Crinetics Pharmaceuticals, Inc. (CRNX) Earnings Call Transcript & Summary

Greetings. Welcome to Crinetics Pharmaceuticals conference call. [Operator Instructions] Please note this conference is being recorded. At this time, I'll now turn the conference over to Chas Schultz, Vice President of Investor Relations and Corporate Communications. Please go ahead.

Thank you, Rob, and thank you all for participating in today's conference call. Before we begin, I would like to point out that there is a slide deck that will be accompanying today's call. This slide deck can be viewed using the webcast link provided on the Investor page of the Crinetics Pharmaceuticals website. Also posted on the website as a news release issued earlier this morning announcing top line data from the multiple-ascending dose portion of the Phase I study evaluating CRN04894, which is the topic of today's call. Before we begin, I would like to remind all listeners that some of the information provided in the news release and on this conference call is covered under the safe harbor provisions of the Private Securities Litigation Reform Act and contain forward-looking statements based on the current expectations, including statements about the initiation of planned clinical trials. 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 the 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 SEC filings, including our annual report on Form 10-K. I would like to point out that the content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, May 25, 2022. 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 would like to turn the call over to Dr. Scott Struthers, Founder and Chief Executive Officer, Crinetics. Please go ahead, Scott.

Thank you, Chas, and thanks to all of you listening this morning. I'm beginning today's presentation along with our Chief Medical Officer, Dr. Alan Krasner, and our Vice President of Clinical Endocrinology Dr. Peter Trainer, who has had over 35 years of experience treating patients with Cushing's disease and congenital adrenal hyperplasia. Our Chief Financial Officer, Marc Wilson, will also be available during the question-and-answer session that will follow the prepared remarks. As Chas mentioned, the purpose of today's call is to walk you through the new data from the Phase I trial, evaluating the safety pharmacokinetics and pharmacology of CRN04894, which I'll refer to as just 4894. As a reminder, 4894 is our oral nonpeptide ACTH antagonist being developed for Cushing's disease and Congenital Adrenal Hyperplasia and potentially for other diseases caused by excess ACTH. Getting straight to the point, I'm very happy to report that the Phase I studies, multiple-ascending dose cohort built upon the pharmacologic proof-of-concept recorded from the single ascending dose portion of the study supporting 4894's advancement into patient trials. Some of you may recall that we made a similar announcement with our 4777 program last quarter, which speaks to the promise of our endocrine development strategy. Specifically, 4894 was shown to be well tolerated at doses from 40 to 80 milligrams administered for 10 days as there were no serious adverse events observed in the Phase I program and all adverse events were considered mild to moderate. We believe these favorable tolerability findings give us the flexibility to dose escalate further in some patients, if necessary. Pharmacokinetic data from MAD cohort were consistent with our expectations from the SAD data as 4894 showed excellent oral bioavailability with a half-life of about 24 hours. These results support the goal of a convenient once-daily oral dosing schedule. Pharmacologic data showed substantial and dose-dependent reductions of basal cortisol as well as clinically meaningful suppression of cortisol in the presence of disease like ACTH concentrations. Even in the presence of high ACTH concentrations and an extra ACTH challenge injected on top of that, 4894 was still able to keep adrenal activity of subjects below normal levels as measured by cortisol. This is an important finding that we hope may be predictive of 4894's efficacy in patients with CAH Cushing's disease or other diseases of ACTH as cortisol levels are a long established biomarker of adrenal activity in healthy volunteers. Collectively, we believe these Phase I data further support the conclusion of pharmacologic proof of concept for 4894 and diseases driven by excess ACTH, suggested by the SAD data. The latest data also established our starting dose range for patient studies and demonstrated 4894's tolerability in healthy volunteers. This is exactly what we hoped to achieve with our Phase I program. We're very excited to advance to clinical programs in CAH and Cushing's disease and Cushing's disease patients to evaluate a once-daily dosing regimen after having engaged with the appropriate regulators to discuss trial designs and other considerations. Just like 4777 and paltusotine before, 4894 is advancing towards its patient clinical trials after demonstrating pharmacologic proof-of-concept in healthy volunteer studies. Many of you have likely heard me talk about our ability to achieve early pharmacologic derisking as one of the most valuable features of Crinetics' endocrine development strategy, which leverages well understood and highly conserved biomarkers that translate from animal models, to healthy volunteers to patients. This allows us to pharmacologically mimic disease states in animals and healthy volunteers as a measure of a drug candidate's effect on biomarkers that are both critical to patient care and in many cases, expected to serve as registrational endpoints in pivotal trials. The successful execution of this strategy has now delivered a pipeline of 3 internally discovered new chemical entities with clinical proof of concept including: one, paltusotine that is currently in a registrational program measuring the same biomarkers utilized in animal and healthy volunteer studies. Given the success we've had to date with this strategy, we believe these current programs are just the beginning. We're using the same approach to advance our parathyroid hormone receptor antagonist as well as a suite of additional therapeutic candidates specifically designed to address a variety of endocrine diseases with high unmet need. With that brief summary complete, I'm going to now turn the call over to Alan to discuss the advantages of 4894's mechanism of action, unmet needs and it's seeking -- the unmet needs it's seeking to address and our study design and results. Alan?

