Welcome to the Crinetics Pharmaceuticals First Quarter 2024 Earnings Conference Call. [Operator Instructions].

I will now turn the call over to Corey Davis of LifeSci Advisors. Please go ahead. .

Thank you, Allan. Hello, everyone, and welcome to Crinetics earnings call. Joining me today are Dr. Scott Struthers, Founder and Chief Executive Officer; Dr. Alan Krasner, Chief Endocrinologist; and Marc Wilson, Chief Financial Officer. Also joining us for the Q&A portion of the call are Dr.

Dana Pizzuti, Chief Medical and Development Officer; and Jim Hassard, Chief Commercial Officer. .

The press release announcing the first quarter 2024 financial results was issued today and is also available on the Crinetics corporate website. .

As a reminder, we'll be making forward-looking statements, and I invite you to learn 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 businesses.

These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release, the company's other news releases and Crinetics SEC filings, including its annual report on Form 10-K. .

I'd also like to specify that the content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, May 9, 2024. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. .

With that, I'll hand it over to Scott. Go ahead. .

Thank you, Corey. Good afternoon, everyone, and thank you for joining us on our first quarter 2024 results call. I'll begin by spending a few moments summarizing our recent accomplishments, before turning the call over to Dr. Alan Krasner, our Chief Endocrinologist. He will discuss our clinical programs and recently reported data in more detail. .

Crinetics had an extremely strong start to 2024. Recently, we reported positive results from 2 late-stage clinical studies for paltusotine in patients with acromegaly and carcinoid syndrome. Behind paltusotine, we've built a remarkably deep pipeline.

This includes our second internally discovered clinical stage compound, CRN04894, which will now be known as atumelnant. .

At the Endo Conference this June in Boston, we will present 5 abstracts from our clinical development programs, including 4 late-breaking abstracts. Two poster presentations will highlight initial data in each of the ongoing open-label Phase II studies, evaluating the safety and efficacy of atumelnant in patients with CAH and Cushing's disease.

We are also hosting an in-person reception to review data from clinical studies of atumelnant in CAH and ACTH-dependent Cushing's syndrome at 6 p.m. on Monday, June 3, for those attending in person. .

Data from the entire PATHFNDR Phase III acromegaly program will be featured in a science and innovation theater, led by Dr. Kevin Yuen of the Barrow Neurological Institute on Saturday, June 1.

Three posters from the paltusotine acromegaly clinical program will also be presented, highlighting results from PATHFNDR-2, the use of acromegaly symptom diary and PATHFNDR 1, and updates on the long-term safety and efficacy data from the ongoing open-label extension study. .

We've also made excellent progress towards new development candidates this quarter in all of our early-stage programs. These include a PTH receptor antagonist for the treatment of hyperparathyroidism; a TSH antagonist for the treatment of Graves' disease, including thyroid eye disease; and our programs for diabetes and obesity. .

Now let me take a few minutes to dive a little deeper into the progress made with the 2 paltusotine indications. We're extremely pleased to have completed our Phase III program in acromegaly, with a successful readout of PATHFNDR-2 in April.

This study evaluated paltusotine in people with acromegaly who are not pharmacologically treated and was the second of 2 pivotal trials. PATHFNDR-2 achieved its primary endpoint of IGF control, and met all secondary endpoints with high levels of statistical significance.

Together with the PATHFNDR-1 results we reported last year, we now have data from 2 Phase III studies to support an NDA filing for the treatment of acromegaly in the second half of this year. .

In anticipation of a potential 2025 launch of paltusotine, we're continuing to work on important aspects of commercial readiness. We have already held multiple advisory boards and conducted market research with physicians to gather their input on how to optimize the communication of the paltusotine program.

We will continue to educate the medical community with data presentations at medical -- at multiple medical conferences in the coming months.

We will launch a campaign later this year directed towards health care providers to increase awareness of the unmet needs with the current standard of care, including injection site pain, breakthrough symptoms and the month-long regimens required to identify the appropriate dosage for their patients receiving injectable depots. .

An accompanying campaign directed at patients will be launched early next year. Our market access team has also been in active dialogue with leading payers to understand the current marketplace and the dynamics for paltusotine to become a valuable treatment option for patients, if approved.

PATHFINDER-1 data has already been well received and we are seeing a similarly enthusiastic response to our early conversations regarding PATHFNDR-2. .

