Good day, everyone, and welcome to this Crinetics Pharmaceuticals investor call. Getting started, all participants are in a listen-only mode, but later you will have the opportunity to ask questions during the question-and-answer session. You may register to ask a question at any time by pressing the star and one on your touch-tone phone. Please note this session may be recorded. I'll be standing by should you need any assistance today. It is now my pleasure to turn today's program over to Head of Investor Relations, Gayathri Diwakar. Please go ahead.
Thank you, Operator. Good morning, everyone, and thank you for joining us to discuss the atumelnant phase II CAH top-line results. Today on the call, we have Dr. Scott Struthers, Founder and Chief Executive Officer, and Dr. Alan Krasner, Chief Endocrinologist. Also joining us for the Q&A are Dr. Dana Pizzuti, Chief Medical and Development Officer, and Marc Wilson, Chief Financial Officer. Please note there is a slide deck for today's presentation, which is in the Events and Presentations section of the Investors page on the Crinetics website. In addition, a press release was issued earlier this morning and is also available on the corporate website. As a reminder, we'll be making forward-looking statements, and I invite you to learn more about the risks and uncertainties associated with these statements as disclosed in our SEC filings.
Such forward-looking statements are not a guarantee of performance, and the company's actual results could differ materially from those stated or implied in such statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release, the company's other news releases, and Crinetics' SEC filings, including its annual report on Form 10-K and quarterly reports on Form 10-Q. I would also like to specify that the content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, January 10th, 2025. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. With that, I'll hand the call over to Scott.
Thank you, Gayathri. And good morning, everyone. Thank you for joining us this morning. Today, we're excited to share the top-line results from our phase II study of atumelnant in participants with congenital adrenal hyperplasia, or CAH. Today's data confirm and extend the preliminary results we shared at Endo last June in Boston. We're excited about the potential of atumelnant to be an important advance in the treatment paradigm for CAH, given its unique mechanism of action and ability to both induce rapid and substantial reductions in hormonal biomarkers and achieve meaningful improvements in multiple signs and symptoms of CAH. As we will detail shortly, taken together, these data strongly position us to initiate our phase III program in CAH this year.
In today's results, atumelnant demonstrated substantial reductions in day four at the first time point of two weeks in all dose groups, 40 mg, 80 mg, and 120 mg. These effects were sustained through the 12-week pre-specified primary endpoint, where the degree of suppression was dose-dependent and highly statistically significant, with an up to 80% mean reduction in the high dose group, corresponding to a 954 ng/dL reduction in day four. Further, a majority of patients in the 80 and 120 mg dose groups achieved normalization of day four, and this occurred in as little as two weeks. In addition, an up to 67% mean reduction in the confirmatory biomarker, 17-OHP, was also observed.
Perhaps more importantly, in addition to observing improvements in these biochemical markers of disease control, we also saw broad improvements in clinical symptoms of CAH, such as a resumption of menses in women, resolution of androgen-mediated polycythemia, and consistent reductions in the size of the enlarged adrenal glands of the participants in this study. This is particularly encouraging since, after all, the name of the disease is adrenal hyperplasia. We're actually shrinking these overgrown adrenal glands. Of course, it's also important to note that atumelnant continues to be well tolerated with no treatment-related severe or serious adverse events. We believe that the efficacy and safety shown in this phase II study support progression to registrational studies with all due haste.
The remarkable atumelnant product team is working hard to start a phase III study in adults and a phase IIb study in pediatric patients, both of which we expect to initiate this year. Turning to slide four, as you may recall, CAH is caused by mutations in the gene encoding 21-hydroxylase that is responsible for the final step of cortisol biosynthesis in the adrenal gland. Among its various actions, cortisol acts as a brake on the production of ACTH by the pituitary gland, and without that brake in CAH patients, excessive amounts of ACTH are released into the circulation, resulting in excessive stimulation of the adrenal gland. This causes it to become hyperplastic, hence the name of the disease. Excess ACTH can also cause the formation of adrenal-like tissue in the gonads, resulting in what are called adrenal rest tumors.
Stimulation of the adrenal by this excess ACTH also results in the oversecretion of precursors to cortisol, since with the enzyme mutation, these cannot be converted into cortisol. The main precursors are androstenedione, or A4, and 17-hydroxyprogesterone, or 17-OHP. A4 is an androgen and can result in complications of hyperandrogenism, such as hirsutism, acne, and polycythemia, or elevated hemoglobin levels. And this is similar to the type of thing seen in people who abuse anabolic steroids. In women, these precursors can be converted to testosterone, which, together with the adrenal androgens, can impair the menstrual cycle and fertility. Men can also have impaired fertility because of the impairment of their reproductive axis. Children face a variety of severe consequences, including early puberty resulting in short stature and virilized genitalia in girls.
Atumelnant was designed and discovered in our laboratories to intervene at the key choke point of this endocrine system with the goal of resolving the biochemical and symptomatic complications of CAH. Atumelnant is a once-daily, oral, selectively targeted non-peptide melanocortin-2 receptor antagonist, or MC2R. This is the receptor for ACTH. Despite knowing about ACTH's pivotal role in the endocrine stress response for nearly a century, no other ACTH antagonist drug candidate has been developed or studied in humans. In addition to CAH, which we are talking about today, atumelnant is also in a phase II study for the treatment of ACTH-dependent Cushing's disease. In slide five, we ask ourselves, excuse me, what does this all mean for the patients?