Thanks, Scott. To provide some context for my presentation today, I'll start by giving a brief overview of the Hypothalamic-Pituitary-Adrenal or HPA access, which regulates the body's emergency response system in times of stress. The HPA axis is intrinsically regulated by a circadian clock, set to create a daily rise in ACTH in the early morning hours. ACTH secretion is regulated via a variety of mechanisms including the peptides arginine vasopressin or AVP, and corticotropin-releasing factor or CRF. The exclusive function of ACTH is to activate ACTH receptors in the adrenal gland, stimulating adrenal activity, ultimately resulting in increased cortisol production and secretion. Cortisol levels peak at approximately 8 a.m. for most people with normal sleep wake cycles. In addition, ACTH and cortisol secretion rises acutely in response to stressful stimuli. In healthy volunteers, cortisol is the dominant marker of adrenal activity. If you turn your attention to the middle portion of this next slide, you can see how the HPA access differs in patients with Cushing's disease who have ACTH secreting pituitary adenomas that are resistant to the negative feedback loop present in healthy individuals. This results in elevated cortisol levels due to increased amounts of ACTH. Persistently high cortisol levels will ultimately lead to a myriad of symptoms and complications such as weight gain, hypertension, hyperglycemia and psychiatric disorders. Turning your attention to the right side of the slide, you can see the pathophysiology of congenital adrenal hyperplasia, or CAH, which is another disease characterized by persistent ACTH excess. Patients with CAH have a defect in the enzyme responsible for the conversion of cortisol precursors into cortisol. This enzymatic defect breaks the negative feedback loop responsible for regulating ACTH secretion, which in turn leads to excess ACTH and results in cortisols precursors being shunted into adrenal androgens such as androstenedione, also known as A4. A4 is used clinically in CAH patients as a biomarker of disease status and therapeutic response. Excessive buildup of androgens such as A4 causes a host of symptoms such as infertility, premature or precocious puberty, short stature, virilization and ambiguous genitalia. This next slide illustrates what happens to hormone levels in healthy volunteers and patients with Cushing's or CAH. On the left, you see the normal circadian rhythm of cortisol rise and fall with peak levels around 8 a.m. These data are actually taken from the baseline period of our multiple-ascending dose study before subjects received 4894 or placebo. The middle chart is from a published paper evaluating a day-long profile of serum cortisol levels in Cushing's patients. Notice that these levels may not actually be that much higher than peak levels in healthy subjects, but they do not decline from their peak as is normal later in the day. On the right is another figure from the literature from a CAH patient, illustrating that these patients also experience a normal circadian rhythm, but because they can't make cortisol, the early morning peak and subsequent decline as observed in the adrenal androgen Androstenedione or A4 instead. Androstenedione is normally quite low in healthy individuals. These data illustrate how the design of our healthy volunteer study allows us to evaluate the ability of 4894 to inhibit adrenal activity. Because activation of the ACTH receptor is the key to the activation of the adrenal in the disease states, we were able to assess the molecule's pharmacologic activity in a way that we hope will be predictive of its efficacy in patients. In the case of future clinical studies in patients with Cushing's disease, we will measure suppression of adrenal activation by suppression of 24-hour urine free cortisol levels. This is the registrational endpoint for drugs intended to treat Cushing's. In the case of CAH patient trials, we won't be able to measure cortisol because patients don't make it. So instead, we will measure androstenedione, which is the clinically relevant marker of adrenal overstimulation by ACTH in these patients. On this slide, you can see an overview of the treatment landscape for Cushing's disease and CAH with molecules that are currently approved or in development listed at the bottom. They fall into 1 of 3 major buckets. First, there are molecules that aim to prevent ACTH secretion by targeting the pituitary gland. For CAH, glucocorticoids have been used for years for this purpose and CRF antagonist as adjuncts to glucocorticoids are in development. CRF antagonists are not being evaluated for the treatment of Cushing's disease. In Cushing's disease, the long-acting somatostatin receptor ligand pasireotide which suppresses ACTH secretion from pituitary tumors is approved, but has limited efficacy and commonly causes elevated blood sugar. The second category of molecules consists of adrenal steroidogenesis inhibitors, which are designed to inhibit the adrenal enzymes responsible for synthesizing cortisol. Notable drugs from this class include ketoconazole, levoketoconazole, metyrapone and osilodrostat. These agents are not useful in CAH because these patients already do not make cortisol. They are used for patients with Cushing's disease, but as a class, it is often difficult for physicians and their patients to find the right balance between sufficient efficacy and the many toxicities associated with these agents. Lastly, only for Cushing's disease, there is the class of molecules designed to inhibit glucocorticoid receptors in target cells. These include mifepristone which is in use as well as relacorilant, which is in development. Mifepristone can be challenging to use in clinical practice because it can result in elevation, not lowering of cortisol levels and therefore, there is no biochemical marker available to monitor efficacy. Additionally, there are other safety issues found in the label of this product. The shortcomings related to the safety and/or efficacy of the aforementioned agents result in poor risk-benefit profiles, Conversations we've had with some of the world's leading experts on Cushing's disease and CAH support this view and point to a significant unmet need for a novel therapeutic approach to treat these ACTH-driven diseases. The ACTH receptor is a unique, highly selective choke point for controlling all downstream ACTH-induced signaling. This is in contrast to targets such as the CRF receptor where receptor antagonism might be compensated for by other mechanisms, stimulating ACTH secretion. In contrast, the sole job of ACTH is to stimulate adrenal function and the only place in the body where 1 can find ACTH receptors is in the adrenal glands. With the unmet medical need in mind and because we believe that blocking the action of ACTH at its receptor, is an attractive and unexploited approach to treating ACTH-driven disease. Our team of drug hunters set out to identify a viable ACTH antagonist for clinical use resulting in CRN04894. To our knowledge, 4894 is the first and only ACTH antagonist to be evaluated in clinical studies. We previously demonstrated the ability of 4894 to potently antagonize the ACTH receptor during our Phase I trial, single-ascending dose cohorts and sought to build on these initial results in the multiple ascending dose portion of the trial, an overview of which is provided here. Similar to the SAD cohorts, the MAD portion of 4894's Phase I study was designed to evaluate safety, tolerability and pharmacokinetics in healthy volunteers, while also addressing 4894's pharmacologic activity even when volunteers have disease-relevant elevations in ACTH. Key differences between the SAD and MAD portions of the study where, of course, the evaluation of safety, pharmacokinetic and pharmacodynamic profiles after repeat dosing in the MAD portion versus after single doses in the SAD portion as well as the evaluation of different dosing regimens with our MAD cohorts. As you can see on the right-hand side of this slide, we evaluated daily morning dosing at 8 a.m. daily nighttime dosing at 10:00 p.m. and twice-daily dosing, so that we could assess the effects of administering 4894 at different points in cortisol's circadian cycle. This allowed us to identify an optimal regimen and a starting range for future patient studies. We plan to go forward with daily nighttime dosing because 4894 showed increased early morning cortisol suppression compared to dosing in the morning after the circadian peak ACTH surge, and there was no advantage seen for BID dosing. For this reason, in today's presentation, we will focus on results from the 3 nighttime dosing cohorts. Here, you can see a schematic of the study procedures used in the nighttime dosing cohorts as well as the naming convention for study days that will be utilized throughout this presentation. We denote the first day of study drug administration day 1 with 4894 or placebo given orally to patients at 10:00 p.m. on each of days 1 through 10. We took blood draws periodically throughout the study to assess serum cortisol while we were also collecting 24-hour urine samples for free cortisol. On select days, the blood sampling was performed repeatedly, sometimes as frequently as every 2 hours to obtain full 24-hour serum cortisol profiles as shown in the bottom left portion of the slide. As mentioned earlier, a key goal of this study was to demonstrate 4894's ability to reduce adrenal activity. From a safety perspective, to ensure the cortisol levels of our healthy volunteers did not fall into a range low enough to precipitate symptomatic adrenal insufficiency, we added a stipulation to the trial protocol that called for glucocorticoid treatment with low physiologic replacement doses in the event that subjects 8 a.m. serum cortisol level dipped below 5 micrograms per deciliter. Dosing with the oral glucocorticoid hydrocortisone, a synthetic form of cortisol allowed these subjects to remain in the trial without the need to discontinue the study drug. It should be mentioned that the elimination half-life of oral hydrocortisone is roughly 1.5 hours, and therefore, would be expected to only transiently raise measured serum cortisol levels after each of the 2 daily doses, resulting in an underestimate of overall cortisol lowering potency in the subjects who required replacement. However, we anticipate that all patients with CAH would be taking the combination of glucocorticoid plus 4894 as an adjunct. So those subjects who meet criteria to be treated preventatively with glucocorticoid replacement, create a nice model of what might well be observed biochemically in the disease state. Lastly, similar to procedures followed in the single-dose portion of the study, we again evaluated the robustness of 4894's ACTH receptor antagonism by administering an ACTH challenge on day 11, after the last dose of 4894, which was administered on the night of day 10. With that overview of the study design complete, let's go to the data. On this slide, you can see that 4894 was well tolerated in the Phase I program. We did not observe any serious adverse events or safety signals in vital signs, laboratory testing or ECGs, and there were no discontinuations due to treatment-related adverse events. As you can see in the table, 11 individuals in the treatment group, all in the MAD cohorts did experience at least 1, 8 a.m. serum cortisol level below 5 micrograms per deciliter. Four of these occurred during treatment with 4894 in the nighttime dosing cohorts and received physiologic glucocorticoid add-back per protocol, which allowed them to safely complete study drug dosing. None of these volunteers with this biochemical finding, experienced symptoms suggestive of clinical adrenal insufficiency at any time. Triggering of the criteria for glucocorticoid add-back was expected due to 4894's potent pharmacologic activity. The fact that no subjects experienced symptomatic adrenal insufficiency confirmed that the protocol safeguards were appropriate and effective. On this next slide, you can see the results of our pharmacokinetic analysis. These data are consistent with what we expected based on our SAD data, including a half-life of approximately 24 hours. 