We're also very pleased with the results from the open-label Phase II study in carcinoid syndrome patients that demonstrated meaningful reductions of both frequency and severity of flushing episodes and bowel movements caused by this disease. These effects were rapid, sustained and consistent with the preliminary data we reported last December.

Overall, we believe the safety and efficacy profile of paltusotine in this study supports progressing into a Phase III study as soon as we can. We plan to discuss these results with the FDA and align on a Phase III study design, which enable us to begin a Phase III study by the end of the year. .

Finally, we strengthened our balance sheet with a $350 million private placement in February from new and existing equity investors. This additional capital has provided us with sufficient runway to fund operations into 2028 based on current projections for our pipeline of product candidates. .

In summary, looking to the rest of 2024 and '25, we anticipate multiple upcoming milestones from our clinical candidates and continued advancement of our deep pipeline of emerging candidates that address increasingly higher prevalence indications.

As has been our practice since inception, we continue to invest in our world-class discovery capabilities that provide the roots for our long-term success. .

With that, I'll hand it over to Dr. Alan Krasner, our Chief Endocrinologist, to talk about our clinical programs. .

Thank you, Scott. Today, I will provide updates on recently reported clinical programs, starting with paltusotine. As a reminder, the Phase III PATHFNDR program was designed to evaluate the safety and efficacy of paltusotine for the treatment of a broad spectrum of patients with acromegaly.

Both PATHFNDR studies met all prespecified primary and secondary efficacy endpoints, and paltusotine was shown to be generally well tolerated.

We, therefore, intend to seek approval for patients who might switch from injected SRLs to paltusotine as studied in PATHFINDER-1 and also in those who are not currently treated with medications and might start paltusotine as a first-line treatment, as studied in PATHFNDR-2. .

We reported most recently the top line results from the untreated patients in PATHFNDR-2. Besides meeting all key end points, it was notable that IGF-1 was reduced from elevated baselines in 93% of patients treated with paltusotine. These IGF-1 declines occurred rapidly, with most of the effect occurring in just 2 to 4 weeks.

These reductions were durably sustained throughout the treatment period. .

Significant improvements in acromegaly symptom control associated with paltusotine compared to placebo have now been documented in 2 major independent controlled trials. As previously discussed, we are very excited to further explore our rich database into which patients reported their symptoms on a daily basis during the trials. .

With the database from PATHFNDR-1, we have already been able to perform additional interesting analyses, which we will be reporting at the Endocrine Society Meeting in June.

We have wondered for a long time whether daily oral paltusotine might result in a difference in the frequency of day-to-day symptom exacerbations that plague many patients with acromegaly treated with long-acting injections, and we look forward to reporting on this soon at the meeting. .

We will also be presenting late-breaking updated data from our long-term open-label extension cohort from the Phase II ACROBAT advance study. A number of the participants in this study have now been treated with paltusotine for over 4 years. .

The overall data set suggests that paltusotine represents a lot more than just a user-friendly, convenient oral substitute for an injection. Unlike the current first-line agents, paltusotine has been rigorously demonstrated to control symptoms of acromegaly as well as biochemical markers of disease activity.

The notably rapid IGF-1 response observed in PATHFNDR-2 could allow patients and physicians to reach the fully effective dose of paltusotine much faster than is the case for the current standard of care. .

A simple once-daily oral agent could prevent the pitfalls, pain and unneeded expense associated with the current standard of care. People that are already dealing with the burdens of acromegaly might not need to schedule their lives around the next injection and dealing with the side effects that often occur after these injections.

With paltusotine, one would not need to worry if the last injection was administered correctly, and whether or not it will last until the next one is due, nor would one need special equipment or to take a course on how to self-administer acromegaly medication at home.

In short, paltusotine may represent a completely new paradigm for somatostatin receptor-based therapy. .

diarrhea and flushing. Participants were either naive to standard of care treatment or untreated and actively symptomatic or were controlled on SRL therapy and willing to wash out prior to entry. .

Paltusotine was generally well-tolerated at the doses evaluated in this trial with no severe or serious treatment-related adverse events. In addition, pharmacokinetics in this patient population was consistent with what we expected to see from prior experience.

We observed significant and meaningful reductions in both the frequency and severity of bowel movements and flushing episodes, consistent with the initial results we reported last December. Importantly, the intensity of these symptoms was also reduced by paltusotine.

These reductions occurred quite rapidly and were sustained throughout the 8-week treatment period. .