Based on our research and feedback from patients and healthcare providers, our treatment goals for atumelnant are to normalize adrenal androgen production, eliminate the need for excess glucocorticoids that result in the complications such as weight gain and hypertension, correct polycythemia, and deal with the signs and symptoms of the disease, including restoring normal menstrual cycles and fertility in women, in men restoring fertility and shrinking testicular adrenal rest tumors, and alleviating the associated pain. There's an urgent need for a pharmacologic treatment that enables both biochemical and clinical improvements with physiologic levels of cortisol replacement that affect the approximately 17,000 addressable adult and pediatric CAH patients in the United States. Our mission is to transform the treatment paradigm for people living with CAH around the world with an unprecedented oral first-line therapy. With that, I'll turn the call over to our Chief Endocrinologist, Dr. Alan Krasner, to go through the trial results in more detail. Alan?
Thank you, Scott. The phase II TOUCAN trial is an open-label global study designed to evaluate the efficacy, safety, and pharmacokinetics of atumelnant when administered for 12 weeks to adult patients with classic CAH caused by 21-hydroxylase deficiency. Eligible patients had uncontrolled disease defined by treatment with high glucocorticoid doses, which we defined in the study as greater than or equal to a physiologic replacement dose of 15 mg hydrocortisone equivalent daily, and despite receiving these super physiologic doses of glucocorticoid, androstenedione or A4 levels were greater than 1.5x the upper limit of normal. As we will discuss later, many of these patients were also burdened with a number of chronic ongoing symptoms and signs of the disease despite these high doses of daily glucocorticoid.
The study includes three treatment cohorts of patients who received oral atumelnant once daily at a fixed dose with no change to the patient's pretrial glucocorticoid dose. 11 patients were treated with 40 mg of atumelnant, 11 were treated with 80 mg, and 6 patients were treated with 120 mg, resulting in a total of 28 participants enrolled. 33 sites across seven countries were activated to enroll in the trial. All countries enrolled at least one participant in the study. The primary efficacy endpoint was the change from baseline in serum A4 levels. A4 is an androgen, or male hormone, that is produced in the adrenal at high levels in response to excess ACTH. An important secondary endpoint in this study was change in serum 17-hydroxyprogesterone, a cortisol and androgen precursor that, like A4, is used in clinic to assess disease activity in CAH.
Excess A4 and 17-hydroxyprogesterone both contribute to the many symptoms and signs of CAH. Both biomarkers are used in clinic to assess the adequacy of disease control. In adults, the goal is typically to reduce A4 to as close to the normal range as possible, but this often requires using high glucocorticoid doses, which are associated with numerous toxic effects. In this study, we enrolled patients for whom even years of super physiologic glucocorticoid therapy did not achieve adequate A4 control. 17-hydroxyprogesterone is a useful but much more variable secondary biomarker. Aiming for normal 17-hydroxyprogesterone is generally not achievable in clinical practice and may not be necessary. I should also note that when a patient takes a dose of a glucocorticoid, both A4 and 17-hydroxyprogesterone levels can go down shortly thereafter.
Therefore, the protocol for this study specifies that blood draws for these measurements were to be collected before the patient's morning dose of glucocorticoid. The most recent dose of glucocorticoid occurs on the day previous to these morning blood draws, and in many cases, the previous day's glucocorticoid effect may have washed out by the time of the morning blood draw. Therefore, the biomarker data reported in the study represent the highest values the patient is likely to have over the course of the day. At Crinetics, we believe strongly that there are a lot of concerns in this disease and all the diseases that we study that are at least as important to patients as biomarker results. As a result, this study also included clinical assessments of many of the symptoms and signs of classic CAH.
Because menstrual dysfunction and infertility in female patients continues to be a common and unsolved chronic problem for many, the study carefully documented menstrual function. We also used MRI scanning to assess the impact of treatment with an ACTH antagonist on the size of the characteristic overgrown hyperplastic adrenal glands from which this disease gets its name. Other clinically relevant endpoints were also assessed. Although we will not have time to review results from all of these assessments in detail today, we will provide some highlights and look forward to presenting these data at scientific meetings. The demographics and baseline characteristics in the trial reflect a real-world adult CAH population. Of note, we see on slide seven that these patients presented with a wide range of baseline A4 levels representing what could be encountered in clinical practice.
As mentioned, patients enrolled in this study had quite high baseline levels of A4, on average over 1,000 ng/dL in all three cohorts. They also had quite high levels of 17-hydroxyprogesterone and high ACTH levels despite treatment with super physiologic doses of glucocorticoid. Atumelnant dosed for the three-month period in the trial was well tolerated. As we can see on slide eight, no severe or serious adverse events were reported. Treatment-emergent adverse events were mild to moderate, mostly transient, and there were no dose reductions, dose interruptions, or discontinuations of study drug due to adverse events. No negative clinical trends relative to vital signs, physical examination, or electrocardiograms were seen. Clinical safety laboratory parameters did not reveal consistent negative trends. One participant in the 120 mg dose group experienced AST and ALT increases without increases in bilirubin and with values reverting to baseline off study drug.