4894 was rapidly and efficiently absorbed following oral administration with dose proportional exposure and a time to maximal concentration of about 1 to 2 hours. These results support our once-daily oral dosing schedule. On this slide, you can see the serum cortisol levels from the healthy volunteers in our MAD cohorts at baseline before receiving placebo or 4894. As I previewed earlier, these data tell us that our volunteers had the expected circadian rhythm of adrenal activity with serum cortisol levels peaking in the early morning and reaching their lowest points later at night. Study Drug Administration, ACTH challenge tests and sample collection time points were carefully scheduled in the protocol to allow us to gain a thorough understanding of 4894's effects on the natural circadian rhythm of ACTH and cortisol secretion. Slide 15 shows the effects of 4894 on adrenal activity at 8 a.m. each morning, which is right about the time cortisol levels should normally be peaking. As you can see from the graph, treatment with 4894 led to a rapid reduction in morning serum cortisol that was sustained throughout the treatment period. We are showing just the 80-milligram nighttime dosing cohort here for clarity, and I'll show you in the next slide that the change from baseline in 8 a.m. serum cortisol was dose dependent. This is the finding we were hoping for as it demonstrates 4894's pharmacologic activity. I'll also note that these serum cortisol levels were drawn prior to the administration of the short-acting hydrocortisone in the 2 subjects in this cohort that required add-back per protocol. The cortisol levels that triggered the add-back in these studies are noted by the diamonds on the graph. On this slide, you can see the full 24-hour profile of serum cortisol secretion in subjects treated with 4894 versus placebo. On the left, you can see that serum cortisol was suppressed throughout nearly all of the circadian cycle with a peak reduction of 53% in the 80-milligram cohort. Turning our attention to the upper graph on the right showing effect -- it shows the effect on 24-hour serum cortisol area under the curve. You can see that 4894's effects were dose-dependent, which suggests that doses could be titrated in individual patients to ensure the proper modulation of hormone levels and diseases such as Cushing's. I'll also note that for completeness, this graph includes data from subjects who received glucocorticoid add-back in each dose group. Their individual values are noted by the white asterisks within the bars, which not surprisingly, are above the mean values, likely due to the inclusion of the exogenous hydrocortisone measured in the serum assay which may well result in an underestimate of the serum cortisol decline measured over the 24-hour period. In the lower graph on the right, you can see robust dose-dependent suppression of peak 8 a.m. serum cortisol concentrations. Please note that data from subjects taking oral glucocorticoid replacement are included here because oral hydrocortisone last taken at 2:00 p.m. the afternoon prior has too short of half-life to affect the following morning's 8 a.m. cortisol measurements. On this next slide, we look at the effect of 4894 on adrenal activation measured using an important well-known and widely utilized clinical assay measuring bioactive-free cortisol in the urine. Approximately 90% of the cortisol measured in serum cortisol assays is bound to protein and unable to exert biological actions and target tissues. It is therefore the nonprotein bound or free fraction of cortisol that is most clinically relevant. This free circulating fraction of cortisol is filtered by the kidney into urine. Therefore, in order to get a sense of the biologically active cortisol in the circulation over the course of a day, urine is collected for a 24-hour period and the total amount of cortisol in the urine is measured. Because of this, normalization of 24-hour urine cortisol has been used as the primary endpoint in recent registrational trials, resulting in approved drugs for the treatment of Cushing's disease. On this slide, we can see 4894 resulting in dramatic dose-dependent reductions in 24-hour urine-free cortisol, reaching a median of 75% in the 80-milligram group. In conjunction with serum cortisol reduction results, these data only give us more confidence in the clinical meaningfulness of the ACTH receptor antagonism that can be achieved with 4894. On Slide 18, we see ACTH concentration measured during day 9 of the study after subjects had reached steady state. Given the consistent cortisol reductions we just saw, it is not surprising to see a rise in ACTH secretion as the pituitary glands in these healthy volunteers try to compensate for the reduction of adrenal activity. However, despite this increase in ACTH concentrations, we saw that 4894 was still able to block ACTH action and sustain reduced cortisol output from the adrenal over the entire course of dosing as shown in the previous 3 slides. A key point to remember here is that while the 4894 treated subjects were experiencing this rise in ACTH, the placebo subjects were not, and yet the 4894 treated subjects had much lower cortisol level. I'll also note that when restoring negative feedback in the subjects who had glucocorticoid replacement added to 4894 per the safety protocol, we see the ACTH decline. These are the ACTH concentrations that we would actually expect to see in CAH patients taking this combination of agents. Overall, we are very pleased that 4894 was able to block adrenal stimulation over a range of ACTH levels, including sustained elevations, the magnitude of which can be seen in relevant disease states. On Slide 19, you can see 4894 suppression of cortisol secretion following administration of an ACTH challenge on top of the healthy volunteers already elevated ACTH levels. In our placebo healthy volunteers who had normal ACTH levels at baseline, injection of 1 microgram of ACTH results in ACTH elevation that are comparable to those seen in patients with CAH or Cushing's disease. In the 4894 subjects, the ACTH challenge being administered further adds to their already elevated ACTH levels, and this provided an extremely rigorous test of 4894's ability to counteract the effects of excess ACTH. As you can see when looking at the open circles curve, subjects on placebo saw their cortisol level spike from about 15 to about 20 micrograms per deciliter on average at 30 minutes post ACTH challenge. In contrast, the serum cortisol levels of subjects receiving 4894 remained below the normal range for healthy volunteers following exogenous ACTH administration, despite the additional ACTH challenge on top of already elevated ACTH levels. Similar results were also achieved in the 40- and 60-milligram cohorts. In summary, we saw strong suppression of adrenal activity in the face of high ACTH levels, suggesting to us that 4894 will also be able to suppress adrenal activity in patients with Cushing's disease and CAH. This leads us to what we believe is the key takeaway from today's data, which is the demonstration of 4894's ability to suppress adrenal activity in healthy volunteers below normal, even in the presence of disease-like elevations in ACTH. As was the case for paltusotine, which is now recruiting for its registrational study, we hope we have once again demonstrated how a healthy volunteer study and provide a disease-relevant model to strengthen our clinical proof of concept prior to entering patient studies. Before I hand the call off to Peter to talk about what today's results mean for patients and our future clinical plans, I'll conclude with a broad recap of 4894's Phase I results. In both our SAD and MAD cohorts, 4894 was shown to be well tolerated with no serious adverse events nor dose discontinuations due to treatment-related adverse events. Pharmacokinetic data support our once-daily dosing schedule moving forward as 4894 was rapidly absorbed, showed dose proportional exposure from 10 to 80 milligrams and had a favorable half-life of approximately 24 hours. Finally, pharmacodynamic data from both the SAD and MAD cohorts of the trial provide pharmacologic proof-of-concept for an ACTH antagonist to suppress adrenal activation and depending on regulatory feedback, established the starting dose range for subsequent studies in patients. We saw strong and dose-dependent suppression of basal and 8 a.m. serum cortisol, serum cortisol over 24 hours and in bioactive urine free cortisol over 24 hours, the latter being a precedented registrational endpoint. Additionally, we observed clinically meaningful suppression of cortisol following disease-relevant ACTH challenge. When taken together, these results tell us that we have accomplished each of the desired goals of our Phase I program and that 4894 is a therapeutic candidate that behaved in healthy volunteers as intended. Based on these data, we believe it is very important to evaluate 4894 in patients to confirm its safety and toleration and also to fully characterize the therapeutic potential of this first-in-class compound. I'll now hand it over to Peter to walk you through some of the goals we aim to achieve in future clinical trials in CAH and Cushing's disease.

