Good afternoon, ladies and gentlemen, and welcome to the Crinetics Pharmaceuticals Data Call. At this time, all lines are in listen-only mode. Following the presentation, we will conduct a question-and-answer session. If at any time during this call you require immediate assistance, please press star zero for the operator. This call is being recorded on Monday, June 3, 2024. I would now like to turn the conference over to Mr. Corey Davis. Thank you. Please go ahead. Thanks, Sheena. Good afternoon, everyone, and thanks for joining us to discuss the initial phase II atumelnant results. Joining me today are Dr. Scott Struthers, Founder and CEO, and Dr. Alan Krasner, Chief Endocrinologist. Then also joining for the Q&A section of the call will be Dr. Dana Pizzuti, Chief Medical and Development Officer, and Jim Hassard, Chief Commercial Officer. Before we begin, I'll point out there is a slide for today's presentation, which can be viewed with the Events and Presentation link on the Investors page of the Crinetics website. In addition, a news release was issued today and is also available on the corporate website. As a reminder, we will be making forward-looking statements. I invite you to learn more about the risks and uncertainties associated with these statements as disclosed in our SEC filings. Such forward-looking statements are not a guarantee of performance, and the company's actual results could differ materially from those stated or implied in such statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release, the company's other news releases, and Crinetics SEC filings, including its annual report on Form 10-K. I'd also like to specify that the content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, June 3, 2024. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. I'll now hand the call over to Scott. Scott, please go ahead. Thank you, Corey, and thank you all for joining us today. We're very excited to share with you data on atumelnant, the first and only ACTH antagonist in clinical trials. ACTH is at the center of the endocrine stress response pathway, and this pathway becomes overactivated or dysregulated. The consequences can be lethal. Both congenital adrenal hyperplasia and Cushing's disease are very serious conditions. People suffering with either are in great need of better medical options. We designed and are developing atumelnant to help. Our vision for these patients is to be able to take a single pill once a day that reliably enables them to return to normal, healthy hormone levels, that in turn, will relieve the challenging complications of the excessive adrenal hormones they currently face. In the case of CAH, we envision atumelnant bringing adrenal androgens like androstenedione, or A4, back to normal levels, relieving its consequences, such as infertility and hirsutism. By normalizing adrenal androgens, we also hope to eliminate the need for excessive glucocorticoid therapy that many CAH patients require. These excessive glucocorticoids lead to their own sets of problems, like weight gain, hypertension, and osteoporosis. In the case of Cushing's disease, we envision atumelnant eliminating excessive glucocorticoids produced by the adrenal gland itself. That, like exogenous glucocorticoids in CAH, can result in severe complications. As you will see in the data today that we have presented at the Endocrine Society Annual Meeting in Boston, atumelnant has recently made great strides towards achieving this vision. Our mission now is to follow through in the clinical development of atumelnant to realize its potential to become a revolutionary new treatment paradigm for people suffering from either CAH or Cushing's disease. If atumelnant continues to perform as it has in these early studies, we anticipate it to become the preferred therapy for both conditions. The team at Crinetics is working hard to enable late-stage development for both indications needed to bring this important new potential medicine to people around the world. We're beyond excited to share the data that was presented today at ENDO. Even in this initial cut of the data, atumelnant is already showing immense promise. First, in congenital adrenal hyperplasia, or CAH, atumelnant demonstrated profound, rapid, and sustained reduction in key CAH biomarkers. All six of the participants receiving 80 milligrams of atumelnant so far have maintained A4 levels below the upper limit of normal at all time points on treatment. Remember, A4 is the key adrenal androgen driving much of the CAH disease pathology, and it is also a potential component of endpoints in registrational trials. We observed over 90% reduction in A4 with 80 milligrams of atumelnant beginning as early as two weeks of treatment, and this was sustained through all 12 weeks of treatment. Likewise, levels of 17-OHP, another adrenal steroid and biomarker of CAH, were reduced by 97% two weeks after dosing and sustained through 12 weeks. As it emerged, we were stunned by this data and decided that we needed to share it with colleagues at Endo, even though the study is not yet complete. This data and the extremely positive feedback we've received here from colleagues drives us to finish this study as rapidly as possible and move to phase III. Similarly, in ACTH-dependent Cushing's syndrome, or ADCS, atumelnant also demonstrated profound, rapid, and sustained effects... impacts on key biomarkers, as well as improvements in signs and symptoms of Cushing's disease. Every participant who received 80 milligrams of atumelnant so far achieved 24-hour urine-free cortisol levels below the upper limit of normal throughout the treatment period. This is the typical registration endpoint for drugs to evaluate drugs for Cushing's disease. Perhaps more importantly, every participant who received atumelnant experienced improvement in two or more symptoms of Cushing's in just this 10-day study. Finally, atumelnant has been generally well-tolerated to date across both these studies and our healthy volunteer phase I program. I wanted to emphasize how remarkable these early results are in both CAH and Cushing's. The data shown here are unprecedented in these two very difficult-to-treat disease populations and have the potential to change the way people live with CAH and Cushing's. We are preparing, we are preparing for later-stage studies in both indications as we work to complete these initial patient studies as soon as possible. With that, I'll hand it over to Dr. Alan Krasner, our Chief Endocrinologist, to discuss the results from both studies in more detail. Alan? Thank you, Scott. Before we discuss the data, I'd like to take a moment to review the hypothalamic-pituitary-adrenal, or HPA, axis, which is dysregulated in both disease states we will be discussing. The normal HPA axis is depicted in the left panel of slide six. It consists of the hypothalamus in the brain, the pituitary gland at the base of the brain, and the adrenal glands on top of the kidneys, working together in a tightly regulated fashion to control the important hormonal outputs from the adrenals. Cortisol comes from the outer cortex of the adrenals and is critical in adapting the body to any kind of stress. When we experience an illness or injury, the process of coping with that stress begins in the hypothalamus, which produces hormones like corticotropin-releasing factor, or CRF, and arginine vasopressin, or AVP, which then travel to the pituitary gland. Certain cells in the pituitary respond to hypothalamic stimulation by secreting into the bloodstream another hormone called adrenocorticotropic hormone, or ACTH. ACTH then travels to