We intend to discuss the Phase II carcinoid syndrome data with the FDA to align on a Phase III study design. We look forward to updating you on the Phase III details, including dose, registrational endpoint and timing once we've had these discussions. .

As Scott discussed, our second investigational compound in clinical development is atumelnant, which is a once-daily oral ACTH receptor antagonist in development for the treatment of both congenital adrenal hyperplasia, or CAH, and Cushing's disease. .

The adrenal glands are the sole source of excessive steroid that cause the clinical complications in both disease states, and the steroid production is driven by excessive exposure to ACTH. It is natural, therefore, to target the ACTH or MC2 receptor in order to fundamentally interrupt the pathologic progression of these diseases.

That is because the receptor is the sole mediator of ACTH signaling, and it is found only in the adrenals. .

The lead indication for atumelnant is classic CAH, a genetic disorder that affects approximately 27,000 patients in the U.S. These patients lack a critical enzyme in the adrenals responsible for cortisol production. The hypothalamus and pituitary responds to these low cortisol levels by producing high levels of ACTH.

This excess ACTH, in turn, causes overstimulation of the adrenal cortex, resulting in overproduction of cortisol precursors like 17-hydroxyprogesterone and adrenal androgens like androstenedione, also known as A4. .

The adrenal's hyperandrogenemia causes many serious medical complications beginning in utero, progressing through childhood and into adulthood. Because CAH patients cannot produce cortisol, exogenous glucocorticoid replacement is required for life, but replacement doses should be very low, and these low doses should not cause adverse effects.

As a result, many physicians find it necessary to use high super physiologic doses of glucocorticoids in an attempt to suppress elevated ACTH levels and thereby, lower adrenal androgen production.

These elevated glucocorticoid doses are frequently associated with adverse effects such as weight gain, elevated glucose, edema, bone loss and a host of other serious medical problems. It is very difficult to find a dose of glucocorticoid, which effectively controls adrenal androgen production without causing these side effects.

This highlights the fundamental challenge in treating this disease to strike the right balance between reducing adrenal androgens, yet minimizing the effects of excess glucocorticoids. We believe atumelnant is the right approach to achieve this balance and look forward to showing initial data from our Phase II studies in the coming weeks. .

Atumelnant was designed to reduce or eliminate ACTH stimulation at the level of the adrenal, thereby lowering adrenal androgen output. Once adrenal hyperandrogenemia is controlled, patients who are taking excessive doses of glucocorticoid should be able to lower their dose and reduce or even avoid steroid therapy-related adverse effects. .

Remember, the ACTH receptor in the adrenals is the only means by which ACTH drives the pathologic adrenal androgen output seen in CAH. And the ACTH receptor is a single chokepoint at which this overdriven system might be turned off.

Our ongoing Phase II open-label sequential dose cohort study in CAH is evaluating safety and pharmacokinetics of atumelnant dosed for 3 months. In addition, we are evaluating pharmacodynamics. And in CAH, this is measured primarily using the androgenic biomarker, androstenedione, or A4, as well as the cortisol precursor 17-hydroxyprogesterone. .

The goal of treatment is to reliably and reproducibly eliminate excessive exposure to adrenal steroids as reflected by these biomarkers. The patients in our study continued their pretrial glucocorticoids at unchanged doses, so we can observe the time course and durability of any response to atumelnant itself.

In future studies, we expect to evaluate glucocorticoid dose reduction once we know that the compound can reduce adrenal androgen output. .

As Scott mentioned, we will be presenting late-breaking atumelnant data at the upcoming Endocrine Society Meeting in June. This will not include the full cohort of patients in the CAH study, but will comprise initial data from a subset of the first 2 dose cohorts.

We expect these early results will give us directional information that will help guide developmental plans for atumelnant in CAH. Initial data from the Phase II single-center trial in Cushing's disease will also be presented at the same meeting. .

With that, I will now hand it over to Marc to review the financials. .

Thank you, Alan. Crinetics continues to be in a strong financial position, having ended the first quarter with approximately $900 million in cash and investments. This includes proceeds from the $350 million private placement equity financing we completed in February.

Our solid financial foundation is projected to fund our current operating plan into 2028. And this includes plans to commercialize paltusotine for acromegaly, the initiation of multiple later-stage clinical trials in additional indications with paltusotine and atumelnant as well as continued investment in our pipeline. .