Thanks, Alan. It's my pleasure to have the opportunity to provide some clinical context on what today's exciting results may mean for future clinical trials and CAH and Cushing's disease patients more broadly. I'll start with Cushing's disease, which is the consequence of long-term inappropriate elevation of circulating cortisol levels driven by ACTH secreted from a pituitary tumor, and left untreated carries a 50% 5-year mortality. Excess cortisol has impacts on all tissues and results in problems as diverse as insulin resistance and diabetes, the laying down of fat, particularly visceral fat around the middle, obesity, hypertension, muscle wasting, particularly of the shoulder girdle and pelvis, osteoporosis, thin, fragile, easily bruised skin, suppressed immunity, particularly to viral infection, women troubled by hirsutism and loss of periods while testosterone deficiency is common in men. Neuropsychiatric problems, particularly atypical depression is common. The link between increased cortisol and these signs and symptoms of Cushing's disease are so well established that prior registration studies have utilized reduction in 24-hour urine free cortisol as a primary end point as Alan mentioned a moment ago. The core objective of our upcoming studies in Cushing's disease will thus mirror the objective we have successfully achieved in our Phase I program by reducing cortisol secretion in the presence of sustained elevation of plasma ACTH. Turning our attention to CAH. On the right, you can see an overview of wide-ranging symptoms and complications faced by CAH patients. With the color coding showing just how many of these complications are related, at least in part, to treatment with supraphysiological doses of glucocorticoids. It's important to realize that this lifelong condition has diverse manifestations across the decades, but all are driven by the consequences of elevated endogenous antigens, inadequate endogenous cortisol synthesis and unwanted effects of exogenous glucocorticoids. At birth cortisol deficiency is life-threatening, babies die of cortisol deficiency, while at the same time, elevated androgens can result in ambiguous genitalia, in newborn girls. Across childhood, CAH impacts on growth, poorly controlled CAH results in significant short stature and the development of and CAH also controls the impact on the development of secondary sexual characteristics. Treatment aspires to control the impact of excess adrenoandrogens and provide physiological glucocorticoid replacement therapy. But all too often, supraphysiological doses of glucocorticoids are required to provide the necessary negative feedback to the hypothalamic pituitary axis to downregulate ACTH secretion and thereby suppress the production of adrenoantigens such as androstenedione. With advancing years, the supraphysiological glucocorticoid doses is up in a well-known side effect of glucocorticoids, which are essentially the features of Cushing's syndrome that I described a moment ago. With that in mind, a key goal of our CAH program will be to normalize adrenoantigens by blocking ACTH action rather than secretion, thus enabling patients to maintain the glucocorticoid dose within the physiological range. This should lead to the improvement of both disease and glucocorticoid-related complications. This is reflected in the expected registrational endpoints for CAH, which will include both glucocorticoid sparing and androstenedione levels. And with that, I'll hand it back to Scott for some concluding remarks. Scott?