specific receptors found only on adrenal cells. When ACTH binds to these receptors, the adrenals rapidly increase the output of cortisol. Cortisol then travels throughout the body to initiate the intracellular metabolic changes needed to help us withstand stressful challenges. But it is important that this system is carefully regulated. Much like a thermostat, the HPA axis has evolved to sense how much cortisol is made and turn down the activation of the pathway when there is enough. This occurs through what is known as a negative feedback loop. The cortisol that is produced, in addition to its various other actions, returns to the hypothalamus and pituitary to turn down the production of CRF and ACTH. The system is normally self-regulating to keep a normal diurnal rhythm of cortisol and return to homeostasis following stressful events. Cushing's disease is depicted in the middle panel. It is caused by a tumor in the pituitary gland that oversecretes ACTH into the bloodstream. This causes the oversecretion of cortisol by the adrenal glands, leading to myriad symptoms, including central obesity, hypertension, diabetes, and bone loss. It affects approximately 11,000 patients in the U.S. To this day, despite the availability of multiple medical and non-medical therapeutic options, safely and effectively controlling Cushing's disease is one of the greatest remaining challenges in clinical endocrinology. Classic congenital adrenal hyperplasia, or CAH, is depicted in the right panel. It is a genetic disorder affecting approximately 27,000 patients in the U.S. These patients lack a critical enzyme in the adrenals responsible for cortisol production. This breaks the negative feedback loop, essentially removing the brakes applied to the hypothalamus and pituitary, allowing ACTH production to go into overdrive. These patients are born and usually live their whole lives with elevated ACTH levels. These ACTH levels, since birth, result in overstimulated and overgrown adrenal glands, hence the name of the disease, congenital adrenal hyperplasia. ACTH-driven stimulation of the adrenals result in overproduction of cortisol precursors, including 17-hydroxyprogesterone and adrenal androgens, such as androstenedione, also known as A4. The adrenal hyperandrogenemia from A4 and other androgens causes many serious medical complications, beginning in utero, progressing through childhood and into adulthood. Fortunately, ACTH receptors are not found outside the adrenal gland. Therefore, the ACTH itself does not cause problems other than through its effects on the adrenals. What Cushing's disease and CAH have in common are chronically elevated blood levels of ACTH. The adrenal glands, which are always responding to this excess ACTH, are the sole source of excessive steroid that cause the clinical complications in both disease states. It is natural, therefore, to try to turn off the ACTH receptor in both diseases because this receptor is the sole mediator of ACTH signaling. We believe atumelnant, which is an ACTH receptor antagonist, is the right approach to target the fundamental driver of the pathologic progression in both of these conditions.... We will begin with our lead indication for atumelnant, CAH. Recall that patients with CAH cannot make cortisol. Cortisol is essential for life, so people with CAH need to take cortisol replacement for life. Cortisol is a glucocorticoid hormone that also goes by the name of hydrocortisone, and many patients use oral forms of hydrocortisone. The doses of hydrocortisone should be very low, simply to replace the normal daily production of cortisol that they lack, and these low replacement doses in general should not cause problems. However, low-dose glucocorticoid replacement is not sufficient in CAH patients to suppress ACTH to normal, and these patients can have adverse consequences from overstimulated adrenal production of androgen molecules like androstenedione. Excess androgen exposure is responsible for menstrual dysfunction, infertility, and hirsutism in women. Even in men, excess adrenal androgen production can also cause reproductive problems. Excessive ACTH exposure in men can also cause tumors in the testes, which can cause pain and infertility. Because low replacement doses of glucocorticoid do not control many of the medical problems seen in CAH, many physicians find it necessary to use high supraphysiologic doses of glucocorticoids in an attempt to suppress elevated ACTH levels and thereby lower adrenal androgen production. These elevated glucocorticoid doses are frequently associated with adverse effects such as weight gain, elevated glucose, edema, bone loss, and a host of other serious medical problems. It is very difficult to find a dose of glucocorticoid which effectively controls adrenal androgen production without causing the side effects of excessive glucocorticoid dosing. This highlights the fundamental challenge in treating this disease, striking the right balance between reducing adrenal androgens, yet minimizing the effects of excess glucocorticoid dosing. Atumelnant is the first oral selective ACTH antagonist designed to reduce or eliminate ACTH stimulation at the level of the adrenal, thereby lowering adrenal androgen output. Remember, the ACTH receptor in the adrenals is the only means by which ACTH drives the pathologic adrenal androgen output seen in CAH, and the ACTH receptor is a single choke point at which this overdriven system might be turned off. Atumelnant, as shown in orange in slide 9, acts at the ACTH receptor to block the fundamental problem of excessive ACTH stimulation. Ideally, atumelnant would reliably and reproducibly eliminate excessive exposure to adrenal steroids, as reflected by key biomarkers A4 and 17-hydroxyprogesterone. Once adrenal hyperandrogenemia is controlled, patients who are taking excessive doses of glucocorticoid should be able to lower their doses and reduce or even avoid steroid therapy-related adverse effects. Slide 10 shows the design of our ongoing phase II open label, sequential dose cohort study, evaluating the safety and efficacy of 12 weeks of atumelnant treatment in participants with classic CAH. Participants in this study were treated with supraphysiologic daily doses of glucocorticoid, such as hydrocortisone. The dose of glucocorticoid is not changed during the study. The study also enriched for patients with elevated A4 levels, at least 1.5 x the upper limit of normal at baseline, indicating poor control of adrenal androgen production despite the fact patients were taking glucocorticoid therapy. The study is ongoing, and today we are reporting data from an interim data cut. There are three dosing cohorts. The study began with the 80-milligram once per day cohort. As of the time of this data cut, four patients were treated with 80 milligrams for 12 weeks, and two additional subjects were treated with 80 milligrams for six weeks. Four patients were treated with 40 milligrams per day for 2 weeks. In total, we plan to enroll 9 participants, each in the 80-milligram and 40-milligram cohorts, and six participants in a third 120 milligram cohort. This will allow us to assess a true dose response to help us best design a phase III program. The primary efficacy endpoint is the change from baseline in A4 levels at 12 weeks, as well as safety assessments. We are also evaluating the change from baseline in 17-hydroxyprogesterone as a secondary endpoint. Slide 11 details the demographics and baseline characteristics for this data cut population. You will see that because of long-term use of high doses of glucocorticoids, like hydrocortisone, many patients