With respect to the financial results, research and development expenses were $53.3 million for the quarter ended March 31, 2024, compared to $38.5 million for the same period in 2023.

The increase was primarily attributable to higher personnel costs and manufacturing and development activities, both of which were driven by the advancement of our clinical programs and the expansion of our preclinical portfolio. .

For the quarter ended March 31, 2024, general and administrative expenses were $20.8 million compared to $12.2 million for the same period in 2023. These increases were primarily attributable to higher personnel costs to support the growth of the organization. .

Net loss for the quarter ended March 31, 2024, was $66.9 million compared to a net loss of $46 million for the same period in 2023. Revenues were $0.6 million for the quarter ended March 31, 2024, compared to $2.7 million for the same period in 2023.

Revenues during the current year's quarter were primarily derived from our paltusotine licensing arrangement with our Japanese partner, SKK, and revenues for the prior year were associated with licensing arrangements for paltusotine and CRM-01941, another somatostatin-targeted development candidate. .

Net cash used for operating activities for the quarter ended March 31, 2024, was $52.9 million. We continue to expect our cash burn to be approximately $50 million to $60 million per quarter for the remainder of 2024. .

I will now hand it back to Scott for closing remarks before we begin Q&A. .

Thank you, Marc. We will continue to build on the strong progress this quarter throughout the rest of the year and beyond.

We look forward to sharing atumelnant data in the coming weeks as well as providing continued updates as we progress paltusotine to regulatory submissions and as we make continued advancements in the exciting new programs beginning to emerge from our discovery efforts. Thank you all for your attention. .

Operator, we are ready to take questions. .

[Operator Instructions] Your first question comes from Yasmeen Rahimi of Piper Sandler. .

Yes. Just -- I know we're going to quite a bit talk in the Q&A about CAH's upcoming readout, but would love to actually dig into the Cushing's data set. I guess it's an interim look. It's been -- it's run by an NIH investigator that's going to share the data. I guess I think we all understand cortisol reduction is key.

Would love to get your thoughts on what we hope to learn from that study and what would potential next steps be in development for Cushing's. And I'll jump back into the queue. .

Thank you, Yas.

Alan, can you take that question?.

Sure. Yas, we are collaborating with a leading KOL at the NIH in our Cushing's disease study. This is a study in which the compound is dosed for 10 days, while patients are in the clinical research center, and there is frequent monitoring of many parameters, but especially, pharmacodynamically speaking, of most interest would be cortisol.

These are patients with Cushing's disease who start with high levels of cortisol excretion. And of course, we'll be interested to see if cortisol is reduced during this 10-day dosing period. .

That is the information we would get from this study that I think will be of interest. We expect that the data we would present at the Endocrine Society Meeting would give us directional kind of information to help guide our future development in Cushing's.

Sort of like when we reported carcinoid syndrome data in December, it was directionally of interest. I would expect we would learn a great deal from what we've seen so far. Of course, it will be a subset of the patients as we discussed in our remarks. But still, again, I hope we have qualitative directional information. .

Your next question comes from Jessica Fye of JPMorgan. .

What elements of atumelnant's profile do you think will best differentiate it from CRF antagonist in CAH?.

Well, thank you, Jess. As we've said over the course of discovery and development in this program, that if you look at the mechanisms by which the adrenal is controlled, they all converge on ACTH acting at its receptor on the adrenal, which is formed by the MC2 protein, but we'll just call it the ACTH receptor.

It's the only way ACTH can act, and it's the only thing that the ACTH receptor does. And so by blocking that, we're blocking a single chokepoint of action of the whole hypothalamic-pituitary-adrenal axis on the adrenal.

And we've always said we expect to achieve good blockade of adrenal activity, whether it's measured by adrenal androgens in CAH or by glucocorticoids in Cushing's patients. .

Your next question comes from Cory Jubinville of LifeSci Capital. .

atumelnant. I'm very intrigued by your Endo abstract title in regard to CAH data. The title is, Atumelnant Induces Rapid and Profound Reductions of A4 in 17-OHP and Participants with CAH. The keyword for me there being profound. .

To the extent you can, can you help us frame expectations on data that we'll see at Endo? And I guess if you can't go into granular detail, at a high level, how satisfied are you with the pharmacodynamics you're seeing with atumelnant in comparison to the CRF1 antagonist in -- we've also seen some mixed results lately across competitors' CAH readouts.