Thank you, Peter. Looking forward, we plan to enable our advancement into patient trials by reviewing our data with regulators and discussing the best choice of trial design options, to advance development of 4894 for patients with either Cushing's disease or CAH. Specifically, we will be looking to confirm our proposed dose range of 40 to 80 milligrams plus while also seeking guidance on Phase II trial designs and registrational requirements. With these interactions and ongoing enablement activities, we expect studies in our patient programs to begin later this year. The data presented today has us extremely excited as we advance towards these patient programs. We believe our Phase I results demonstrating 4894's novel mechanism of action in healthy volunteers has derisked our upcoming patient trials and highlighted its potential to become not only the first-in-class ACTH antagonist, but it could enable us to become the best of all classes of drugs to treat Cushing's disease and CAH, which collectively affect approximately 37,000 patients in the United States. Taking a broader view of the MAD data we reported today also caps off what has been a transformational period for Crinetics. It began February with the announcement of 4894 and 777 entering into the clinic. Since that time, we have grown from a company with a single clinical stage program recently completing Phase II to 1 that has demonstrated clinical proof of concept with 3 well-crafted therapeutic candidates, one of which is in registrational program and 2 of which are now ready to enter patient studies. The rapid growth in advancement seen in our pipeline over this time is a testament to the extensive expertise of our drug hunters and developers as well as to the dedication of all those making up the broader organization supporting these efforts. It also speaks to the unique efficiency of our development strategy. As mentioned earlier, this strategy takes advantage of the well understood and highly conserved nature of endocrine pathways to enable early derisking in preclinical and healthy volunteer studies that mimic disease states and assess the molecules effects on biomarkers that are also used by regulators as registrational endpoints and by physicians as critical metrics to inform the treatment of patients. Empowered by the success we have had with this strategy to date, we are now working to expand its application to bring our next generation of non-peptide therapeutic candidates into the clinic. We expect a lead from our parathyroid hormone receptor antagonist program to be up next and are also pursuing additional discovery programs designed to address nonfunctional pituitary adenomas, polycystic kidney disease and other endocrine disorders with well-understood therapeutic targets and high unmet medical needs. Moving forward, we will continue to follow this endocrine development strategy as we further leverage our in-house scientific expertise and continue to recruit additional world-class talent throughout the organization. We firmly believe this will enable us to build on our success to date and solidify our position as the leading endocrine innovator. We've accomplished a lot recently. And on this next slide, you can see the remaining near-term objectives we expect to accomplish this year as we work towards our broader goals. These include beginning patient studies for both 4777 and 4894 programs as well as initiating IND-enabling studies on a parathyroid receptor antagonist program. In parallel with these efforts, we will continue to advance paltusotine's 2 Phase III trials in acromegaly, both of which remain on track for top line data in 2023. Finally, I'll conclude my formal remarks by thanking all the Crinetics employees, partners and clinical trial participants who have contributed to the company's success and then open it up for questions. Thank you, everybody. Operator?