There were no clinical sequelae. As is often the case with asymptomatic liver function changes, one cannot rule in or rule out a relationship to study drug, but there were no worrisome features here that would prompt any changes to existing clinical trial safety monitoring procedures. Another patient treated with 80 mg also experienced hepatic transaminase elevations. This case was confounded by initiation of a new medication that can affect liver function. There were no clinical sequelae. This event was deemed to be not related to study drug treatment. As mentioned, all participants in the study completed 12 weeks of dosing. Slide nine summarizes all treatment-emergent adverse events. As mentioned, no severe or serious adverse events were reported, and no adverse events resulted in discontinuation of study drug. Two patients experienced symptoms suggestive of transient adrenal insufficiency, as can often occur in this patient population.
Both cases were resolved without sequelae. In slide 10, we see individual treatment-emergent non-serious adverse event terms that were reported in at least two study participants. The most common adverse events were headache, fatigue, and loss of appetite. Overall, the majority of the adverse events were mild and transient. As we can see on slide 11, atumelnant resulted in rapid and substantial reductions of A4. The bar graph shows mean A4 at baseline and at week 12 across each of the cohorts. Note that baseline A4 levels are greater than 1,000 ng/dL across all three cohorts, and despite this difficult level of disease severity, atumelnant resulted in marked dose-dependent reductions in A4 levels. The 120 mg dose resulted in an 80% reduction of mean levels with mean levels at or below the upper limit of normal.
As you can see on the table in the bottom right of this slide, all groups showed highly statistically significant effects in this primary efficacy endpoint. We know that these reductions are clinically important because relevant outcome improvements were seen, particularly in the 80 and 120 mg dose groups, as we will discuss. Slide 12 shows individual participant A4 levels at each time point of the study. At all doses, A4 responses are evident within two weeks. Notably, seven of 11, or 64%, and four out of six, or 67% of patients in the 80 and 120 mg dose cohorts, respectively, reached A4 levels below the upper limit of normal within two weeks.
As would be expected with these biomarkers, there is some variability across patients and across time, but there is a clear trend of increasingly flatter time course curves as the atumelnant dose increases, which are generally sustained for the 12-week period of treatment. As you can see in the week 14 period after dosing was complete, A4 levels returned toward baseline, also a measure of the potent effect seen with atumelnant. Atumelnant also induced a rapid and substantial reduction in 17-hydroxyprogesterone, with sustained reductions of 65% in week 12. On slide 13, we can see from the individual patient data plots on the right that 17-hydroxyprogesterone is a more variable biomarker, but overall trends show a robust lowering of what are some very high baseline levels. These data represent a supportive demonstration of the impact an ACTH antagonist can have in CAH.
As discussed, in addition to biomarkers, clinical outcomes are also very important to help us more fully understand the patient experience with atumelnant. In particular, abnormal menstrual function and its downstream effects, such as infertility, remain a clinical challenge for many female patients with CAH. We therefore ask for careful tracking of menstrual cycling in female study participants. Of the 11 female participants not on hormonal contraceptive therapy or having undergone hysterectomy, six resumed menses during the study. Three of these participants previously had no menstrual cycling at all or amenorrhea for years before the trial. Three additional participants had irregular cycles or oligomenorrhea, which became regular during the study. Many variables can result in changes in menstrual patterns, so to support the hypothesis that they were related to the changes in the hormonal milieu induced by atumelnant, we also measured testosterone levels.
Testosterone is the most potent androgen and is often found at abnormally high levels in women with CAH. This is because the high level of adrenal A4 in these patients is converted in the ovary and elsewhere in the body to excess testosterone. Although there are multiple reasons for female reproductive problems in CAH, overexposure to testosterone and other androgens is an important contributor. On the right side of slide 14, we can see that mean baseline testosterone levels in the female participants were up to approximately seven-fold elevated above the upper limit of normal. After atumelnant treatment, testosterone levels were markedly reduced, even to the normal range in eight of 13 patients. These clinical observations, supported by biochemical data, make me hopeful that atumelnant might someday represent a way to help solve a very long-standing and vexing clinical problem for these patients.
One clinical finding in CAH that dates from birth is enlargement of the adrenal glands due to lifelong exposure to excess ACTH. As mentioned, this hyperplasia of the adrenals is how this condition gets its name. Although the enlarged adrenals usually do not cause symptoms directly, the degree of their enlargement is a useful reflection of how well controlled the disease is. Very large adrenals correlate with poorly controlled disease and even cardiovascular risk factors. Furthermore, adrenal glands in CAH can occasionally become massively enlarged, resulting in symptoms that can only be resolved with surgical adrenalectomy. As mentioned earlier, we used MRI scanning to measure adrenal volumes at the beginning and end of the three-month course of treatment to test the hypothesis that atumelnant could result in some regression of the adrenal enlargement. These scans were assessed centrally by an expert radiologist.
The normal adrenal gland volume is 4-5 mL, and the total for both adrenals is therefore 8-10 mL. In the patients enrolled in this study with evaluable adrenal scans, the median baseline total adrenal volume was 19.7 mL, or roughly twofold increased. With atumelnant treatment, we see consistent reductions in adrenal volume across dose groups, up to 5.2 milliliter reductions in the high dose group. The right-hand side of slide 15 illustrates an example of this effect. This male participant experienced a 79% reduction in adrenal volume on the right. There was a similar reduction in the left adrenal, although this is not shown on the slide. Once again, an important clinical observation is supported by biochemical changes. This subject experienced marked reductions in A4, 17-hydroxyprogesterone, and a newer exploratory biomarker called 21-deoxycortisol.