Can you help us better understand the types of patients that you've been enrolling in this Phase II study?.

Yes. Sorry, Cory, I think you'll have to wait until Monday, June 3 at 12 p.m. Eastern Time when the embargo lifts before we can really get too deep into this. But we look forward to seeing you at our poster presentations and welcome everyone to our Investor Relations event, which is at the Omni Hotel on the 3rd, at the same day, at 6 p.m. .

In terms of phrasing -- sorry, can you repeat the second half of your question, if you're still on the line?.

Yes. I guess at a high level, how satisfied are you with the pharmacodynamics you're seeing in comparison to some of the CRF1 antagonist. And we've also seen mixed results in competitors' CAH readouts.

And can you help us understand the types of patients that you've been enrolling into this Phase II study in terms of whether it be compliance or whether it be severity of disease or degree of control the... .

Yes. I realize there's been a lot of people wanting to set the bar, and I've always encouraged people to think about treating the whole disease, not defining a bar of one compound or another. .

In terms of how satisfied we are, again, you'll need to see the data at Endo. And generally -- maybe I'll just leave it at that. I'll just leave it at, come and see us. We look forward to presenting it and talking to everybody about it. .

Maybe, Scott, I could address the question on what sort of patients are enrolled in this study, if that would be helpful. .

Yes. Please take it. .

Okay. So these are patients -- these are adult patients with classic CAH, which means they have the most severe form of enzyme deficiency. So they're born with this condition. And generally, throughout life, need to take glucocorticoid replacement. So these are all now adults with this condition, who are all on glucocorticoid therapy.

In general, they will start the study with elevated adrenal androgen levels. There will be a variety of disease severity that we looked at. We're trying to be as inclusive as possible in this study. And there's a 3-month dosing period. During the 3 months, we administer a fixed dose of atumelnant.

The background pretrial glucocorticoid therapy has not changed during the study. As I mentioned during my remarks, our first goal is to assess how well 4894 reduces adrenal androgen output in and of itself without the additional variable of adjusting glucocorticoid doses ultimately in future studies.

Assuming 4894 is successful at controlling adrenal hyperandrogenemia subsequent studies, we would look at glucocorticoid dose reduction as well because a lot of these patients are on super physiologic doses of glucocorticoid and they would benefit from being brought down to the floor replacement dose levels. .

Your next question comes from Joseph Schwartz of Leerink Partners. .

Congrats on the progress.

Given the Phase II CAH atumelnant study continues to enroll patients, I was wondering if you could talk about what more you hope to learn or demonstrate beyond the interim data, which you'll be reporting at Endo? Are there additional questions you need to answer before you can advance to Phase III? And when will the next look at the CAH trial be?.

Thanks, Joe.

Alan, why don't you take that question?.

Yes. So we will be presenting, Joe, a subset of the study. The goal of the Phase II study is to fully evaluate the relationship between the dose of an experimental agent and the safety, of course, but also pharmacodynamic response at various doses. So this will be a subset.

I think we will get good directional information from the doses tested, but we do want to complete the study to make sure we have a complete range of dose response evaluated to help us best design subsequent development for the compound. .

Your next question comes from Jon Wolleben of Citizens JMP. .

One more for me on 894 and then carcinoid syndrome.

When we're thinking about the data at Endo, how do you balance the relative importance of a percent reduction in A4 versus achieving normalization as far as clinical development and also management of patients in the real world? And then wondering if you could give us some high-level thoughts on the Phase III preliminary design in carcinoid syndrome?.

All right. We'll let 2 questions flip by on that one. But I'll take the first part, and Alan, maybe you take carcinoid syndrome. But generally, percent is always just a shorthand. And it depends on where you start for the magnitude of the effect that you might see expressed as a percentage.

So I do think the goal of therapy is to get people as low as you can on their androgens so that you can adjust -- we'll get rid of the androgen effects and adjust the glucocorticoid to a physiologic level. So percent is a good shorthand and perhaps an easy way to make some comparisons. But in the end, it's patients that is the focus.

And by the way, it's not just biomarkers, it's the effect of those changes in hormones that may have on the symptoms and expression of the disease in these patients.

And Alan, do you want to comment on carcinoid syndrome?.

Sure. Yes. As we've reported Phase II data, we are actively designing the Phase III program for carcinoid syndrome. The plan, of course, is to review with the FDA the full data set from the Phase II study as well as our proposals for Phase III and to align with them on the design of Phase III. .