[Operator Instructions] And our first question comes from the line of Charles Duncan with Cantor Fitzgerald.

Yes. Scott and team, fascinating results this morning.

Thank you, Charles.

So I had a quick question regarding what you're seeing in this study in normal volunteers. I guess I'm wondering what would you anticipate as you go out beyond 10 days to, say, 10 months and 10 years of dosing. And I realize you need to speculate on this. But it looked like at 9 days, you saw a greater effect than at 2 days. And so it perhaps doesn't suggest taciflaxis. But I guess I'm wondering what would you anticipate over dosing period longer?

Well, maybe I'll just comment that the overall state of the adrenal is dependent on continued stimulation by ACTH. And so you would expect, if anything, adrenal activity to be continued to decline with time. But maybe I can ask Peter to comment on some of the clinical analogs that might bear more directly on your question. Peter?

No, this is one of the fascinating things that we will study as we expose patients for longer. What we know is that if you make -- render a patient ACTH deficient, it takes 6, 8 weeks for the adrenal glands to atrophy and become unresponsive to ACTH. So this -- and 1 can anticipate in these -- in the secretive [indiscernible] ACTH congenital adrenal hyperplasia, they have big glands. And the hope is that with -- we will see increasing benefit as those hypertrophic glands become gradually atrophic, which is a process that could easily take 3 months, potentially longer. So we may see added benefit over time in CAH and in the hypertrophic glands that patients with Cushing's disease have. So we are very excited about what we might see with longer therapy.

That's helpful. And if I could ask 1 follow-up, and that's related to next steps. And again, I know that you haven't had the feedback from the agency. But I guess going back to that question on kinetics of change. I'm wondering what would you like to do in the next study? First of all, you mentioned either Cushing's or CAH. If you had a favorite to start with what would it be? And secondarily, what kind of dosing duration would you look to accomplish over the course of the next study?

Well, just to be clear, we're intent on developing for both CAH and Cushing's disease. And exactly which study starts slightly ahead of the other is a tactical question that will be worked out at the team level, but we're committed to both indications. But Alan, maybe you can talk a little bit about duration of prior studies in both these indications.

Sure. Generally, Phase II studies in this area range from 6 weeks to 3 months or so in treatment duration and the traditional Phase III trial would be around 6 months in treatment duration. I anticipate ours will look about the same in terms of treatment duration. But as Peter discussed, we may see increased efficacy evolve over time if the adrenal atrophy is achieved with the compound. We would -- that would be sufficient time, of course, to see it at least in the early stages. By and large, all of our major clinical trials would be followed with long-term open-label extension trials beyond that, typically going out for at least a year, usually more than that. So I think we'll -- with our larger scale patient trials, we'll certainly see the full therapeutic picture and be able to document very well, both safety and efficacy in those kinds of trials.

Our next question comes from the line of Josh Schimmer with Evercore ISI.

Apologies, I guess the from the prepared remarks, I'm just not understanding some of the as on up, but do you expect there to be a compensating chronic increase in ACTH secretion -- and so would there be any risk of stating in emitting perhaps listening to...

I had a little difficulty hearing the question. Alan, were you able to make it at all?

I can try again to be a little louder if that helps.

There you go. Okay.