are overweight or obese, despite comprising a relatively young adult population. All groups had mean baseline biomarker levels above the upper limit of normal. I will note that 2 participants in the 80-milligram group entered the study based on elevated A4 levels measured in local laboratories that were greater than 1.5 x the upper limit of normal. These A4 results proved to be lower when samples were measured in our central laboratory. For analysis purposes, all data shown are based on the standardized results from the central laboratory. A summary of safety data to date is shown on slide 12. Both the 80-milligram and 40-milligram doses have been generally well-tolerated to date. There have been no severe or serious adverse events observed and no discontinuation. In addition, we observed no significant changes in safety labs or electrocardiograms to date. In the 80-milligram dosing group, atumelnant rapidly reduced A4 levels by 91% within the first 2 weeks of treatment. In participants who completed the treatment period so far, this effect was sustained with a 96% reduction at 12 weeks. As a reminder, A4 is an androgen that is pumped out of the adrenals in response to excessive ACTH stimulation in patients with CAH. A4 is the most important biomarker and is used in clinical practice to assess the adequacy of disease control. If we look at the data on an individual patient level on Slide 14, you can see that all 6 participants treated so far with 80 mg of atumelnant showed profoundly reduced A4 levels after starting treatment. All were below the upper limit of normal within 2 weeks of treatment, regardless of baseline level. This effect was sustained through 6 weeks for all 6 participants and through 12 weeks for the 4 participants who completed the treatment period in this data cut. Notably, 2 of the female participants in the 80-mg cohort resumed normal menstrual cycles for the first time in over 2 years. This was associated in these patients with significant reductions in androgen exposure. Because of the marked biochemical responses seen consistently with the 80-milligram dose, the Safety Review Committee recommended starting evaluation of the 40-milligram dose in cohort 2. In Slide 15, we see available data from the 40-milligram, 40-milligram cohort, with treatment for 2 weeks in 4 participants. We clearly see initial responses to this dose, but there are too few data to draw conclusions about the 40-milligram dose. When we complete this cohort and the third cohort with 120 milligrams, we hope to be able to fully describe the dose-response relationship and use that data to design further studies. 17-hydroxyprogesterone is another biomarker used in the diagnosis and treatment of CAH. It is not an androgen, but it is a chemical precursor of cortisol. Because the enzyme that processes 17-hydroxyprogesterone toward cortisol is missing in CAH, 17-hydroxyprogesterone often builds up to very high levels. The goal in treatment is not to normalize 17-hydroxyprogesterone. However, physicians do look for lowering of these levels when deciding if patients are responding to therapy. As shown on Slide 16, 80 mg of atumelnant rapidly induced reduction of mean 17-hydroxyprogesterone levels by 97% within 2 weeks of treatment for the 6 participants in this cohort so far. Similar to A4, this effect was sustained, with a 94% reduction at 12 weeks in those who completed the treatment period. These effects are not subtle, and along with the A4 results, speak to the unique potential of atumelnant. Individual subject data are shown on slide 17. Atumelnant reduced 17-hydroxyprogesterone levels in all participants within 2 weeks, regardless of baseline level. Again, we see a sustained effect through 12 weeks in those who have completed the treatment period. Slide 18 shows the observed reduction in 17-hydroxyprogesterone levels within 2 weeks of dosing with 40 mg of atumelnant. As with A4, we do see responses with the 40-mg dose but do not yet have enough data regarding this dose with which to draw conclusions. While this phase II study is still ongoing, we're very excited about the compelling results from this initial data cut. Based on these data, we believe atumelnant is working exactly as designed to reduce A4 levels through blockade of the ACTH receptor. In this phase II study so far, we have demonstrated that participants with high A4 levels receiving high glucocorticoid doses, who then receive 80 mg atumelnant, respond with rapid and profound reductions in A4, and all these participants maintained A4 levels below the upper limit of normal while on treatment. As we think about goals, goals for atumelnant beyond phase II, I am reminded that the endocrinologist's goal in any endocrine disorder is for all hormones to be corrected into the normal range. In the case of CAH, the goal of therapy is to normalize A4 and for A4 to stay normal even when glucocorticoid doses are reduced to those that achieve normal cortisol or cortisol-equivalent levels in the blood. Because of the magnitude of the biomarker responses we are seeing so far with once-daily oral atumelnant, we are certainly thinking ahead to a possible phase III program designed to evaluate whether atumelnant can not only normalize A4, but also allow glucocorticoid dose reductions to physiologic levels while keeping A4 in the normal range. An ACTH antagonist is the most promising mechanism of action by which to achieve this. We have previously shown in our phase I healthy volunteer study that atumelnant at 80 mg can maintain low adrenal activity even in the face of extreme ACTH challenge and low glucocorticoid levels. Therefore, we would expect to achieve similar suppression of A4 in CAH, even as the glucocorticoid therapy dose is reduced to normal physiologic replacement levels. Overall, the therapeutic goal for CAH is to help patients eliminate excess androgen levels and excess glucocorticoid therapy. Although reduction in glucocorticoid dose is an important goal in and of itself, many patients need relief from hyperandrogenemia as well.... For example, the two participants on atumelnant described earlier resumed menstrual function because of a reduction in androgen levels, even though glucocorticoid doses were not reduced. In the next section, we will review our ACTH-dependent Cushing's program. Unique to this mechanism of action, an effective ACTH antagonist would be expected to be helpful in any disease of ACTH excess. Cushing's disease is caused by a pituitary tumor that secretes excess ACTH. These ACTH-secreting tumors are not normally regulated by cortisol-driven negative feedback. This results in excess cortisol production by the adrenal gland, causing all the adverse consequences of excess glucocorticoid exposure. The goal of atumelnant treatment is to block ACTH activation at the adrenal gland, thereby reducing cortisol production and thus alleviating symptoms and adverse consequences of overexposure to cortisol. Rarely, ACTH-secreting tumors can arise outside of the pituitary gland. This is called ectopic ACTH syndrome. Together, Cushing's disease, caused by pituitary tumors, and ectopic ACTH syndrome, caused by tumors outside the pituitary, are termed ACTH-dependent Cushing's syndrome or ADCS. Both forms of ADCS would be expected to respond to an ACTH antagonist. ACTH-dependent Cushing's causes a great deal of suffering and premature mortality, if not controlled. Endocrinologists will often say this is among the most difficult diseases to treat and that these patients are among their sickest. Although there have been recent advances in treating ACTH-dependent Cushing's, there