I can give you some sort of high-level thoughts about Phase III. Again, we have to remember that we haven't had those regulatory discussions yet. So it's not set in stone. But in general, based on regulatory history in this disease state, I would anticipate we're looking at a placebo-controlled trial. .

diarrhea and flushing. And as we already reported in Phase II, we see reductions in both the frequency of these episodes but also the severity of diarrhea and flushing, too, with paltusotine therapy. And I think we will very likely, very carefully measure those things in Phase III as well. .

And in terms of sample size, historically, carcinoid syndrome pivotal trials, first of all, they're generally single pivotal trials for carcinoid syndrome. And the sample sizes in the past have ranged between roughly 80 and 150 patients.

And based on our power calculations to date, I think that's right about the range I would expect for our Phase III trial as well. I hope that's helpful. .

Your next question comes from Leland Gershell of Oppenheimer. .

Congratulations on the progress. Also a couple for me on carcinoid, maybe for Alan.

With the benefit now of a few months since the reveal from the Phase II, I want to hear of any feedback you've received from physicians with respect to their interest in using paltusotine in patients who are untreated on SRLs given the large population segment who is not currently on therapy. And then I'll have a follow-up. .

Go ahead, Alan. .

Thanks for the question. We, of course, work closely with a number of specialist physicians, oftentimes oncologists who specialize in neurologic patient care and also themselves usually treat those patients with carcinoid syndrome. A lot of them are our investigators and our study steering committee.

And the feedback has been generally very positive from them. They're very excited about the data we have, and I would say pleased to be helping us think about what's coming up in Phase III. And probably many of them would participate in Phase III as well. .

I think it's recognized by many of the physicians who treat this that there are some shortcomings with these injections that are the standard of care for the control of carcinoid syndrome. And we went through many of those limitations in my prepared remarks, but these are just very burdensome from patients in many ways.

They're also technically difficult to deliver in a reproducible way. And this has actually been shown in the literature in this patient population, in particular. So I think both the patients and the physicians have expressed, to me, at least, positive thoughts that this would be a real contribution to the field. .

And then further to the point of the data you've shown. So the 5-HIAA levels in serotonin were pretty well-reduced by paltusotine. It seems like that was much better than we've seen with the SRLs.

Wondering if that particular finding has resonated with respect to maybe longer-term efficacy beyond, I think, the 8 weeks that you've shown with the Phase II for longer-term control of the cardinal symptoms. .

Yes. It's an interesting question. I'm afraid I don't know the answer. I'm not sure the answer is even in the literature. The ability of the biomarker response is to sort of predict longer-term responses with respect to these tumors or the symptoms, not really established.

These biomarkers are generally used in clinic primarily to diagnose carcinoid syndrome. But their ability to monitor therapy is not well established. But I would -- and thank you for pointing out that. .

We did see some actually pretty nice responses, and it is hard to find those in the older literature, and I suspect that might, in part, have to do with improvements in the methodology for measuring these things. We're using the latest assays for these biomarkers.

And I have a feeling that, that may have contributed to our pretty clear symptom and biomarker responses that we saw. And we, of course, want to leverage this for our Phase III program as well. .

Just to follow up a little -- sorry, this is Scott. Just to follow up a little bit. I did want to note your comment about potentially getting to those patients who currently are treated. And I think that is a unique opportunity.

That's very surprising to me that there is a significant population of patients with carcinoid syndrome that are not being treated at this point when they clearly should be. .

And I can only explain it by somebody -- they must be making some judgment on the burden of treatment versus the burden of disease and/or access to medicines. And it's causing far too many to not have access to medicines that would help them.

So we look forward to trying to find ways to bring this to more patients than are currently on the injectable depot therapies. .

Looking forward to hearing more at Endo. .

Your next question comes from Douglas Tsao of H.C. Wainwright. .

I was just curious, maybe, Scott, on the earlier-stage pipeline, you have a number of sort of therapeutic areas that you're targeting, many of which you're sort of talking about candidate selection for this year. I think you've talked about sort of diabetes and obesity for something for next year.

I guess what's the -- or is there any kind of prioritization within those? And how do you think about sort of the pace that those would go into the clinic and start to read out? You guys have a track record for doing sort of innovative early-stage studies that give us pretty good PD data early on in development.

And I'm just curious if that's how you anticipate seeing for those candidates as well. .

