of concept benefits from evaluation of disease markers early in development and reaches patients via targeted SG&A footprint, all of which is strongly aligned with Vertex's strategy and our own strengths in development, regulatory and specialty commercialization.

As we've discussed previously, it's not only the assets, but the people and culture that factor heavily into our assessment of companies. It's no different in this instance. The Crinetics team focus is singular. Their science is rigorous. They are committed to world-class commercialization and their culture is dedicated to excellence and patients. We value deeply this alignment on these important dimensions and believe it will ensure our combined success going forward. We are excited to work with the talented Crinetics team to build on the momentum they've created and to bring these specialty endocrine medicines to more people faster.

On strategic fit, we have a high bar when we evaluate acquisition opportunities, applying a consistent set of criteria that you can see detailed here on Slide 5. Serious diseases with high unmet need, well-understood causal human biology, validated biomarkers that enable efficient clinical and regulatory pathways, specialty markets and first-in-class or potentially best-in-class medicines. Both PALSONIFY and Atumelnant meet every one of these criteria and check every one of these boxes. We believe Vertex's global infrastructure and commercial footprint will meaningfully amplify the reach of Crinetics science, and we are confident that we can accelerate the trajectory of both lead assets.

Let me walk you through these programs in more detail, starting with PALSONIFY in acromegaly. Acromegaly is a rare chronic hormonal disease caused by the overproduction of growth hormone, most commonly due to a benign pituitary tumor, which in turn stimulates excess insulin-like growth factor 1, or IGF-1, from the liver, which is responsible for most of the overgrowth symptoms that define acromegaly. An estimated 20,000 people in the United States are diagnosed with the disease and more than 35,000 people outside the U.S. It's a serious disease. If left untreated, patients with acromegaly face enlargement of the hands and feet, serious heart and metabolic consequences, reduced quality of life and shortened lifespan.

Surgery is a first line of treatment, but unfortunately, only 40% to 50% of people achieve durable remission and thus, the majority of patients require lifelong medical therapy. The current standard of care injectable somatostatin receptor ligands or SRLs are used to reduce production of growth hormone and IGF-1. However, current standard of care SRLs are viscous, require large gauge injectables that must be administered intramuscularly or via deep subcutaneous injection. They're inconvenient, often need to be administered by a health care professional and carry low patient compliance.

Outside of PALSONIFY, oral options have limited efficacy, challenging dosing logistics or are not indicated for treatment-naive patients. In short, there is significant unmet need to be addressed. This is where PALSONIFY comes in. PALSONIFY is an oral selective somatostatin receptor type 2 or SSTR2 non-peptide agonist. By binding to SSTR2 receptors, PALSONIFY suppresses growth hormone release, which in turn suppresses IGF-1 secretion. PALSONIFY offers multiple important features for patients, first and only once-daily oral therapy, simpler dosing logistics, fast-acting efficacy, a well-tolerated profile with low discontinuation rates and a broad label indicated for both SRL switch and treatment-naive patients.

The Phase III PALSONIFY data are compelling and detailed on Slide 8. PATHFNDR-1 on the left side of this slide enrolled patients switching from injectable SRLs. 83% of these "switch" patients treated with PALSONIFY maintained IGF-1 levels within the normal range compared to just 4% on placebo. Indeed, when you look further into the data, you'll see all but 1 patient in the PALSONIFY treated arm had IGF-1 levels that were lower than 1.1x the upper limit of normal. On the right-hand side of the slide is PATHFNDR-2, which enrolled treatment-naive patients as well as patients who stopped treatment for 4 months or more or patients who were washed out of treatment for at least 3 months. In this study, 56% of acromegaly treated naive patients achieved IGF-1 normalization compared to just 5% on placebo.

Both results were highly statistically significant with p-values of less than 0.0001. PALSONIFY was well tolerated with no serious adverse events and low discontinuation rates. Given the differentiated mechanism of action, benefit risk profile and significant patient dosing advantages as well as the broad label, we see blockbuster potential for PALSONIFY, which I'll now ask Duncan to highlight.

Thanks, Reshma. The left side of the chart details the unmet need and significant gaps in the current standard of care. At 3 years, less than 20% of patients remain on SRLs given the painful monthly injections with large gauge needles and end-of-dose symptom breakthrough. The right-hand side of the slide highlights the market research that indicates high target physician awareness and very positive perception for PALSONIFY. Physician awareness is building quickly. Market research conducted in quarter 1, 2026 shows approximately 80% unaided awareness amongst endocrinologists and approximately 70% indicated a high intention to prescribe.

Physicians perceive PALSONIFY as equivalent to injectable SRLs in IGF-1 reduction, symptom control, safety and best-in-class for speed of onset, duration of response, route of administration and dosing convenience. This physician awareness, the broad label in both switch and treatment-naive patients and the quality of the product profile are a compelling combination. In the context of the depth of unmet need in acromegaly, this has led to strong early launch dynamics for PALSONIFY.

Based on quarter 1, 2026 data, as previously disclosed on May 7, PALSONIFY generated $10.3 million in net product revenue with strong patient enrollment forms and good breadth of prescribers. Overall, in just its second quarter of launch, PALSONIFY achieved an impressive 40% to 50% share of new-to-brand prescriptions with broad uptake across both pituitary centers and community endocrinologists and across all patient segments, injectable SRL switch, treatment-naive, switch patients from other therapies and patients who have discontinued therapy entirely.

With respect to reimbursement, this market is 60% private pay and the remainder Medicare and Medicaid. The Crinetics team have made excellent progress securing reimbursement. Payer coverage currently stands at 60% through either formal coverage or medical exceptions. Crinetics have emphasized that they are on track to achieve 75% coverage by quarter 3 2026.

And on the next slide, let me double-click and give some more details on PALSONIFY. Overall, given the unique attributes PALSONIFY offers to physicians and patients, we believe it is positioned to become first-line therapy in a growing specialty disease area with a high unmet need. We see multiple target patient populations totaling 10,000 in the U.S., including patients on injectable SRLs or other therapies, those who are post surgery, actively managed by an endocrinologist who may now need treatment, those who have discontinued therapy and those patients who are new to treatment annually. While switch patients represent the majority of the patient opportunity, PALSONIFY has a uniquely broad label and is the only oral therapy with data and the label in treatment-naive patients.

Market research confirms that HCPs would start the majority of treatment-naive patients on PALSONIFY. We believe Vertex's experience in commercializing medicines for rare genetic diseases around the globe, combined with the extremely strong foundation Crinetics has built in endocrinology, positions PALSONIFY to become the standard of care in acromegaly, and our expectation is that PALSONIFY holds the promise to be a blockbuster medicine.

Back to you, Reshma.

Thanks, Duncan. Let me now turn to Atumelnant and congenital adrenal hyperplasia or CAH. Classic CAH is a rare chronic genetic disorder affecting about 17,000 people in the U.S. with an additional 15,000 or more outside the U.S. In about 95% of cases, it's caused by mutations in the CYP21A2 gene, resulting in a deficiency of adrenal enzyme 21 hydroxylase. That enzyme deficiency means people can't produce adequate cortisol. Low cortisol levels lead to increases in ACTH production, which in turn causes steroid precursor buildup. Ultimately, this leads to excess production of adrenal androgens.

To manage the disease at minimum, patients must take glucocorticoids for life. Glucocorticoids are administered to these patients to replace the missing cortisol and patients are often given high or super physiologic doses in order to suppress the androgen production. This creates a dual burden for patients. High androgen levels drive abnormal growth, early puberty, infertility and long-term physical and emotional consequences. High-dose glucocorticoids can cause heart disease, obesity, diabetes, bone loss and persistent quality of life issues. There has been limited therapeutic innovation in this field for the last 50-plus years. No currently approved medicine can both normalize androgens and allow people to be maintained on physiologic glucocorticoid doses.

A recent market entrant works upstream in the pituitary gland and has shown it can reduce glucocorticoid doses modestly, but it does not concurrently improve androgens with physiologic glucocorticoid dosing, leaving both the steroid burden and androgen excess incompletely addressed for many people. Atumelnant takes a fundamentally different approach. This is the key point. It's an ACTH receptor antagonist that acts directly at the adrenal cortex. By blocking ACTH signaling at the adrenal level, Atumelnant suppresses excess androgen production while concurrently enabling people to reduce their glucocorticoid doses to physiologic levels, the true goal of CAH management. In terms of program status, Atumelnant is currently enrolling its Phase III CALM-CAH study of 150 adults.

CALM-CAH is a 2:1 randomized placebo-controlled study with a primary endpoint of proportion of participants with A4, that's the androgen level at or below the upper limit of normal, while on physiologic glucocorticoid replacement therapy at week 32. To be clear, no other drug for CAH has ever evaluated this control of androgens and maintenance of physiologic GC replacement, glucocorticoid replacement as the primary endpoint. The study enrolled its first patient in December of last year and is currently enrolling and dosing patients. So 2 is a Phase II/III pediatric study in CAH. Atumelnant has also demonstrated therapeutic potential in ACTH-dependent Cushing's syndrome, where our Phase II trial has initiated.

I'll turn it back over to Duncan to recap the Phase II Atumelnant data in CAH, which is a major value driver and one of the primary reasons we are so excited about this acquisition.

Thanks, Reshma. As Reshma alluded to, the true goal of therapy in CAH is to normalize androgen levels and simultaneously enable patients to be managed with physiologic levels of glucocorticoids to replace their missing cortisol. Currently, this means seeking an almost impossible balance between androgen suppression and glucocorticoid treatment to avoid adrenal crisis while also preventing the metabolic and cardiovascular consequences of excess glucocorticoids. Essentially, physicians and their patients are currently forced to choose between androgen excess or supraphysiologic doses of glucocorticoids. As a result, there are 2 important points to share regarding the Phase II data from the Atumelnant TouCAHn study.

Firstly, the impact of Atumelnant on androgen levels; and secondly, the impact of Atumelnant on glucocorticoid dose. To that end, the Phase II Cohort 4 data demonstrated both rapid reduction in A4 and down titration to physiologic levels of glucocorticoids. Specifically, there was an unprecedented 67% reduction from baseline in mean A4 androgen levels even with tapering of glucocorticoid dosing. 87% of patients achieved physiologic glucocorticoid dosing while A4 reduction was maintained.

In summary, we believe Atumelnant achieves the previously unattainable holy grail of CAH management. It has the transformative potential to concurrently and durably normalize androgen levels while also allowing physiologic doses of glucocorticoids as well as being well tolerated and given through once-daily oral dosing. In addition, market research with target endocrinologists confirms high awareness of these impressive Phase II data and the top reason physicians select Atumelnant's profile in research is efficacy. Specifically, 75% of respondents cite the data on androstenedione and glucocorticoid reduction.

Physicians see Atumelnant as the future standard of care for people with classic CAH. We believe Atumelnant has multibillion-dollar potential in the CAH market alone and meaningful additional opportunity in Cushing's syndrome.

Before I turn it back over to Reshma to cover Cushing's, let me take one moment to step back and summarize the commercial opportunity. Going back to the strategic fit of the deal, these rare endocrine diseases are all managed by specialty endocrinologists that can be reached with a small commercial footprint. As an example, Crinetics currently serves the acromegaly market with a roughly 40-person field sales team. In total, there are approximately 8,000 endocrinologists in the U.S., and each of these diseases is managed by a subset of approximately 3,000 to 4,000 specialty endocrinologists, where we also see opportunity for synergy across these rare endocrine diseases.

I'll now turn the call back to Reshma to describe the additional opportunity for Atumelnant in Cushing's syndrome.

There are several additional areas of opportunity within the Crinetics pipeline, both clinically and preclinically. Tonight, I'll highlight just one, ACTH-dependent Cushing's syndrome or ADCS. ADCS is another serious rare endocrine disease with high unmet need affecting about 10,000 patients in the U.S. and about 50,000 patients outside the U.S. Surgery is first-line therapy, but many patients will require chronic medical management. Excess cortisol secretion from a benign pituitary adenoma accounts for 80% to 90% of ADCS, while another 10% to 20% comes from ectopic ACTH secretion. This prolonged excess cortisol can lead to high patient morbidity, including heart disease, obesity, diabetes and more. By directly blocking ACTH signaling, Atumelnant reduces cortisol production and thus holds transformative potential for this disease.

The data in Cushing's syndrome are impressive. The Phase I/II study of Atumelnant in patients with ADCS treated at 40 milligrams showed at day 10, a rapid lowering of urine-free cortisol, or UFC, with 3 of 6 patients having UFC within the normal range, while on physiologic doses of glucocorticoids. Data from the 80-milligram cohort also demonstrated rapid lowering of UFC with 5 of 6 patients or 83% achieving normalization of urine free cortisol on physiologic doses of glucocorticoids.

With regard to program status, the Phase II study has been initiated, and we are excited about taking this program into pivotal development and further. Post closing, we look forward to sharing more on the other Crinetics pipeline programs. For now, let me reiterate our excitement for the lead assets, PALSONIFY and Atumelnant, our admiration for the Crinetics team's deep scientific expertise in endocrinology, GPCR biology and their drug discovery platform as well as the culture they have built.

I'll now turn over the call to Charlie for highlights of the transaction and our outlook for the combined companies.

Thank you, Reshma. Vertex will acquire all outstanding shares of Crinetics common stock for $85 per share in cash. The total equity value is approximately $10 billion or $8.8 billion net of estimated cash acquired. To finance the transaction, Vertex expects to use a combination of cash on hand and debt, supported by $4.5 billion of fully committed bridge financing. The transaction is subject to customary closing conditions, including approval by Crinetics shareholders and receipt of regulatory approvals. We currently anticipate closing in the third quarter of 2026.

In terms of financial impact, this transaction is consistent with Vertex's capital allocation priorities, which remain focused on internal and external innovation in disease areas where we can deliver transformative benefit to people and sustainable value for shareholders. The financial case is straightforward and compelling. PALSONIFY is already generating revenue and building momentum with the potential to be a blockbuster drug in acromegaly. Atumelnant has the potential to be a multibillion-dollar opportunity in CAH with meaningful additional upside from the market opportunity in Cushing's syndrome.

At peak, these assets have the potential to deliver more than $5 billion in combined annual revenue. That revenue profile furthers Vertex's goal of sustained double-digit revenue growth and is expected to be margin accretive over time. Oral small molecules in specialty endocrinology markets carry attractive commercial profiles and Crinetics' capital-efficient development model is well aligned with Vertex's own approach to operating leverage. The transaction is expected to become accretive to non-GAAP operating income in 2029. On guidance, given the anticipated Q3 2026 closing, the impact to 2026 revenue and non-GAAP operating expenses is expected to be modest. We will provide updated 2026 guidance at the time of closing.

I'll take a minute now to frame what this acquisition means for Vertex's long-term growth story. Beginning in 2023, we've spoken about our goal of 5 launches in 5 years. With this transaction, not only do we reach that goal more than 2 years ahead of schedule, we're also adding a fifth pillar, endocrinology to our disease area and commercial framework alongside cystic fibrosis, heme, acute pain and our emerging renal area. Across each of those 5 areas, we have a uniquely attractive product portfolio and pipeline. In CF, ALYFTREK and TRIKAFTA continue to generate strong revenue with growth driven by approvals in younger patients, geographic expansion and patients living longer.

In heme, CASGEVY is approved for both sickle cell disease and transfusion-dependent beta thalassemia. And importantly, just last week, CASGEVY received supplemental approval in the U.S. for patients ages 2 years and older with either SCD or TDT. In acute pain, JOURNAVX is in year 2 of its launch and on track to triple prescriptions in 2026 versus 2025. Additional pain programs are in development. In renal, povetacicept is advancing rapidly in IgAN with a November 30 PDUFA date and is also in a Phase III study in primary membranous nephropathy and a Phase II study in myasthenia gravis. To this mix, we now add endocrinology as a fifth pillar with PALSONIFY already on the market and Atumelnant in pivotal development plus the Vertex internal endo assets of our type 1 diabetes programs.

We also see value in Crinetics' additional pipeline assets, and we'll discuss that post close. We believe this combination makes Vertex a stronger, more diversified company with a long runway of growth while staying true to the strategy that's driven our success. To reiterate the investment thesis behind the acquisition, Crinetics is an excellent strategic fit for Vertex. Both PALSONIFY and Atumelnant meet every element of our strategic acquisition criteria, serious diseases with high unmet need, well-understood causal biology, validated biomarkers, specialty markets and best-in-class potential. Together, these assets add more than $5 billion in combined peak sales potential, and they do so in a disease area, specialty endocrinology, where Crinetics has built deep, durable expertise and exactly fits our commercialization framework. We're excited about this combination, and we look forward to sharing more details as we progress toward closing and beyond.

With that, we're happy to take your questions.

[Operator Instructions]

And our first question for today will come from Jessica Fye with JPMorgan.

Curious on the $5 billion peak projection for PALSONIFY and Atumelnant. How do you break that out between the assets? And does it factor in carcinoid for PALSONIFY, too? And then related to Atumelnant specifically, how much diligence were you able to conduct on the clinical profile? Did you see any safety data from ongoing trials?

Jess, it's Reshma. Let me take those 2 questions. I'll take the second one first. We were able to do the kind of diligence you would expect from Vertex. And everything we've seen, including efficacy, safety makes us feel really good about what Atumelnant could do for patients, not only in CAH, but in ACTH-mediated Cushing's syndrome as well.

On the $5 billion, one of the reasons we like this deal so much is that there are many paths to the $5 billion in revenue that we outlined. Maybe the most visible and straightforward path is just focusing on the 2 lead assets. We see PALSONIFY in acromegaly as a blockbuster medicine. And then we have multibillion-dollar potential for Atumelnant in CAH and then add on to that really significant opportunity in ACTH-mediated Cushing's syndrome. You add that all up, and that's the $5 billion revenue we outlined. But there are many other pathways.

As you mentioned, there's a program in Phase III in carcinoid based on mechanism of action, I have every reason in the world to believe it will be successful. There are very interesting preclinical programs in other rare endocrine diseases that are of interest to us. I'll just call one out, Graves' disease and thyroid eye disease. So many paths to the $5 billion that we outlined. The most straightforward is the focus on 2 lead assets.

The next question will come from Salveen Richter with Goldman Sachs.

With regard to Atumelnant, could you speak to how we think about the ramp of the drug and the sales outlook in the context of what's played out with Neurocrine's drug here? And then secondly, for PALSONIFY, the -- maybe speak to the ex U.S. launch outlook here given the recent EMA approval?

Yes. Sure. Thanks, Salveen. Let me take the first question on how we see the Atumelnant ramp, and then I'll ask Duncan to comment on PALSONIFY and commercialization. Let me just make a top line comment for both. Obviously, we're just announcing the merger agreement today. The deal still has to close. So I'm going to be thoughtful about not going too far forward before the deal closes. That being said, as you heard Duncan say, the awareness for Atumelnant in CAH is very high. And this idea that you can have a drug that can control both physiologic levels of GC, glucocorticoid and concurrently manage the androgens, that is the holy grail of what physicians and patients want. And so we see a lot of opportunity, a lot of awareness, and it's an oral small molecule. So for this opportunity to play out in a nice launch uptake. But I won't go further than that until the deal closes.

Duncan, do you want to say a couple of words about PALSONIFY and where you would take that once the deal closes?

Yes. Salveen, briefly, PALSONIFY has been approved in Europe in April earlier this year. And without sort of prejudging exactly what we would do, our plan would be to conduct a global launch of PALSONIFY beyond, of course, the excellent launch that the Crinetics team are executing here in the U.S. right now.

The next question will come from Cory Kasimov with Evercore ISI.

This is Josh on for Cory. In regards to Atumelnant, what data did you see to make you feel comfortable that there won't be a liver safety signal as was a concern that was brought up by investors previously. And we'll leave it at that.

Yes. We've looked at the totality of available data generated to date with Atumelnant in all of the indications. So that means CAH as well as in the early study in ACTH-dependent Cushing's. What we see is minor elevations. I believe there were a handful of cases, I think 7 actually to be exact, of minor elevations in LFTs. There are no cases of LFTs plus bilirubin. There -- most of the cases, 6 of the 7 resolved without any intervention on continued therapy. So we feel really good about the safety profile, not only in the liver dimension, which you asked about, but as we reviewed the data, we felt really good about the profile overall.

The next question will come from Andy Chen with Wolfe Research.

And I think you mentioned that the deal is going to be accretive by 2029 based on your internal assumptions. Would this largely be driven by PALSONIFY? Or is it possible for Atumelnant to launch before then? If you can provide some metrics on timing of Phase III data, that would be great.

Charlie, do you want to comment on that?

Yes. Thanks for the question. Obviously, the commentary about this becoming accretive to operating margins in 2029 factors in both our view on revenue ramp as well as OpEx trajectory over the next couple of years. We'll be more specific about that at the time of close.

The next question will come from Geoff Meacham with Citibank.

This is Jarwei on for Geoff. Maybe 2 from us. First, on PALSONIFY, what gives you confidence that the Phase II CAH profile would be reproducible in a larger, more heterogeneous Phase III population? And then on Atumelnant, what's the one risk you're most focused on as you move through the Phase III study?

Sure thing. I think you mean Atumelnant in CAH, what gives us confidence that we're going to recapitulate the results in Phase III as seen in Phase II. One of the really -- one of the things we like so much about this platform is the disease biology is extremely well understood. The manifestation of the disease is clear. You can tell if the medicine is working, as I said in my prepared remarks, early on because these are exactly the biomarkers that we study as you're developing proof of concept as is the endpoint in Phase III. So based on the mechanism of action, the presentation of the disease, it is a rare genetic endocrine disease and the strength of the data, the magnitude of the treatment effect, I have high confidence in the Phase III program.

You also asked about what risks are we looking for. There's nothing special that I would call out here. The risks for any program that is transitioning between Phase II and Phase III is simply to ensure that the safety and tolerability profile is the same in Phase III as was in Phase II, and we already talked about the efficacy. But I see no unique risks that concern me here.

The next question will come from Evan Seigerman with BMO Capital Markets.

Congrats on the proposed acquisition. So mechanistically, when you think about the kind of competition out there, walk me through why you think the Crinetics asset is potentially better than Crenessity. I know you have some data in the slides, but when you did your diligence, what was it that was striking that caused you to decide to acquire the company or propose the proposed acquisition of the company?

Yes. You bet, Evan, and thanks for your kind words. So the key here, Evan, if we just focus on CAH is that the long-standing and very well known to the field. So this is a rare endocrine disease taking care of by a small number of endocrinologists. Endocrinologists in any case, is only 8,000, 9,000 endocrinologists in the U.S., kind of the same number as nephrologists. So it's a small specialty. And of that, only like 4,000 or so take care of this kind of rare endocrine disease.

When you look at the disease itself, it's very clear that it's this dual burden of needing to supplement with glucocorticoids, but the best outcome would be using physiologic doses of glucocorticoids or GCs. But that's not really possible. People end up using super physiologic doses of GCs because without doing so, the androgens, which have a whole host of complexities, as I described in my prepared remarks, growth challenges, hirsutism, virilization, a whole host of excess androgen challenges. So you use more GCs. And when you do that, you're constantly teetering between too much glucocorticoids and the downstream negative consequences of that or too little glucocorticoids and then having excess androgens.

So I think Duncan described it exactly right. The holy grail has been can we have a medicine that allows glucocorticoids at physiologic levels while suppressing androgens. And when you look at the Phase II data, and we shared some of it on the slide, that is exactly what you get. And I would say, Evan, the key thing to look at is look at the end of the trial period where you have GCs at physiologic levels and look at that point at the androgen or A4 level. That's the key data. When we saw that data, we were floored. That is very, very important to this field.

I'm going to ask Duncan to see if he wants to make any additional comments.

My only additional comment to that is, and we believe that's unique that there is no other company that have data that has shown the ability to achieve that holy grail of both managing androgen levels as well as and simultaneously enable patients to be treated with physiologic doses of glucocorticoids. And that is unique and no one else has shown that.

The next question will come from Michael Yee with UBS.

Mike Yee from UBS. Two questions, maybe Reshma. One is just thinking about the premium on the acquisition of approximately 100% and appreciating that nearly every deal, I think, year-to-date nearly has been a much more modest premium speaking to sort of bid-ask spreads and where we are in the market. So talk a little bit about either was this a very competitive situation? Or how do we arrive at such a high premium? The second question is more scientific and competitive in nature. And in understanding the difference between your drug and Crenessity, it looks like your -- Crinetics is using quite a different endpoint in Phase III. And perhaps is it that endpoint that speaks to exactly what you're trying to address in terms of normalizing both hormones?

Yes. Michael, this is Reshma. Let me take the second question first, and then I'll turn it over to Charlie to tell you more about how we think about value. You are exactly right about the endpoint. And I do think that the Phase III endpoint of the Atumelnant CAH study tells you exactly what you need to know about what we think is most important in this disease. And to reiterate that, it is physiologic doses of glucocorticoids and at physiologic levels of glucocorticoids getting the androgens under control. So you're spot on, on that.

With regard to value, let me top line it by saying we see significant intrinsic value in this acquisition, and I'll ask Charlie to give you some more color.

Yes, Mike, thanks for the question. Listen, there are obviously a lot of ways to think about value, both absolute and relative. To Reshma's point, as we looked at the opportunity to acquire Crinetics, what we saw was the potential for best-in-class products with transformative benefit. We toplined for you the potential for $5 billion in peak sales and as well as a meaningful addition to profitability after a few years. So it's a very attractive fit, both strategic and financial. And on those merits, we see a lot of intrinsic value that justifies the price.

Maybe if you think about other measures, if you think about the value relative to peak sales, so roughly 2x, those measures are right in line with -- if you think about other deals of really high-quality assets, either commercial or near commercial, I think it's right in line. So we feel great about this. The price reflects the value that we see, and we look forward to both growing and accelerating this business once the deal closes.

The next question will come from Brian Abraham with RBC Capital Markets.

This is Nevin on for Brian. Just wanted to touch on and expand on what you think the commercial dynamics may look like in the event that Atumelnant is approved. So some of the patient feedback that we've gotten on CAH patients -- from CAH patients indicate that there might be some hesitancy for those who are currently on Crenessity to switch just given the potential need to re-equilibrate their glucocorticoids.

So how are you thinking about this as a potential barrier to switching off of Crenessity in the case that Atumelnant is approved? Would you look to pursue a switch study? And what specific profile do you think could potentially demonstrate a compelling enough profile to incentivize switching?

This is Reshma. Maybe I'll just answer with a top line. I don't want to go further than where we are at the moment that the deal hasn't closed yet. We'll have more to say on this. But what we have heard from patients and physicians and as you heard Duncan outline, is high awareness of the possibility of Atumelnant in CAH, very, very clear goals from physicians and patients that they want to have both their glucocorticoids at physiological doses with control of androgens and there's high awareness that that's not happening.

This is not an asymptomatic disease. It's actually a very pronounced and symptomatic disease and troubling to patients because they feel the excess of the glucocorticoids or the excess of androgen. So it doesn't go by quietly or unnoticed and both physicians and patients want these measures under control. The point that you raised about switch studies is a very good idea. I'll just leave it at that, and we'll talk more after the deal closes.

The next question will come from Phil Nadeau with TD Cowen.

I guess our question is on the timing of the deal. Why is this the right time for Vertex to add a fifth pillar? I think you have a lot going on in your early-stage pipeline or early-stage launches with JOURNAVX, CASGEVY in the early stages of their commercial uptake, povetacicept and inaxaplin, not yet making it to market but being pretty close. So a skeptic would say you have plenty going on already. What are you trying to diversify away from? Why is this the right time to add a fifth pillar to Vertex's commercial strategy?

Thanks for the question, Phil. We see ourselves as a company that is looking to bring transformative medicines to patients around the globe. We see ourselves as a growth company. We see ourselves as a company that has the ability, bandwidth resources, judgment, taste, commercial prowess to do this in many areas. And when we saw the data from Crinetics, met the team from Crinetics, looked at the pipeline, looked at the potential, this is absolutely the kind of deal that fits us perfectly. And the timing is now because the company is available now. The data are available now. And we believe that we are the right group to take on PALSONIFY, add to what the Crinetics team has done and take this around the globe, accelerate the launch in the U.S. and start the launch ex U.S.

And we feel really terrific about what they designed in Phase III. And we feel like this is the right time to get to the company with the Phase III program well underway, so we can now help shape how that launch is going to go. So we're doing this now because we are interested in ensuring that we remain the kind of company that when we see wonderful assets in our own pipeline or outside, we take full advantage of it and we drive hard. This is exactly the kind of deal that fits us perfectly.

The next question will come from Tazeen Ahmad with Bank of America.

I wanted to get a sense of the synergy that you think these group of assets will have on your already established commercial infrastructure. And also the particular focus on endocrinology, can you just talk about why that makes sense just given everything else that's already been mentioned that you're developing in the pipeline? And do you think there's opportunities to leverage that in the future beyond the assets that you're acquiring?

Tazeen, I couldn't hear the end of your question, but I think the fundamental point was why endocrine and do we see synergies. I'll ask Duncan to comment, but I'll just top line it by saying, of course, we have our T1D cell therapy-based program in endocrine. And so that's an important thing to consider. And I'll ask Duncan to comment on that as well as the synergies we see between these various assets in the Crinetics portfolio. And lastly, to talk a little bit about why we like the endocrine space so much and why it reminds us of CF. Duncan?

Yes. So just to cover a couple of points here. So there clearly will be synergies between the different diseases in the Crinetics portfolio. They're essentially all treated by about a total of 8,000 endocrinologists in the U.S. But each of those diseases is probably treated by about 3,000 or 4,000 physicians, and there's going to be significant synergy and significant overlap between those patients -- sorry, between those physician groups. There's certainly plenty of synergy with the endocrinology space.

And as we've talked about before, it's a space where there is an incredible significant patient unmet need in the diseases that we're talking about. They are symptomatic diseases and they are serious diseases for patients, and we have highly differentiated best-in-class molecules in each of those diseases. So we see that candidly very similarly to how we think about our CF portfolio. So certainly, there's plenty of synergy in that area. I think the first part of your question might have been about synergy on these assets across the rest of our commercial infrastructure. And with regard to that question, I think it's a little bit early to be making any comments in that regard at this point.

The next question will come from Brian Skorney with Baird.

Congrats on the deal. I guess how do you think about the market opportunity for PALSONIFY in acromegaly versus carcinoid syndrome versus nonsymptomatic NETs. I think the market for injectable SRL is more heavily weighted towards neuroendocrine tumors. So do you have a perspective on how that market is currently split up for the injectables? And do you think ultimately at peak PALSONIFY has a different market dynamic in terms of the ratio of acromegaly versus neuroendocrine?

Brian, I think you're asking how do we see the market for PALSONIFY for acromegaly versus neuroendocrine tumors, maybe including carcinoid. I think that's what you're asking. It was a little hard to hear.

Yes, that's exactly correct.

Okay. I'll ask Duncan to comment. I don't think we're going to have any specific comments on the split between the market. But what I can tell you is we see real opportunity for PALSONIFY as best-in-class for acromegaly and we'll hold on the neuroendocrine tumors in carcinoid after the deal closes.

But I will ask Duncan to comment on PALSONIFY in acromegaly.

Sure. So Brian, as far as acromegaly is concerned, just to repeat some of the comments we made earlier, this is about 20,000 patients in the U.S., about 35,000 patients around the world. As we've talked about before, there's a very significant unmet need for these patients and PALSONIFY offers a unique oral once-daily dosing with rapid and sustained up to 22 months symptom control, which compares very favorably with the current sort of standard of care after surgery, which is sort of large gauge intramuscular injections that are given once a month. They're fairly viscous injections cause a number of painful injection site reactions and tend to have a tapering of symptom control towards the end of the month.

So you sort of start the month with the injection site reaction and you end the month with limited symptom control. So we think PALSONIFY in acromegaly, for sure, has the opportunity to become best-in-class, as I say, as an oral once-daily treatment. And as you know, it's priced at around about $290,000 here in the U.S. So we're very excited about the opportunity for acromegaly and very excited about the work that the Crinetics team have already done in order to drive physician awareness, uptake, patient enrollment forms and really nice broad market access this early in launch.

Your next question will come from Ellie Merle with Barclays.

This is Jasmine on for Ellie. Congratulations. So a couple on PALSONIFY. First, how would you segment the addressable acromegaly market across switch versus naive patients? Where do you expect the strongest initial uptake for PALSONIFY? And how do you expect to work to gain share across both segments?

And then secondly, can you talk a little bit about the level of motivation across these rare endocrinologist prescribers to actually switch to new therapies like PALSONIFY?

Yes, you bet. I'm going to ask Duncan to comment on the -- let's just narrow down the buckets and maybe Duncan will expand, but there's the switch population and then there is naive, discontinued as well as the group who have just recently had surgery but are not yet on medicine. And then to talk a little bit about the new prescriptions that we're seeing, which I think speaks directly to your point about comfort of physicians. Duncan?

Yes. Thank you for the question, Ellie. I'm not going to go into too much detail in providing sort of guidance on where we expect the business to come from. But safe to say, as I mentioned in our prepared remarks, we do expect, at least initially, the vast majority of PALSONIFY business to continue to come from switch patients. As I alluded to in my answer to the last question, these are patients that are on very unpalatable injectable SRLs. And so we see a significant opportunity for the switch patients. But there are also, as Reshma alluded to, patients who are treatment-naive. There's about 500,000 new patients a year. There's also patients who...

500, I think.

500,000, sorry...

And equals 500.

And there are also about a number of patients that have treatment discontinued. As I showed in the presentation, there's a lot of patients that start on these therapies, but because of either the challenges in taking them or lack of symptom control, they tend to come off those therapies. So there's plenty of patients who have discontinued existing treatments for existing available treatments who we think would be great candidates for PALSONIFY.

I would say in terms of the level of motivation from HCPs, both the engagements that we've had with physicians, the market research we've done and the data that Crinetics have themselves communicated, there is incredibly high awareness of PALSONIFY. There is incredibly high awareness amongst the target endocrinologists of the Crinetics organization and PALSONIFY. And we've seen really nice uptake in terms of new physicians prescribing each month, patient start forms and as I alluded to before, strong payer coverage, all of which I think are good indicators of, a, the significant and visible unmet need in the disease; and b, the clinical impact of PALSONIFY.

The next question will come from Carter Gould with Cantor.

Congrats on the deal. Follow-on to an earlier question around adding a fifth vertical. What are the implications for future BD, both in terms of capacity and areas of focus? Should we expect a downshifting in BD as you rebuild cash balances? And I guess, should we rule out you adding a sixth or seventh pillar in the near term with this recent deal?

This is Reshma. Thanks for the question. First things first, super excited about announcing the merger agreement today. We have a close still to go. As you heard Charlie say, we are very serious about our R&D strategy. We're very serious about our capital allocation approach that it goes to innovation. Nothing changes on that front, and you should not expect any change going forward.

Chuck, can you give the replay info, please?

We'll do. That will conclude our question-and-answer session as well as our conference call for today. A replay will be available shortly after the call concludes by dialing 1 (855) 669-9658 or 1 (412) 317-0088 using replay access code 1734853. Thank you for attending today's presentation. You may now disconnect.

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.