remains a great need for new treatment options. Surgery to remove the causative tumors is usually the first step in treatment. However, it is not always possible to remove these tumors completely. The medical treatment options for those who are not cured by surgery can be effective, but are often accompanied by a litany of potential downsides, including burdensome and prolonged titration requirements that may delay cortisol normalization and symptom relief. The need for multiple doses per day, unpredictable side effects, and potential toxicities may also limit patient tolerability and ability to take these drugs that are available now for long-term control of disease. In short, the availability of an optimal medical treatment for those suffering from ACTH-dependent Cushing's is not yet a solved problem. Crinetics is collaborating with a team of experts at the National Institutes of Health, led by Doctors Lynnette Nieman and Henrik Elenius, on an ongoing phase I-B/ phase II-A study in this patient population. The design of this study is shown on slide 23. It is an open-label, sequential, multiple ascending dose study evaluating the safety and efficacy of 10 days of atumelnant treatment in participants with Cushing's disease or ectopic ACTH syndrome. The key efficacy biomarker here is cortisol, which is measured frequently in both urine and serum. It should be noted that the registrational endpoint for recent approvals in this disease state is the proportion of patients who achieve normal 24-hour urine-free cortisol levels, as is recommended by the FDA. Slide 24 shows the demographics and baseline characteristics in this group. We are reporting initial results from the first five patients treated with atumelnant in the first 80-milligram dosing cohort. Four of these patients had pituitary tumor-driven Cushing's disease, and one had ectopic ACTH syndrome due to an ACTH-secreting tumor, which arose in the lung. You'll notice that all these subjects have active cortisol overexposure or Cushing's syndrome, demonstrated by elevated urine-free cortisol at baseline. In all cases, the Cushing's is driven by ACTH, as can be seen in the inappropriately elevated ACTH levels in the face of excess cortisol. This study represents the first attempt I am aware of to lower cortisol in humans who have ACTH-driven Cushing's using an ACTH antagonist. A summary of safety data to date is shown on slide 25. Consistent with the CAH data and data from healthy volunteers, atumelnant at 80 milligrams has been generally well tolerated. As expected, predefined biochemical adrenal insufficiency was observed in all patients treated to date. Two participants had minor isolated increases in ALT, less than 1.5 x the upper limit of normal, which were not indicative of significant liver toxicity. It is important to note that like many patients with Cushing's, both patients had pre-existing steatosis or non-alcoholic fatty liver disease, which is frequently associated with fluctuations in liver function tests. Overall, adverse events were mild to moderate. Some reported symptoms, such as headache, nausea, and decreased appetite, coincided with morning cortisol levels less than 5 micrograms per deciliter and improved with hydrocortisone add-back. Slide 26 shows levels of morning serum cortisol during the 10-day treatment period in all five participants. As you can see, 80 milligrams of atumelnant rapidly reduced morning cortisol levels below 5 micrograms per deciliter in all five participants. The threshold of 5 micrograms per deciliter for early morning cortisol is significant because this is where the protocol requires treatment with low-dose replacement hydrocortisone. You can also see serum cortisol rising during the atumelnant washout period after the 10 days of dosing. Serum cortisol assays measure both biologically active free cortisol plus biologically inactive protein-bound cortisol. 24-hour urine collections for free cortisol measure only biologically active free cortisol and have been used as the registrational endpoint in pivotal trials for Cushing's disease. As you can see in slide 27, atumelnant resulted in rapid and consistent normalization of 24-hour urine-free cortisol that was sustained throughout the treatment period. This was achieved rapidly with one fixed dose and no cumbersome titration. Cushing's-related symptoms experienced by each participant in the study were carefully assessed, and safety laboratories were measured frequently. Slide 28 shows that every participant seemed to benefit in multiple ways and often felt better during treatment than they did at baseline. Like all of the conditions we study, we are committed to understanding the patient's overall experience with our drug candidates, in addition to biochemical measures of disease control. To summarize, we observed rapid and sustained adrenal steroid reductions of notable magnitude in both CAH and Cushing's. We understand that so far, we are looking at small numbers of patients with these rare diseases. However, the magnitude and consistency of these changes are compelling, and we feel important to share. These results in two distinct diseases of ACTH excess could only be seen with a potent ACTH receptor antagonist and represent the natural progression of what has previously described with atumelnant in animal models and in human healthy volunteers. Atumelnant has been generally well-tolerated in studies to date. We believe these initial results support advancing atumelnant in both indications towards phase III in CAH and towards later stage development in Cushing's. With regard to next steps, we continue to expect top-line results from the complete CAH study in the second half of 2024. We also expect to complete the phase I-B/II-A study in Cushing's in 2024. We plan to design a phase III trial in CAH following discussions with the FDA, and we will also be designing a later stage program in Cushing's. With that, I will now hand the call back over to Scott for final remarks. Thank you, Alan. It's been great to be here in Boston at ENDO. I've been attending ENDO since 1986 and cherish the time with friends gathering from around the world to talk all things endocrinology. It was wonderful to share with them this exciting and incredibly exciting data from atumelnant. The field has known about diseases of the stress axis for more than 100 years, and we've known for a long time that blocking the action of ACTH was likely the best way of intervening. Now, with these data, we're beginning to see that this may indeed be true. Today's results bring us another step closer to delivering a much-needed therapy to those living with CAH and Cushing's. I'd like to thank all the patients who are participating in our studies, as well as the investigators, site staff, and Crinetics' team, who continue to work hard to make these studies a success. Atumelnant is the second of our internally designed drug candidates to report out remarkably positive clinical data. Today's data in CAH and Cushing's was accompanied by presentations at ENDO from additional data from paltusotine in the treatment of acromegaly. Our 2024 plans remain on track. Next steps this year include filing the paltusotine NDA for the treatment of acromegaly, completing these studies of atumelnant, and transitioning multiple new drug candidates from our discovery efforts into preclinical development in preparation for multiple new clinical programs in the near future. The whole company is focused on continuing to execute on this long-term strategy for helping more patients with endocrine-related diseases and building long-term value in the company. Crinetics is well positioned to become the premier, fully integrated endocrine company. We are just getting started. Thank you all for joining us today, and we're happy to take your questions. Thank you. Ladies and gentlemen, we will now begin the question-and-answer session. Should you have a question, please press star followed by the one on your telephone keypad. You will hear a prompt that your hand has been raised, and should you wish to cancel your request, please press star followed by the two. If you are using a speakerphone, please lift the handset before pressing any keys. One moment, please, for your first question. Your first question comes from the line of Yasmeen Rahimi from Piper Sandler. Please go ahead. Good afternoon, team, and congrats to the really outstanding data set. Truly profound responses. I guess the question that we have gotten is: How do we take this, you know, 100% response rate and A4 normalization and figure out what to power for or what to show in steroid tapering, which will be an additional, obviously, a registrational endpoint? And given that you're also seeing symptom improvements, is there also some thought process on potentially incorporating some of those endpoints in the registrational study? Would love some color around that. I'll note, and I'll jump back into the queue. Thanks, Yas. Alan, you wanna take that? Yeah, no, Yas, I think so. I mean, I actually, in terms of what we measure in phase III to demonstrate biochemical and symptoms responses, we are certainly thinking a lot about. Certainly, we know in the case of CAH, the reduction in glucocorticoid background doses important, potentially even primary endpoint. As I mentioned, but during the remarks, I think, you know, based on what we're seeing in terms of controlling the hyperandrogenism, you know, substantial reductions in background glucocorticoid dosing should be demonstrable. And again, our goal is not only to reduce glucocorticoid doses, but also while that's happening, to keep the A4 levels as close to the normal range as possible. In terms of Cushing's, there is precedent for primary kind of registrational endpoint, as I mentioned, and that's typically urine free cortisol. But then again, there are also newer ways to measure cortisol burden, and we will certainly be looking at all these possibilities. Certainly, at least there's a precedent there. And as I also like to emphasize, just like in acromegaly, we are very interested in the patient's symptom burdens and other experiential burdens that they experience with this disease. And that's another way to measure response to therapy, besides just blood and urine testing. So we fully intend to, as we've already started doing in these phase II studies, look at that in even more detail in phase III. Thank you, Alan. Maybe just one other question to squeeze in is: what are your developmental plans, or what are the next steps for Cushing's at this junction, like, in terms of between now and the next twelve months? Well, the first thing we need to do, Yaz, is finish out the current study. Mm-hmm. But as part of that, we're also beginning to lay designs for what a late-stage program may look like. But we've, we've clearly got some work to do, but we're super excited to get moving on it. These are the types of data in Cushing's that, you know, my friends who deal with these patients are really just shocked by how quickly and deeply the cortisol levels are normalized. So we've got a lot to work with here, a lot of excitement to work with, but we need, we need to spend a little time on it. Got it. Thank you, and congratulations again. Thank you. Thank you, and your next question comes from the line of Cory Jubinville from LifeSci Capital. Please go ahead. Thanks for taking our questions, and congrats on the exciting data across the board. I think we learned a lot at ENDO about how inadequate the current standard of care is CAH and the high level of excitement and optimism there is among prescribers for drugs that can potentially actually address the pathophysiology of disease. So, curious if you could help us contextualize the two primary goals of treatment in CAH. You know, on one hand, we have the reduction in GC dose to physiological levels. On the other, we have reductions in androstenedione. And how would you rank the negative impacts of each component, as well as the significance of achieving normalization in A versus B? Look, Corey, high A4 levels are a real problem. High glucocorticoid replacement levels are a real problem. Patients shouldn't have to choose between the two of them, and that's the goal of therapy for us. How that plays out in kind of the both the long term and the short-term consequences is something that we will need to see in larger patient populations. But, I mean, look at these cases here. Two of the women, even on this very short period of treatment, resumed normal menstruation when they hadn't menstruated in years. And that kind of impact on individual patients' lives, hopefully, that results in fertility, if that's what they're looking for. But that type of impact on the patients' lives, beyond just the biochemical endpoints, is something I think we always have to keep in mind. And same thing with the Cushing's patients. I think it's remarkable that in a 10-day inpatient study, every patient had improvement in two or more different things that were bothering them when they came into the study, including some lab values, which, you know, are completely objective. So I think we shouldn't have to choose one or the other. We should be able to treat the whole disease. Fantastic. Thank you so much. Very exciting. Thank you. Your next question comes on the line of Gavin Clark-Gartner from Evercore ISI. Please go ahead. Hey, guys. Congrats on the data and all the positive feedback at Endo. Just had two questions. First one, how low do you believe we may be able to take glucocorticoid doses over time? Do you think we could get closer to the endogenous synthesis rate of around seven nanometer squared a day? Maybe also just discuss the feasibility of doing this in a trial with a defined taper period. So I think that's a great question. Our goal is not to get closer to normal physiologic replacement. Our goal is to get to physiologic replacement. So maybe you want to talk about what that means, Alan. Yeah, and, so absolutely. I mean, the, in theory, what you want to do is dose enough glucocorticoid simply to replace the normal daily production rate from the normal set of adrenals under unstressed conditions. You might want to give people a little buffer in case there should be a stress-unanticipated stressful event. And again, all patients with any kind of adrenal insufficiency, on the basis of CAH or other causes, would need to have what we call stress doses available in case there's a bad day and they need extra glucocorticoid to cope with any stress. So, you know, the goal is to get to a level which doesn't cause adverse consequences of excess glucocorticoid. We refer to that as iatrogenic Cushing's syndrome. We want a dose which yields no clinical evidence for excess glucocorticoid dosing, no excess weight, no excess swelling, none of the adverse things we think about with this. What the exact level that is might vary from person to person, so I don't want to quote a specific number. But we do know that, when you know, when I was in training in endocrinology, we typically would dose 30 milligrams a day of hydrocortisone for replacement purposes. We now know that's too much. Probably the right answer is closer to a 15 milligram -20 milligram per day dose of hydrocortisone is probably right for most adults. Certainly in that range. Got it. That's very helpful. And one other question we've gotten in a few different variations, this week. Thinking about the high end of the potential therapeutic window for ACTH antagonism, how do familial glucocorticoid deficiency patients do when they're on a glucocorticoid or mineralocorticoid supplementation? Is this a good proof of concept for very high levels of antagonism being safe? Thank you. It's a good question. So this is a fairly rare genetic condition where patients are basically born without the ACTH receptor, functional ACTH receptor. You could imagine it as a model. My understanding is the patients do fine with routine glucocorticoid replacement. So, if that is a model, I would say it bodes well for this mechanism of action. Yeah, that's an insightful observation on human genetics. But I think just broadly, Corey, that, or sorry, but that, the ACTH axis, ACTH is one of these hormones, which is very, what we call professional. It does one thing and one thing only. It goes to the adrenal and it activates those adrenal cortical cells. So I don't worry about other things that ACTH is involved in, in the body. Thanks. Thank you. Your next question comes on the line of Jon Wolleben from Citizens JMP. Please go ahead. Hey, thanks for taking the questions, and gentlemen, congrats. I saw in the slides you mentioned starting a pivotal program first half of next year. Just hoping you could talk a little bit how you're bridging into pediatrics, and what that path forward could look like and the importance of that opportunity. Thanks. Yeah, I think, you know, pediatrics is something we're really interested in getting to. The probable part of the problems in the pediatric population is either the excess androgens or the excess glucocorticoid replacements can have changes to children that affect them the rest of their lives. So it really is important that we get down to the younger kids. But maybe you want to talk, Alan, a little bit about how we might get there. Although I will add a little bit more adult experience is probably the first step. All right. An important point is that generally we would need a bit more safety data from adults and more information on dose response as we can, you know, go down the age range, hopefully, in future studies. The trials in children with CAH, of course, would have to include very important additional endpoints that we don't study in adults, particularly growth. Growth can be a problem in children with this condition, either because the excess androgen exposure accelerates premature puberty, and therefore premature stopping of growth in the bone, or the glucocorticoids themselves, if the children are taking too high a dose of glucocorticoid, that itself can also reduce growth potential. It's really a very difficult situation for children with this disease. All the more reason we do want to advance into pediatric development. If I could squeeze one more on the adults. It looks like you guys are really knocking down A4. I'm wondering, physiologically, should we be seeing a slight rebound in gonadal A4 if patients are having, you know, physiologic changes? Or, you know, is there any risk being to super low levels of A4? And I'll jump back in the queue. Thanks. No, actually, you know, I think, by reducing A4 would actually allow the normal reproductive axis, including, for example, including the gonads and the pituitary and hypothalamus, to recover normal reproductive steroid output. A4 coming from the adrenals can actually suppress LH and FSH secretion from the pituitary, and thereby suppress the ability to stimulate the gonads. And by reducing the A4 suppression of pituitary function, this should allow the reproductive axis to recover. So for example, our 2 patients who had a resumption of menstrual cycling, that was because the compound resulted in reduced androgen suppression at the level of the pituitary gland. Thanks, Alan. Thank you. Your next question comes in the line of Jessica Fye from JP Morgan. Please go ahead. Hey, guys, this is... on for Jessica Fye. Really good, consistent data we are following the abstract. Just one at the higher level. What else, if anything, do you want to see from trials be able to start clinical trials with the best possible information? And then, another one, I know it's a little bit early, but how do I think about the ultimate uptake for atumelnant with crinecerfont on the market for CAH before, and then doctors, you know, usually having the position that they're not switching patients off of treatment unless they're not doing well. Thank you. I'm sorry, you were a bit garbled. We, we think we heard you wanting to know what else we would be looking for in this trial, and then how it would affect prescriber patterns in the face of CRF antagonists. Was, was that the question? Oh, so the first question was, what, if anything else, you want to see, on this trial, for you to start the pivotal trial in the best possible, with the best possible set of information? And then the second question was that, knowing that crinecerfont will be on the market before you guys will hit the market, how do you think about, you know, influencing doctors, or how do you think about the uptick for atumelnant, thinking that the doctors will be more familiar with crinecerfont, and they will not switch patients off of it if they're not, you know, if they're not, not doing well? Great. Alan, why don't you talk about what else we need to see, and I'll talk about the long-term plans. Right. So, in our trials, yeah, for the CAH trial, for example, what we really need next is sort of a full picture of the dose response, with atumelnant at different doses and looking at the corresponding biochemical responses. That will allow us to construct sort of a more pivotal phase III type study, and that will fill in the last remaining gap, or one of the remaining gaps, which is how would we use atumelnant to allow not only normalization of androgens, but also dose reductions in patients taking super physiologic doses of glucocorticoids? So that's kind of the order I see things going in for CAH. In Cushing's disease, this is a, you know, meticulously constructed 10-day treatment period in Cushing's disease. These patients are basically inpatients in the clinical research center at the NIH, and we're collecting an enormous treasure trove of data in that timeframe. But of course, we will need longer term duration, treatment to periods in Cushing's disease. And, some more dose response information, of course, in order to really, prepare for phase III. I hope, I hope that's helpful. Yeah, and in terms of kind of the future of therapy and treatment for patients with CAH, I think it's important to remember that there hasn't been anything new since glucocorticoids, which are, you know, remarkably old therapies. And they don't work very well in these CAH patients because so many patients end up going to these high glucocorticoid levels and still have high A4 levels. And I think it's really great that we're starting to see a couple different mechanisms now come into play. And the CRF antagonists are gonna be a step forward. They show some glucocorticoid sparing, which I think is a step forward for many of these patients. But we have a big job to educate the community that there's more to life with CAH than just giving glucocorticoids. I think what atumelnant may promise is the ability to not have to choose between too much glucocorticoids and too much A4, but you can have it all and get it all back to healthy, normal levels. That's certainly what we're trying to achieve in the rest of the development program. Thank you. And your next question comes from the line of Joseph Schwartz, from Leerink Partners. Please go ahead. Joe, are you on the line? Sorry, can you hear me now? Yes. Sorry about that. So all my questions on atumelnant have been answered, but since you've demonstrated a few times now that you have a knack for drugging some elusive targets, I'm wondering if you can put into perspective for us how difficult it was to design your ACTH receptor antagonist, and how the challenges you encountered and overcame in your chemistry development there, compared to the other targets that you have in your earlier stage pipeline. I'm just wondering, are these all roughly equivalent in terms of difficulty, or are any of the remaining ones particularly difficult? I'm just wondering if you can give us any insight into how replicable the success you've had to date might going forward. Thanks, Joe. I think, you know, every drug discovery program we've done is difficult in its own unique way. And this class of targets that we're working on, which is peptide hormone receptors, is generally quite difficult to drug, largely because they're meant to recognize fairly large with this receptor with a small orally available drug-like molecule. And that's a big challenge that is, not at all easy to do. Now, ACTH receptor or melanocortin receptor two was particularly difficult because we've known about ACTH since the 1930s, and nobody else has been able to get to this point. And it was particularly difficult because it's not just a single receptor, it's actually three molecules that form a receptor. It's melanocortin type two protein, together with two copies of a melanocortin receptor accessory protein that was discovered in these genetic mutations of humans by, by Adrian Clark, which was a breakthrough in the field in the mid-2000s. But since then, it's still been a very difficult drug target, and our crackerjack team of discovery scientists have been knocking down a bunch of tough targets. And I think you'll see this year and next, quite a few additional molecules making their way into development, whether it's for our PTH antagonist program for hyperparathyroidism, or our thyroid-stimulating hormone receptor antagonist for Graves' and thyroid eye disease, or the team's also making great progress on the obesity projects and starting to see some very encouraging animal models. So look for this data coming out throughout the rest of this year and into next, and very excited to see what the future holds. Super. Thanks, Scott. Thank you. And your next question comes from the line of Catherine Novack from JonesTrading. Please go ahead. Hi. Afternoon, guys. Congrats just on the really great data again. So I'm wondering about, you know, pivotal trials. By next year, you know, we have potentially one FDA-approved treatment for CAH, and, you know, in Cushing's disease, we have, mifepristone cortisol synthesis inhibitors. Do you have plans to mitigate the impact that these approved therapies might have on pivotal trial enrollment? You know, just thinking from talking to people, I know it sounds like endocrinologists who treat CAH are excited to use anything that could potentially be GC-sparing. So would, you know, if approved, would start patients on crinecerfont, even if it doesn't control androgen levels for all patients? Yeah, I'll take part of it, and maybe Alan can talk about, you know, the unmet need that I think will still drive people into trials in the US. But remember that in our acromegaly program, we've used more than 100 sites in more than 20 different countries. And those countries won't be having new agents on the market for some time, unfortunately. So I don't foresee that having an impact per se. And then in the States, there's still a high unmet need in Cushing's disease. You know, we're reminded of that today by all the practitioners visiting our poster and the excitement that they're seeing. So I'm not particularly worried about the environment changing the enrollment capabilities. These rare diseases, enrollment is always a challenge, and we have to work hard to educate and make sure we make our trials easy for patients to participate in and easy for sites to conduct. We work very hard at that. Did you have anything to add, Alan? Not really. I think that's a nice summary. I mean, we work hard also on building relationships with endocrinologists, in particular, all across the world. And when we started with our acromegaly clinical trials, and a lot of them also, for example, treat Cushing's. Or CAH. Or CAH. And so yeah, that those relationships have a lot of value with respect to our ability to execute these trials as well. Okay. Thanks, thanks very much. That helped answer my question. Thank you. Thank you. Your next question comes from the line of Jeff Hung from Morgan Stanley. Please go ahead. Congratulations on the data, and thanks for taking my questions. My first is for Alan on something you mentioned. Atumelnant maintains control in urinary free cortisol despite elevated ACTH, but could you add more color on what gives you confidence for that translating over to CAH? What level of glucocorticoid reduction would you envision based on the phase II data? Then I have a follow-up. Well, again, it's based on this fundamental mechanism of action, that if you block the ACTH receptor, you deprive the ability of the adrenals. You take away the ability of the adrenals to produce any steroids that are secreted in excess in either of these conditions. So I think what that means is what we've shown is reduced cortisol in Cushing's disease, and hopefully, we'll also show that in later stage trials as well. In CAH, the adrenal steroids that we want to reduce are those that have androgenic properties, and we're seeing that now with three months of treatment in our ongoing phase II study. So I think those two things, I mean, the whole hypothesis underlying this whole program is fitting together and staying together very nicely. I think, how much glucocorticoid dose reduction we might see in phase III, as a result of the very marked reductions in androgen, I would predict we should see very nice reductions in glucocorticoid doses if this effect holds true through phase III. The goal is nothing short of getting to low physiologic replacement doses of glucocorticoid and keeping A4 and other androgens normal. ... Great. And then with the different datasets that have come out in the last few days, do you have any additional insights into the relative contributions between, ACTH, ACTH-dependent A4 versus CRF-dependent A4? Thanks. Yeah, so I think, I think the way to think about it is dependency of adrenal activation. We measure that by A4 and 17-OHP in congenital adrenal hyperplasia, and we measure that activation in Cushing's disease and healthy volunteers by cortisol. All of that comes through ACTH. It's the single way for ACTH to act, and that's what we're blocking. The only way that other mechanisms, like the CRF antagonist, can affect the adrenal is through lowering the production of ACTH. And you can lower it somewhat, but with an ACTH antagonist, I think what we've shown today is you can block almost all that signaling, irrespective of the disease, at the level of the adrenal. And we haven't even gone up to 120 yet, but there's not much left to block. Great. Thank you. Thank you. Thank you, and your next question comes from the line of Douglas Tsao from H.C. Wainwright. Please go ahead. Hi, good afternoon, and congrats. I guess, Scott, given the robustness of the data that we've seen for the first two doses, do you think there's futility for the 120 milligram dose in driving the sort of A4 even lower? And then just also, when you think about designing a phase III, obviously, given the strength of the data, we would anticipate to see very strong or very nice, you know, reductions in glucocorticoid steroids. But do you think how do you think about designing a study just to make sure that you can truly sort of characterize the benefits that you can achieve? So I think, Doug, on the 120, if I heard you right, you're asking about the futility or utility of 120. And there's two reasons- The utility, yeah. Yeah. There's two reasons to do it. One, you're absolutely right, there's not much left to block. We are probably at the top of the dose range with the 80 milligrams, although we still would like to see some more patients, so I think you need to make sure we get a broader sampling. But on the other hand, you also have a unique opportunity now to explore that higher dose and make sure we characterize the safety above 80 milligrams, as well as going below, down to 40 milligrams, which is beginning to show that it's a bit less efficacious than 80 milligrams, even though it's still a bit early. But if you show then that 80 milligrams is maximally suppressive, and 120 milligrams is also maximally suppressive, and that 40 milligrams is only partially suppressive, I think you've really determined the dose response range in a way that gives us great confidence in moving forward. Scott, just, you know, sort of my question about sort of undesigning the phase III to just sort of truly characterize the reductions in glucocorticoids. Yeah, GC reductions in glucocorticoids. Oh, yeah. So I mean, I think, again, the dose, the glucocorticoid dose reductions would be built into a phase III protocol. Typically, I mean, there's two ways it can be done. One is by sort of, in the protocol, forcing the dose to be reduced. The other is to wait for A4 to come to a certain target, presumably normal, and then to reduce the dose. In the case of atumelnant, to me, it doesn't seem like it's gonna be an issue, because we see the A4 come down to, well within the normal range, within days, typically, so far at this 80 mg dose, at least. And so I think, it will be both happening fairly seamlessly. I think that A4 will come down, hopefully, and that will allow a protocol-driven glucocorticoid dose reduction. And I think, you know, the only reason to have high levels of glucocorticoids is to try and suppress the excess androgens. So if you take those excess androgens away, there's no longer any need for high levels of glucocorticoids. You should be able to get down to physiologic replacements. And kind of mechanistically, as I was talking about before, it doesn't matter if you're taking some breaks off of ACTH secretion by lowering the glucocorticoids, if you've got a complete block of the ACTH action at the adrenal in any case. Okay, great. Thank you so much. Thank you. Thank you, and your next question comes from the line of Brian Skorney from Baird. Please go ahead. Hey, guys. Thanks for taking the question. This is Charlie on for Brian. We just wanted to ask about something we saw in competitor data. Crinecerfont showed good early A4 reductions, but then a rebound back to almost baseline by week 24, based on the New England Journal of Medicine publication. So how are you guys thinking about that potential effect on the longer-term follow-up? And do you think that the ACTH kind of choke point theory here would prevent that kind of thing from happening? Thank you. The simple answer is yes. So again, when you take the break off of ACTH secretion by reducing glucocorticoids, it doesn't matter how much ACTH is made, as long as you can block it all. And what we showed in our healthy volunteer studies in phase I, and there's some clear diagrams, some clear graphs of that in the phase I data release, is that after 10 days of dosing with atumelnant, or 04894 at the time, patients started to get adrenally insufficient with low levels of glucocorticoids, too low of levels, frankly. And their ACTH levels went up multiple times normal, and we gave them a challenge of ACTH levels that are in great excess compared to what one would expect, even in ectopic ACTH syndrome. Under those circumstances, with atumelnant on board, they still could not respond to that ACTH challenge and kept adrenal activation levels below normal. So I think that gives us great confidence that we don't expect to see a loss of that activity as you begin to taper down glucocorticoids in this patient population. Then I'd also point out, if you look at the A4 levels in the graph on the, I believe it's slide. Well, it's actually A4 17-OHP, slides 14, 17. You'll notice that even 2 weeks after they've discontinued atumelnant, and the drug will have completely cleared by the system, those A4 and 17-OHP levels do not go all the way back up to where they started. They're still suppressed. And this comes back to the mechanism that Alan has often called the angry adrenal. When the adrenal has been stimulated for a long period of time with ACTH, it becomes hypertrophic, and it produces excess either glucocorticoids, in the case of Cushing's, or A4, in the case of CAH. And we've shown preclinically that we can calm that adrenal down, prevent the hypertrophy, and I think we're seeing something along those lines here in the human data. Wonderful. Thank you. Thank you. Thank you. And your last question comes from the line of Dennis Ding from Jefferies. Please go ahead. Hi, thanks for taking our questions, and congrats on all the great data. So, as you're thinking about, as you're thinking about the phase III for CAH, what is your target patient population on A4? If you're thinking about any upper or lower bounds on the baseline A4. And then secondly, on pediatrics, I you know, totally appreciate your comments on needing some more data before fully committing to a pediatric phase III. But I'm wondering what work you've done on this front, and if you can even share any preclinical work you've done, perhaps even qualitatively. Thank you. Yeah, thanks. You know, I think we tried to illustrate that in slide 19. But in terms of patients coming into the study, there are patients out there that have high levels of A4, even though they're on normal glucocorticoids, because they couldn't tolerate the high glucocorticoids. And there are patients who have normal A4, who are on high doses of glucocorticoids. And then there's the third group, which is high on both levels, so those are the worst patients, and those are who we enrolled in this study. All of those patients should go into phase III. All of them deserve a chance to get both normal A4 adrenal androgens and normal glucocorticoid replacement. And in terms of, I think you're asking about the underlying tox program to enable juvenile. That's underway, as is pediatric formulation work, making sure that it's something that kids can take. Thank you. Thank you. That concludes our question and answer session. I will now hand the call back to Mr. Scott Struthers for any closing remarks. Thank you, everybody. We appreciate you joining today on the call, and especially appreciate all of you who made it out to Endo. We're really gratified to see the crowds around the posters and the great questions, and I think it was very fun for many of the investigators to talk to all the people. So thank you for coming out. Thanks for your attention, and look forward to talking to you all later. This concludes today's call. Thank you for participating. You may all disconnect.