Thanks, Doug. Yes, the emerging pipeline is really super exciting. And we are really committed to what I call the craft of drug discovery. So we want to make sure that these are really the best possible molecules we can make before we invest in development.

And so those programs are now really starting to get close to molecules that might be good enough. .

PTH is probably first. We've been doing some non-GLP tox studies on multiple candidates, and it looks like the team is getting close to selecting the best one out of several good ones. And then the other programs are successively behind that.

Fortunately, we've been in a financial position where we don't need to make difficult prioritization decisions about which good molecule to slow down over the other good molecules. .

And I do think there's a little bit of just internal prioritization we have to do as we balance workloads between some of the different projects. But largely, all projects are moving forward as fast as we can.

And I'm optimistic that, that's going to leave a whole sequence of upcoming clinical information on these programs over the next 12, 18, 24 months. .

Okay. Great. That's really helpful. Congrats on the progress. .

Thanks. .

Your next question comes from Catherine Novack of Jones Research. .

I'm just wondering, when it comes to commercialization, what's the overlap in terms of treatment centers and prescriber base for CAH and acromegaly? And then was there any overlap extended to carcinoid syndrome? Is that a completely different institution that you're looking at?.

Thanks, Catherine. There's a high degree of overlap. And maybe, Jim, you could get into some more detail there. .

Yes. Thanks, Catherine. In terms of acromegaly and especially carcinoid syndrome, when we look at the 35 to 40 pituitary treatment centers, typically, they are academic centers that also overlap with the National Comprehensive Cancer Center network.

So when we're doing some sales force sizing, we see a lot of overlap between acromegaly and carcinoid syndrome. Even in terms of endocrinologists, there's a high degree of overlap with acromegaly and Cushing's disease, of course, because it's pituitary, but we're also seeing the same for congenital adrenal hyperplasia.

So a lot of the specialist endocrinologists are seeing all 3 pituitary or adrenal diseases. .

And I'll just add that, that was really part of our long-term strategy when we started getting into these indications.

So that not only from a commercial point of view do we start building into the same centers and same prescribers, but also from a development point of view so that we start using the same investigators and centers again and again and again, and trying to find synergies and ways of working well together as those relationships go for the long term. .

Your next question comes from Jeffrey Hung of Morgan Stanley. .

This is Michael Riad on for Jeff Hung. Circling back to the Phase III design for carcinoid syndrome.

Is there any ability for the study design to accommodate or potentially show the ability to prevent like breakthrough symptoms in the typical waxing and waning versus SRLs, maybe during the initial screen or wash out? Just wondering if there's any potential for that analysis. .

Thanks. I think that's an important question, and we are asking ourselves that. Alan, you might want to comment a bit on it. .

Yes. It's a very important concept because that's -- as I was talking earlier about the limitations of the current injection therapy for carcinoid syndrome, that is a major issue.

As you take these long-acting injections sometimes more frequently than once a month and yet you still have these days where you have active breakthrough of either diarrhea or flushing or both, sometimes more than just a day, and these patients often end up having to take additional medications, sometimes antidiarrheals or sometimes even short-acting subcu boluses of octreotide itself on top of the long-acting octreotide they're already taking.

.

Why that kind of breakthrough occurs is not fully understood. But I suspect that it might be related to some variability in exposure to the drug from month to month. We do know that there are -- there is variability in technique of actually accurately delivering, for example, octreotide to the intramuscular space.

So I suspect that contributes to this breakthrough phenomenon. .

And yes, in our trials, we will be very interested in asking patients every day how they're feeling using an electronic diary, as we did in Phase II and as we did in Phase III for acromegaly.

And I am hoping we will learn interesting things about whether that problem we see with these long-acting injections could potentially be solved with a daily oral dose of a simple oral agent. .

Your next question comes from Brian Skorney of Baird. .

This is Charlie on for Brian. So just wanted to switch gears a little bit towards the PTH asset or assets. Just kind of wanted to ask what from the presentation earlier this year at the Bones and Teeth Gordon Research Conference really gave you confidence in the profile of the molecules you're developing.

And if maybe you could kind of walk us through what excites you about it as well as if this is kind of the profile that you're looking for from the other assets that you're selecting from. .

Got it. How about Alan, I'll talk about the preclinical and you can talk about why we're excited about it clinically. But very much, this is like many of our programs where the endocrinology in animal model species is almost identical to the endocrinology in humans.