In males with difficult-to-control CAH, there tends to be lower intratesticular production of testosterone, but total testosterone levels in the blood do not necessarily drop to the low range because peripheral conversion of the excess A4 to testosterone partially compensates for lack of testosterone coming from the testes. Intratesticular testosterone concentrations, though, are important for fertility, meaning that the androgen mixture seen in males with CAH is not a healthy one. Therefore, A4 to testosterone ratios are used in clinic to assess male reproductive health. We see the A4 to testosterone ratio markedly improved in this participant, concomitant with the adrenal volume reduction. Seeing easily measurable changes in adrenal volume in a relatively short three-month time period is remarkable. We do not currently have information on whether this trend might continue with longer periods of treatment.
Slide 16 highlights many of the clinical outcome benefits we have already observed in this short phase II study. Like in the participant just discussed, we actually saw improvements in the A4 to testosterone ratios in multiple male participants, which raises the prospect of improving reproductive health in males. This is very analogous to the potential to restore reproductive functioning we discussed earlier in females. Androgens are also known to stimulate red blood cell production, and hyperandrogenemia can result in abnormally high hemoglobin levels, otherwise known as polycythemia. Polycythemia is a risk factor for thrombosis and cardiovascular complications. There were six patients who entered the study with polycythemia related to their hyperandrogenemia. Five of them had resolution on treatment with atumelnant.
As in our other clinical development programs, we have collected here a unique and valuable database, which will allow us to evaluate the relationships between biochemical markers and many relevant clinical outcomes. Currently, there is very little available information on this important topic, and we look forward to presenting findings at upcoming medical meetings. In summary, based on these phase II data, we are preparing to advance atumelnant into phase III clinical development for the treatment of congenital adrenal hyperplasia. phase II showed that atumelnant treatment resulted in rapid and substantial biomarker reductions in participants with classic CAH across a wide range of disease severity. These data establish a clear dose response, and 80 mg and 120 mg are likely the doses to be used in phase III. As discussed, we saw evidence for meaningful improvements in multiple symptoms and signs of CAH.
Atumelnant was well tolerated, and no serious or severe adverse events were reported, and all participants completed the 12-week treatment period of the trial. We aim to initiate the phase III trial in the first half of 2025. We're also planning a phase IIb/III trial in pediatric patients, in whom there is also a great medical need. Now I will turn the call back to Scott for some concluding remarks. Scott?
Thanks, Helen. I'm incredibly pleased with today's data that strongly support the potential for atumelnant to help CAH patients achieve healthier hormone levels and help manage the clinical consequences of their disease. The strengths of atumelnant's novel mechanism of action as an ACTH antagonist was clearly on display with today's data. This final slide 18 illustrates the spectrum of CAH patients that are seen in clinical practice and the ultimate biochemical goals for all of them.
These goals are twofold: reduce adrenal androgen levels to a healthier range and allow patients to reduce their glucocorticoids to low physiologic replacement levels. Achieving these biochemical goals should allow atumelnant to address the burdensome signs and symptoms many patients have to live with on a daily basis: symptoms and problems caused by the ongoing hyperandrogenism and too much glucocorticoids. Today's data from this phase II study are exciting in that they give me hope that this twofold goal might be achievable. For this reason, we at Crinetics are highly motivated to assess as soon as possible the full potential of atumelnant in the treatment of CAH. We're aggressively proceeding towards registrational studies that should allow us to reproduce these biochemical and clinical improvements while at the same time reducing glucocorticoid dosage to healthier levels.
Our remarkable atumelnant product team is working hard to start the phase III study in adults and a phase II B III study in pediatric patients, both of which we expect to initiate this year. Our vision for atumelnant is to provide the CAH community with a single pill taken once daily that eliminates excess ACTH-driven adrenal activation and its clinical sequelae, and do this without the need for damaging high levels of exogenous glucocorticoids. Today's data are a major step forward towards realizing this vision. Before we open the call to your questions, I'd like to take a moment to thank all those who contributed to obtaining these results: from our atumelnant team members, study site teams and investigators, and most importantly, the trial participants and their caregivers. Our strategy remains firmly rooted in our unwavering commitment to patients and ensuring that their voices are heard and acted upon.
We'll continue to put the patient front and center in everything we do as we proceed with additional studies for both adult and pediatric patients impacted by CAH. With that, I'll hand the call over to the operator to begin Q&A. Operator?
Thank you, Doctor. And to our phone audience, if you would like to ask a question at this time, simply press star and one on your telephone keypad. Pressing star and one will place your line into a queue, and I will open your lines one at a time. If you find that your question has been asked and you'd like to remove yourself from the queue, simply press star and two. Once again, ladies and gentlemen, that is star and one if you would like to ask a question today. We'll hear first from Yasmeen Rahimi at Piper Sandler.
Good morning, team. Congrats on really outstanding results. Two quick questions. One, we're very much looking forward to the initiation of the phase III study. To the extent you can comment on, could you maybe talk about some of the, given this incredible product profile, how you're thinking about endpoints for primary and key secondary that you hope to power forward to show key differentiation that we've seen already in this open-label data? And then question two is, as we think about this product, could you think about how it could be used in classic versus non-classic patients and what that ratio of patients are currently out there? That would be very helpful, and I'll jump back in the queue. And congrats on a great start of the year.
Great. Thanks, Yas. Dana, maybe you could take the question on the phase III of planning. And Alan, could you jump in on non-classical CAH?
Yeah, sure.
Thanks, Yas, for the question. As far as the endpoints go, as we've demonstrated in the phase II, we feel that the reduction in glucocorticoids is important, but also the reduction in the androstenedione and other biomarkers. So we're actively in discussion with regulators about the specifics of the design for the phase III program. And so at this point, we're still processing the feedback that we've received, and we hope to be able to elaborate on that in the near future. Maybe I'll turn it over to Alan for the second part of the question.
Sure. Hi, Yas. So thanks for bringing up non-classic CAH. It's certainly something we've thought about quite a bit. It is otherwise known as adult-onset CAH. It's a much milder form of the condition clinically.
Although later in, when adults declare themselves with this condition, it can cause ongoing problems with reproductive health, including hirsutism and other problems like this. It is much more common than classic CAH. Classic CAH that we're discussing today is a rare genetic condition. Non-classic CAH is actually probably underdiagnosed in the larger community. I mean, in theory, an ACTH antagonist could be helpful in those patients as well. Some of them do find difficulty treating the condition. It's usually treated with oral contraceptives and then sometimes even glucocorticoids. I would say that this is not something we have data on at this time, but it's certainly an area of great interest to us to learn more about in the future.
Our next question today will come from the line of Jeffrey Hung at Morgan Stanley. Please go ahead. Hi, this is Michael Riad on for Jeff Hung.
Thank you for taking our questions, and congratulations on the top-line results. Looking at the A4 and 17-OHP rebound, once patients get off drug at the end of study, can you comment on how you see atumelnant being positioned in the clinic? Is it more of a chronic treatment? And then what would happen to the adrenal hyperplasia when patients get off drug?
Thanks, Michael. Alan, do you want to take that one?
Well, yes. I do envision atumelnant being a long-term chronic treatment to control the ACTH-driven adverse effects in this disease, again, as an adjunct to glucocorticoid therapy. The issue of whether adrenals might grow back after stopping the drug, we don't have information on this. In theory, there could be some regrowth.
But as I mentioned, I don't see that patients would necessarily stop the drug if they're doing well and it's helping to control their disease.
Thanks. And if I could just say one more last one. You mentioned intervening at a key choke point and appreciating the wide spectrum for the way CAH manifests. I wonder, are you learning better about biochemical control at different nodes of the axis? And is there a rationale to suggest improved symptom control going down to ACTH?
Yeah, I think.
Go ahead, Alan.
Well, I was going to say that, yes, I think the answer is yes.
You see, the reason this is an important choke point in the system, as Scott described it, is that when you block the ACTH receptor in the adrenal gland, you're kind of blocking the stimulation of a whole host of steroids that come out of the adrenal gland. The one we use as our clinical biomarkers are kind of representative of a whole family of steroid-related compounds. And so, yes, I think this is why it's a particularly effective way to prevent and deal with the symptoms in this disease. Pretty much all of these biomarkers we showed you correlate well, and we are learning about the correlations between the biomarker changes and those symptoms, as I mentioned during my discussion. And we really look forward to presenting that kind of data.
Sorry, maybe to elaborate just a little bit.
There's a variety of inputs on the HPA axis or the stress axis, but they all at the level of the hypothalamus and the pituitary, but they all converge into the secretion of the one hormone that goes to the adrenal, which is ACTH. And ACTH has one way of activating the adrenal, and that's through its receptor, the MC2-MRAP complex. And so we're blocking that one way in which ACTH can activate the adrenal. And that's why it's a central choke point to the whole HPA axis.
Thank you. Very helpful.
Our next question comes from Jessica Fye at JP Morgan. Ms. Fye, you may have us on mute.
Hey there. Can you hear me now?
Good morning.
Ms. Fye, welcome. Please go ahead.
We had you for a moment, but lost you.
All right. Not hearing a response. Ms. Fye, please press star and one.
We'll move forward now to Gavin Clark-Gartner at Evercore ISI.
Hey, guys. Congrats on the data. Thanks for taking the questions. Just first, on the liver enzyme elevation, it seems like it didn't result in a discontinuation. I just wanted to clarify that the patient finished the trial, asked if they received any treatment for this event, and if it was mild or moderate.
Alan?
Yeah. The patient did complete the dosing period of this study, Gavin. Actually, the peak level of the transaminase occurred right toward the end there, and as mentioned, the elevation promptly resolved after the treatment period. Overall, we follow this carefully. We are obligated to report these kinds of things, but in general, this case did not meet criteria for intensifying monitoring in our clinical trials or anything like that. That makes sense.
Just on the female testosterone reduction shown, is that data over a 24-hour period or in the morning window specifically? Then just quickly on the male side, what do you see in the TART volume reduction? Could the adrenal volume reduction be a harbinger of TART benefit? Maybe just remind us, crinecerfont's impact on this measure. Thanks.
The testosterone measurements are generally A.M. blood draws. We do follow any males with TARTs in our study. TARTs are testicular adrenal rest tumors that can be found in males that can be associated with discomfort and infertility. We have too little data yet to report there, but we certainly hope to have some in the future. I would expect an ACTH antagonist to be helpful for those, and we will certainly follow this carefully in larger scale studies, in particular phase III.
Next, we'll move to Douglas Tsao at H.C. Wainwright. Hello, Mr. Tsao.
Sorry, I was on mute. Hello. Can you hear me now?
We got you.
Okay. Sorry about that. I had you on mute. Scott, I'm just curious, or whoever wants to answer this, obviously, to the extent that glucocorticoid reduction plays into the pivotal study, how well do you think or confident are you, based on the A4 reduction, that you sort of have the dosing right to sort of achieve differentiation in the market versus the recently approved product? Thank you. And I have a follow-up.
Thanks, Doug. Yeah, I think to answer that question, you got to look at the program as a whole. Yes, we did not have time in this 12-week study to do the glucocorticoid reduction.
As you recall, back in the phase one program, we had healthy volunteers with normal glucocorticoid levels, whom we treated with atumelnant, and they became very low glucocorticoid levels, even to the point where some had to be rescued for hypoadrenalism. In those patients, they had elevated ACTH levels, and we gave them excess boluses of ACTH and an ACTH challenge test. In the face of those low glucocorticoid levels, in the face of those high ACTH levels and low glucocorticoids, we were still able to keep the HPA axis strongly suppressed. That's one piece of evidence. Also, in the Cushing's study, we had patients with Cushing's disease who rapidly resolved at low glucocorticoid levels.
And I think this mimics the potential end state of CAH patients where, in the face of high ACTH levels, you can reduce glucocorticoids because you're blocking the action of the ACTH with atumelnant very effectively. So I think if you put the whole package together, it gives us a great deal of confidence that, yes, indeed, with these strong suppressions of the adrenal in the CAH patients, those should be maintained in the presence of lower glucocorticoid levels.
Okay. Great. That's helpful. And then, just Scott, I guess, if we compare this final data to what was presented at Endo, we maybe didn't quite see as much consistency. Were you able to see if there were any sort of characteristics of some of the patients who didn't see quite as robust A4 reduction as what was seen in that first initial cohort?
Yeah.
Alan, you want to talk about that?
Sure. Yeah. I mean, actually, I think that overall, the robust responses we see are very consistent with what was described at Endo. Remember, at Endo, we had the first few patients participating in this study being summarized. And yes, they had very nice responses. Now that we have a more real-world, larger population of patients treated with all three doses, we see, I think, similar robust responses. And we have to remember, with these biomarkers in particular, there's a great deal of variability both over time and within patients. But given all that, I'm very optimistic that this compound will succeed in phase III.
Okay. Great. And if I can, do you identify the 80 and 120 mg doses as the ones you're moving forward?
Would you anticipate sort of just two arms, or would you anticipate sort of having patients potentially sort of start at 80 and titrate up to 120 if their responses weren't quite as robust? Thank you.
Go ahead, Alan.
Yeah. I envision, as mentioned, studying both doses in phase III. Now, there are multiple ways to do that, which are being discussed. There are ongoing discussions with health authorities in the U.S. and elsewhere as well in Europe. I would say that it isn't always necessary. I mean, as we did in our acromegaly program, it seems to me that most patients could do just fine with the first dose, 80 mg. And as necessary, some patients who may need more could up-titrate to 120 per the protocol. But again, this is being finalized.
But it does remind me of sort of the paltusotine situation we had, where most patients did well with 40, and in the protocol, were allowed to up-titrate to 60 as necessary.
Okay. Great. And congratulations.
Thanks, Doug.
Our next question will come from Dennis Ding at Jefferies.
Hi. This is Anthea on for Dennis. Thank you for taking our questions. On the reductions on adrenal volumes, which we thought looked very promising, curious how the FDA views that endpoint and what has been the feedback there, and just if there is a way to leverage that commercially with payers, and also as a point of differentiation versus crinecerfont. Thank you.
Dana, you want to take the regulatory side?
Yeah, sure. Since this really hasn't been shown before, I think there's no outstanding or current regulatory precedent.
So this is one of those things that we'll be discussing with the FDA and obviously looking carefully at across the trial. So obviously, from our perspective, it's a very striking way to demonstrate some efficacy of the drug. But right now, I would have to say that it's a very active area for consideration from our perspective.
And just to partially address the second part of your question, the adrenal volume changes are really remarkable and I think indicative of how well this agent is acting over time to mitigate the overstimulation of the adrenal. But the biomarker data was remarkable, but also more remarkable to me is the effects on so many different types of signs and symptoms of the disease, which are the things that really the patients care about the most.
And that kind of clinical benefit, I think, is really important to all aspects of moving this drug forward.
Thank you. I guess a follow-up on that, just given the focus, as you said, on both biochemical control and reducing GC doses, are you exploring a potential co-primary endpoint as well?
Well, I think the way you specify the cascade of endpoints is something the statisticians and regulators will work on. But in the end, it's about a sequence of different endpoints, whether they're co-primary or just a cascade as in sequence. I think in the end, you pre-specify what you want to measure, and you generate data that'll help you understand it and hopefully make it into the label.
Okay. Thank you. Congrats on the data.
Thank you.
Mr. Schwartz, please check your mute function, sir.
Hi. Can you hear me now?
Hi. Yes, we can.
We got you. Hi, Joe.
Okay. Great. Thanks. Yeah. Appreciate you taking my question. Congrats on the strong results. I know you're still working on designing the details of the phase III, but I was just wondering, in general, will you be doing anything differently from others in order to take advantage of the opportunity to distinguish atumelnant from other options which are now available?
I think what we've shown here is some remarkable effects on not just trying to mitigate some of the biomarkers, but also on the clinical outcomes of that. But yeah, from a regulatory point of view, the biomarkers are the key way that you get approval of the drug. So I think we'll have a comprehensive set of measurements that will help us understand the full benefits of atumelnant. And maybe I'll leave some of the details of that until we finalize the trial design.
Understood. And then given the wide array of clinical issues people living with CAH have, how do you view the different market segments or value propositions that atumelnant can address? Are there any where you'd expect your drug to make stronger inroads relative to crinecerfont, who might be first?
Again, I'll kind of come back to the depth of A4 suppression that we've seen, the rate of A4 suppression that we've seen, the impact on multiple clinical signs and symptoms that we've seen. I think that CAH patients out there today are really in a bind, and this is impacting all aspects of their disease. And all they have right now, or up until recently, was glucocorticoids. And if the CRF antagonist class can help them lower glucocorticoids, that's a real step forward.
But I want to achieve a state where you not only lower glucocorticoids, but you get androgens under control. And with that combined activity, you bring all these other things back under control. I mean, I think you know that people struggling with infertility, that's just a stressful and heartbreaking challenge. Struggling with some of the aspects of development in children with excess adrenal androgens and things because of CAH, I think that's also a remarkable challenge for those kids and their parents. So I'm very eager to see what happens when we can dose larger numbers of patients, get into the pediatric population, do this for longer periods of time. And I think atumelnant will display some remarkable benefits for these people.
Makes sense. Thanks for the insights.
Our next question will come from Brian Skorney at Baird. Hi.
This is Charlie on for Brian.
Thanks for taking our question and congrats on the data. Just two quick ones from us. Kind of thinking about the pediatric population, how much translatability do you see from these results to the younger patients? And in general, are they easier, harder, or roughly the same in terms of getting their hormones under control? And then secondly, is there any indicators that you're paying particular attention to with the crinecerfont launch and how that might inform your strategy with an eventual commercial launch? Thank you.
Alan, you want to talk about pediatrics?
Yeah. Children with CAH have many challenges. For decades, the only treatment has been glucocorticoid therapy as an adult. It is very challenging to balance the dose of glucocorticoids at a place where patients don't have toxicity from excess glucocorticoid and still have adequate suppression of adrenal androgen levels.
These children often have challenges with normal growth and normal pubertal development. And I wouldn't say it's easier or harder than treating an adult, but in general, each patient generally has their own challenges to face. And it's quite a bit of work, as you can imagine, for all involved to ensure the dosing is such that the child can grow normally and develop normally. The key issue in children as well as adults is overdrive from ACTH overexposure. And therefore, I would expect an ACTH antagonist to be quite effective as well in the pediatric population.
Yeah. Just to follow up on that, I mean, the pharmacology is the same. So I really would expect these results to inform the pediatric population. And with regards to crinecerfont, I think the group at Neurocrine has proven to be a very sophisticated and successful commercial group.
And this is the first new treatment for CAH patients in forever. We'll be watching it closely, and I wish them well. Patients need some help on every front.
Great. Thank you.
Josh Schimmer at Cantor, you have our next question. Please go ahead.
Thanks very much. Congrats on the update. Curious, as you move forward, especially as you're thinking about titrating down the steroid utilization of patients, might you consider exploring higher doses of atumelnant? Is there anything that might preclude that? And if not, what might trigger a decision to do so?
Thanks, Josh. I think that it's pretty clear from the pharmacology that we probably do not need to go any higher, although I think we could. We still have some exposure response modeling to do to kind of lay the foundations for that and some conversations with regulators to converge on it.
But no, I'm quite happy with 80 and 120. And I don't foresee any need or desire to go higher.
Okay. Thank you.
Next, we'll hear from Jon Wolleben at Citizens JMP.
Hi. This is Catherine on for Jon. Just two quick questions. One is whether patients were able to roll over on an open-label extension trial and what dosing regimens are you going to look at for that trial if so. And then if you are considering any challenges to actually enrolling the pivotal trials in the presence of an approved drug. Thanks.
Yeah. Thank you for the question. So the open-label extension is underway. We didn't have it in place at the beginning of this phase II trial, so we don't yet have all the patients into the open-label extension, but that'll be happening. And then sorry, I missed the second half of the question.
Can you repeat it?
Oh, what doses you guys are going to continue in that open-label extension, whether you're going to go with the 80 and 120 mg or if there's going to be a 40 mg option?
Oh, yeah. They'll be able to actually, maybe Alan, you should comment on it. I don't remember all the details on the OLE protocol.
Yeah. The OLE, I think we would allow the investigators to titrate or adjust the dose of atumelnant if they feel that's necessary between the same doses we use in this parent trial. So we would potentially allow the use of 40, 80, or 120 depending on the patient's individual needs.
Thank you. And then the other question was just about the approval of crinecerfont and then enrollment in the pivotal trial.
Oh, right. Yeah. I don't think that's a huge factor.
The study, as you saw, was conducted in multiple countries around the world, including the U.S., and it'll be a while before that fully gets out to patients even in the U.S., so no, I think I'm optimistic about recruitment. I'm in the earlier part of this phase II and the later trials for some of the other agents. Remember, those were done in the face of the pandemic and multiple competing trials, and I think we've got a much more clear field going into phase III.
Perfect. Thank you so much
And now we'll go to Jessica Fye at JP Morgan. Please go ahead.
Hey, guys. Good morning. Hopefully, you can hear me now. Congrats on the continuing success with the molecule.
Most of my questions have been asked, but maybe just for the avoidance of doubt, can we spend another moment on the elevation in liver enzymes you saw that I think was not associated with increased bilirubin? Just a couple more details, like was this just going above the upper limit of normal or some threshold like three times upper limit of normal? How long had the patient been on atumelnant, and what was that other drug that they started that might have been what actually caused it? Thank you.
Yeah. Alan, you want to comment?
So just this LFT peak occurred right at the end of dosing after the three-month period.
It was in the range that can be seen in significant liver problems in the 1.5 or I'm sorry, the five-fold elevated kind of range, which is sort of the beginning of where you would consider intensified monitoring. It was a one-time peak, and it didn't stay in that range. It certainly resolved quickly after discontinuation. As I said in the preparatory remarks, this is a case there were no clinical sequela, and this is just a case that cannot be ruled in or ruled out with certainty. I think that that's why we carefully monitor liver functions and measure these things so frequently in our clinical trials. We continue to monitor, but right now, there's been no change in the necessary procedures.
I think you said the enzymes came down after the patient went off drug.
Did the patient ever go back on for the extension?
No. No. This patient has not enrolled in the extension, and there was no re-challenge. As I mentioned, that peak occurred right at the end of the dosing period. And so no.
Okay. Got it. Thank you very much.
Thanks, Jess.
Cory Jubinville at LifeSci Capital, please go ahead and pose your question.
Thanks for taking our questions. Congrats on this really exciting data. I guess just coming back to the magnitude of response in the 80 mg group with the data on slide 12, it looks like many of these patients who did not achieve A4 normalization at week 12 in the 80 mg group also didn't have week 14 data in terms of follow-up. And many of those patients had really strong A4 improvements at week two that somewhat rebounded over time.
I'm, of course, speculating, but were there any issues with non-compliance in some of these patients who experienced a lesser response, or were there any specific characteristics that could have predicted a lesser response in that group as compared to those who responded really well as it relates to the phase III either enrollment selection or dose selection?
Yeah. Alan, you want to comment?
Yeah. No. We noticed variability in these biomarkers. The reason they might fluctuate from visit to visit is not always clear, and no, we cannot clearly attribute this kind of thing to non-compliance. Generally, the recorded compliance with atumelnant was quite good in the trial, but remember, patients also need to be compliant with glucocorticoids in order to control these biomarkers as well, but in general, there are many potential underlying variables, including just the natural history of adrenal output in this condition.
So this is why the biomarkers in general are important. They're used in clinic, but they're not as they're not necessary. For example, the primary endpoint for a phase III trial for crinecerfont was not the biomarker. It was the change from baseline in glucocorticoid dose. The biomarkers are important supplemental information, but you do have to study a number of patients to see the group trends.
Excellent. That's helpful. Thank you.
Catherine Novack with JonesTrading. Please go ahead. Your line is open.
Hi. Good morning, everyone. Congrats on the data. Just one follow-up on the pediatric study. Really excited to see that you're moving forward in this population given the really severely negative impact of GC doses for young patients. With that in mind, do you have a timing in mind for the initiation of pediatric studies? What's gating?
And then if you would mind sharing, what ages do you anticipate starting dosing at? Thanks.
Yeah. Thanks, Catherine. We're working very hard to get started on a variety of things. So the adult CAH is first in the queue. Then we're also working on pediatric CAH, and then, of course, a later-stage program in Cushing's disease. So the team's just knocking these down one at a time. And we're going to get them up and rolling this year, but I don't have specific timing for you at the moment. But Alan, you want to talk a little bit about age groups?
Well, in pediatric studies, generally, you kind of work down in the age from the oldest pediatric patients and generally that would start in the adolescent age range and work down to patients potentially as young as two years old eventually.
I should point out, though, that the discussions for the design of both phase III trials in adults and pediatrics are still being reviewed both internally and with health authorities. So the exact dose ranges and designs, we will certainly share when available.
Got it. Thanks very much.
And next, we'll hear from Ash Verma at UBS. Please go ahead. Your line is open. Hi.
Thanks for getting my questions here. I wanted to drill down on the A4 reduction in the 80-mg dose arm, please. So does this 11-patient data include the four-patient that had shown 96% at the interim? That would mean that to get to the 70% A4 reduction that you're reporting for 11 patients, the new seven-patient would have achieved roughly 40% A4 reduction. Let me know if I'm missing something here.
And then if you can comment on the median A4 reduction for these 11 patients as well, that would be great. Thanks.
Alan?
Interesting. I'm not sure about your calculations. I would have to check that. Remember, when we report average or mean reductions, we're looking at it by patient and not looking at the we're not just subtracting overall means. But yes, I mean, the first initial patients in that dose group happen to, by chance, have had the most robust responses. I agree with that observation. The second part of your question, could you repeat?
The median A4 reduction, if you can comment on that.
Oh, sorry. I don't have the numbers at hand. But in general, we did not have outliers, which made medians very discrepant from means. But I would have to report back to you on exact numbers.
Thank you.
That was our final question for our session today. Dr. Struthers, I'm happy to turn it back to you, sir, for any additional or closing remarks.
Thank you, everybody, for joining us this morning. I look forward to seeing many of you next week in San Francisco. Enjoy the rest of the day and the weekend.
Ladies and gentlemen, this does conclude today's teleconference, and we do thank you all for your participation. You may now disconnect your lines.