Yes. So I was just wondering if there's a risk of chronic compensatory ACTH elevation in these patients and a risk of changes -- getting color changes or worsening of pituitary adenomas?

Got it. Alan, do you want to answer that?

So I think we'll have to -- let's talk about each patient population. First, the congenital adrenal hyperplasia patients. These patients, of course, do not have pituitary adenomas. They do have chronically elevated ACTH levels due to their underlying enzymatic defect. These ACTH levels are controlled with glucocorticoid replacement. The addition of an adjunctive therapy like 4894 would not affect that situation, it would not worsen their ACTH or cause their ACTH levels to further increase. These patients, although they -- I heard you ask about hyperpigmentation. These patients, to my understanding, despite these chronically elevated ACTHs, which are mainly controlled with glucocorticoid, do not have hyperpigmentation. I'll ask Peter also to comment on his clinical experience.

So certainly, in -- I've never known a patient with CAH where hyperpigmentation was a concern because they're established on glucocorticoid replacement. So that's not been a clinical issue I've ever come across.

And I think the second part of the question was around similar question in Cushing's patients?

Right. disease -- Go ahead, Peter. Go ahead.

Sure. Well, the observation I'd make in Cushing's disease, where the ACTH comes from a pituitary tumor and the characteristic of pituitary tumors is that they are resistant to the normal feedback mechanisms. So that one may not necessarily see any change in ACTH with a change in cortisol status or it may be significantly less than one sees in healthy volunteers. So it would be surprising if we saw the changes that we see in healthy volunteers in patients with feedback resistant pituitary tumors. Do you want to add anything, Alan?

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

I was hoping you could elaborate a little bit on how you're thinking about any potential need to dose explore in patients with Cushing's and CAH in the context of the healthy volunteer data that you've seen so far? And then I've got a couple of others.

Why don't you answer that one, Alan?

Yes, I do think we have a dose range explored in healthy volunteers, which is definitely going to be relevant to the patients. And as we said during our prepared remarks, I think we have a good idea of starting doses in the various patient populations. Of course, Phase II is all about dose range and dose response exploration in patient populations. And although we have what I think is a very effective dose, what should be a very effective dose in CAH patients. Cushing's disease -- the severity of Cushing's disease can be very heterogeneous. And that's a disease where I anticipate this compound would be titrated. The dose of the compound would be titrated to individual needs and treatment goals. CAH, I anticipate would be more probably a 1 dose or limited number of doses needed to control the early morning ACTH surges in those patients. So certainly, in Phase II, we will include the doses we've studied here in these healthy volunteers, but we would also like the option to explore beyond the 80-milligram sweep evaluated in this study.

Okay. Got it. And then just a couple of others. The ACTH challenge, was that done at all the dose cohorts in the MAD study or just the 80? And then on the tolerability side, what can lead to that contact dermatitis that you saw? Is that on or off target? And would you expect to see that in patients?

So first of all, the ACTH challenge test was done in all dose cohorts, and we saw inhibition of ACTH-stimulated cortisol in response at 40, 60, 80 milligrams. Contact dermatitis is a very common observation in Phase I studies because they are typically related to the procedures used in the studies. In this case, all of these cases resulted from things like ECG electrode placement, tape used to secure IV catheters and a phlebotomy tourniquet in one case. This is an irritative phenomenon of the skin. It is not an allergic phenomenon and I don't think it in any way reflects an adverse event in response to drug. These -- all of these cases you see in this table were deemed by the investigator not to be treatment-related. They were all mild and attributed to study procedures.

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

I'm wondering if you can talk a little bit about the reduction we saw in urinary free cortisol and what you have been hearing from KOLs in terms of what is meaningful in the patient population, specifically in Cushing's disease?

Well, I can take a partial shot at that. Thanks, Catherine. I think the way to think of it is that here, we have taken patients who have already elevated ACTH levels and reduce them to below normal levels of serum cortisol and dramatically reduced the levels of urinary free cortisol. So we'll still need to confirm some of this in patients. But the depth of this shows that we can suppress the adrenal activity pretty profoundly beyond what should be experienced in any healthy volunteer. These are really approaching adrenal insufficiency. Maybe I'll let Alan or Peter comment on that a little further.

Well, I would say the urine free cortisol reductions are dramatic. And if this is what we see in the Cushing's patient population, I suspect we'd have a very high rate of normalization in urine free cortisol. And recall, that is the primary endpoint in Cushing's disease, registrational trials. Some of these patients had almost near complete suppression of urine free cortisol. And I find that very encouraging. I really wasn't expecting to see that in a cohort of healthy volunteers. Remember, these are volunteers who start out with normal urine free cortisol and showing that they go down using this measure is actually quite difficult. And the fact that it's so apparent and an obvious effect of this compound just gives me a great deal of hope it will be very effective in Cushing's disease patients. Peter, feel free to add any comments.

Well, my comment is that I used to be a KOL and I'm an employee because this is the route for treating Cushing's that people have been looking for. and uniformly among the KOLs there is an impatience for us to proceed to patient studies. And what data they've seen, I think, has only reinforced that.

Got it. One more question on excessive ACTH in CAH patients. Are there any potential drawbacks to inhibiting at the receptor, but not actually lowering ACTH levels overall?

The short answer is I don't think so. I think this is actually the ideal place to drug the whole system, and it's something that's been obvious to anybody who's looked at the whole system for decades, it just hasn't been able to be done before. So if there are drawbacks to this approach, the only one is potentially over suppressing the adrenal in the Cushing's patients, but then we just got to replace it as necessary or reduce the dose. Alan, did you have any thoughts on that question?

No, I don't think so. What I can say is that even if ACTH levels are slightly elevated, we know that this compound can prevent the ACTH from fully stimulating the adrenal gland because we've demonstrated even in these healthy volunteers that the adrenal is appropriately suppressed even when in the presence of high levels of ACTH. So it's not like it will prevent the drug from working. And again, I should also caution this is what we see in healthy volunteers. The situation is quite different when we're talking about the negative feedback regulation of pituitary tumors in Cushing's disease. And again, CAH this really -- we would not expect to see any change in ACTH by adding adjunctive 4894 to their already existing glucocorticoid therapy.

[Operator Instructions] The next question is from the line of Jon Wolleben with JMP Securities.

Congrats on the data. Just wondering how you guys are thinking about these 2 opportunities, Cushing's being a more mature market, adrenal hyperplasia, nothing available, but a couple of candidates further in development. Just wondering how do you think about the potential opportunities between the 2?

I think both are in tremendous need of a better agent. But Peter, out of all of us, you've treated the most patients with these diseases. What do you think?

There is a real need in both conditions. I think that the CAH hasn't had any truly novel therapy since glucocorticoids were discovered. And we know that we overtreat patients. And this is a life-long condition. So potentially you start therapy at a very young age and are on it for life. And that obviously, is an attractive notion, and we can have a lifelong benefit. The currently available drugs with Cushing's all have limitations. The most effective are those that act on the adrenal glands, but that is at -- with various complications associated with either overtreatment or the raising of androgen levels. So that -- who shouts loudest? The Cushing's community probably makes the most noise but the CAH community are very keen to be able to better treat their children.

That's helpful. And maybe just one logistically, you're going to have multiple Phase II trials kicking off later this year, hopefully. You previously said you had runway with your cash on hand in the second half of 2024. Did that prior guidance include the expectation for both of these, Cushing's and CAH trials to kick off?

Marc?

Jon, yes, good question. So yes, we've accounted for both of these indications in our operating plans that led to that cash runway into late 2024. So to further Scott's point, we plan to move 4894 into both of these indications, and it's really a tactical matter, which one gets in first

Our next question is from the line of Joseph Schwartz with SVB Securities.

I'm Joori dialing in for Joe. Following up on a question asked earlier, but asked a little bit differently. Could you talk a little bit more about how the 2 doses might differ between the 2 indications I know you mentioned that in Cushing's patients, they might need to be titrated to individual doses whereas CAH might need to be -- they might just need the one dose. But I guess I'm curious if one indication requires more ACTH antagonism than the other? Does one indication have a higher bar than the other, I guess, is the question that I'm asking.

Well, I think Alan answered that in part by talking about the range of severities in Cushing's patients. In the CAH program, we anticipate trying to find a single effective and safe dose for all patients, maybe with some additional smaller doses for pediatrics. But in Cushing's disease, there are some patients with a very extreme phenotype, often from ACTH secreting tumors that are not in the pituitary. Some of the lung nuts, for example, can make very high levels of ACTH. And so they may require some higher doses, although that's a relatively rare type of tumor. And then in the Cushing's patients also, we expect dose customization for patients because if you have very mild disease, you don't want to suppress them into adrenal insufficiency. And if they have very severe disease, they may need a little higher dose. Does that help?

Can I just add something to that, Scott?

Please, Peter.

Another point I would make is that in the patients with CAH, if we were to, from an endocrine point of view, overtreat them, they would become deficient in androstenedione, in adrenal androgens. And that's not a clinical entity. There is no concern or problem being deficient in those hormones so that we don't have to dose titrate to a particular target, which -- while in the Cushing's as Scott was explaining, you have a disease of varying severity between patients and even fluctuates within a patient. And one wants to dose titrate to place the cortisol not too high and not too low. So it's more individualization in dose in Cushing's patients with other agents, and I would anticipate with ours.

Does that help, Joori?

Yes, that helps. And then I know some companies have had a difficult time enrolling their CAH trial. I was just wondering how competitive you believe -- it will be based on your survey of the landscape? And then also, if you have any strategies to kind of ease the enrollment process?

We are always paying close attention to enrollment strategies. And I think maybe I don't want to get too specific on that. But you'll see the scope of our acromegaly trials as an example, where we are activating sites all around the world and operating in regions that I think some of the prior CAH studies have not operated in. But apart from that, we just have a deep commitment to endocrinology. Any competing products are by companies that have a single product. These investigators that we're working with for Cushing's disease will be many of the same investigators that are doing the acromegaly trials. And all are endocrinologists who we are working with every day. So I think we have a fundamental difference from anybody else, which is we are trying to innovate broadly across the endocrine space. We're going to be doing new trials with new drugs in the coming years. And I think we're a part of that community. And that overall relationship is different than many companies.

At this time, we've reached the end of our question-and-answer session. And I'll now turn the call over to Dr. Scott Struthers for closing remarks.

Thank you, everybody, for joining today's call. We look forward to continued advancement of our programs and providing additional updates on their progress in the future. Thank you, again, and have a great day.

Thank you. This will conclude today's call. You may now disconnect your lines at this time. We thank you for your participation.