And we know that it's very robust way in rats, for example, to induce hyperparathyroidism by infusing excess of parathyroid hormone, and we can watch calcium go up. And then we can introduce one of our antagonists and watch calcium normalize, and also take normal rats and we give them PTH antagonist and see their PTH levels rise. .

So this type of pharmacodynamic response in a model system is very much the same type of thing we would do in a healthy volunteer. And it goes up and down our pipeline.

And it's a reason why, from a business perspective, endocrinology is just such a great field because you do so much derisking so early on, whether it's in animal models which closely mimic humans, or its early healthy volunteers or early patient studies where you're measuring biomarkers that are completely objective and well defined. .

But maybe, Alan, you can comment on clinical need and why we're excited about a PTH antagonist for these different patient populations. .

Yes, sure. This is a novel mechanism of action for -- that could potentially help a great number of patients who have parathyroid hormone excess for any number of reasons. And by the way, also parathyroid hormone-related protein excess. So beginning with hyperparathyroidism.

This is a fairly common endocrine disease, primary hyperparathyroidism in which the -- one of the parathyroid glands in the neck typically overgrows and causes unregulated excess secretion of parathyroid hormone.

That results, as Scott mentioned, in hypercalcemia, high calcium levels in the blood, but it's really a multi-organ systemic disease that also damages the bones and the kidneys, in particular. And the hypercalcemia itself can cause sometimes very serious symptoms. .

Now fortunately, for patients with primary hyperparathyroidism, there are very, very effective surgical options available, and many of these patients are cured surgically. However, there is a very important subset of patients who don't get cured by surgery, sometimes because more than one gland actually enlarges in some patients.

And there is really a great number of patients who could benefit from having a medical option to control hyperparathyroidism when surgery has not worked. .

And the other thing I would point out is even with patients who potentially could have surgery, it turns out, a lot of them don't have surgery for any number of reasons, including the fact that they may not be surgical candidates. And so therefore, I see a lot of potential for a medical option in this area. That's just one potential. .

It's probably the most straightforward indication, but there's also something called hypercalcemia malignancy, which is caused by parathyroid hormone-related protein, which also binds to the PTH receptor. Those patients could also use a new option. There are treatments available, but they all have limitations, and these patients can be quite ill.

And I think it's an exciting prospect also potentially for the future for a PTH antagonist. And then there's more, but we don't have time to talk about more. .

Your next question comes from David Lebowitz from Citi. .

With respect to the data being presented for CAH, how should we benchmark it versus what we've seen from other therapies? And what should we expect? And conversely, what should we not expect?.

Alan, maybe you want to reiterate that. .

Yes. I mean I think, again, we're expecting directional information in the biomarker responses. Again, as we discussed, it's more than just what's the percentage reduction in the biomarkers. It's also about how many patients actually get into -- get normal levels of biomarkers.

And then there's all the clinical features of the disease we want to carefully assess when we look at our data. .

So again, it's -- our Phase II interim data will not be a statistical exercise. But I'm hoping we'll get good directional guidance in terms of what doses may or may not be effective and what doses we -- and designs we may want to contemplate for future development beyond Phase II. .

Your next question comes from Dennis Ding of Jefferies. .

Congratulations on all the progress. If I can ask on CAH, maybe just talk about how you're thinking about having to go to the high 160-milligram dose as it was an optional cohort. And just wondering if that cohort has started enrolling or not or do you even plan to. .

Alan, do you want to talk about how we think about cohorts and dose selection?.

Yes. So this is a sequential dose cohort study. And the first cohort of patients with CAH receive an 80-milligram once-per-day dose of atumelnant. This is based on the Phase I healthy volunteer data showing that, that dose looked like it should be effective.

After we complete the first cohort of dosing, all the data from that cohort is reviewed by a safety review committee, and that committee then recommends the dose for the next cohort. .

That dose -- that next cohort could be a higher or a lower dose. We will certainly share that information at the Endocrine Society Meeting as part of the scientific presentation. And I think it's fair to assume we'd have patients from the first cohort as well as some of the second cohort as well. .

There are no further questions at this time. I would hand over the call to Dr. Scott Struthers, Founder and Chief Executive Officer, for closing comments. Please go ahead. .

Thank you, everybody, for being with us today, and we look forward to seeing many of you in Boston in the beginning of June and throughout the year, as more and more interesting things start coming out from the pipeline. Thanks again for your time. Good night. .

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect..