Crinetics Pharmaceuticals Inc (CRNX) 2024 Q1 法說會逐字稿

Welcome to the Crinetics Pharmaceuticals First Quarter 2024 earnings conference call.

At this time, all participants are in listen only mode.

Following management's prepared remarks, we will hold a question and answer session.

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

Please go ahead.

Thank you, Alan and 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 Mark 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 hazard, 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 two 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 CRNO4894 which will now be known as an

[amendment]

At the end of conference this June in Boston, we will present five abstracts from our clinical development programs, including for late-breaking abstracts.

Two poster presentations will highlight initial data in each of the ongoing open label Phase 2 studies evaluating the safety and efficacy of [atymylan] in patients with CAH and Cushing's disease.

We are also hosting an in-person reception to review data from clinical studies that amount at NCHNACTHN dependent Cushing's syndrome at 6:00 PM on Monday, June 3, for those attending in person.

Data from the entire PATHFNDR-1 phase 3's acromegaly program will be featured in a science and innovation theater, led by Dr. Kevin UN of the Barrow Neurological Institute on Saturday, June1.

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 and all of our early-stage programs.

These include a PTH receptor antagonist for the treatment of hyperparathyroidism ITSH antagonist for the treatment of grave 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 two paltusotine indications.

We are extremely pleased to have completed our Phase 3 program in acromegaly with the successful readout of PATHFNDR-2 in April.

This study evaluated paltusotine and people with acromegaly who were not pharmacologically treated and was the second of two 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 two Phase 3 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 input on how to optimize the communication of how to protein program.

We will continue to educate the medical community with data presentations at medical comp 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 need 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 and accompanying campaign directed at patients will be launched early next year.

Our MAC, our market access team has also been 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.

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

We were also very pleased with the results from the open-label Phase 2 study in carcinoid syndrome patients that demonstrated meaningful reductions of both frequency and severity of flushing episodes in Belgium bowel movements caused by this disease.

These effects were rapid and 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 3 study as soon as we can.

We plan to discuss these results with the FDA and align on a Phase 3 study design, which enable us to begin a Phase 3 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, talk about our clinical programs.

Thank you, Scott, for today.

I will provide updates on recently reported clinical programs starting with paltusotine.

As a reminder, the Phase 3 PATHFNDR program was designed to evaluate the safety and efficacy of paltusotine for the treatment of a broad spectrum of patients with acromegaly for 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 PATHFNDR-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 at the top line results from the untreated patients in PATHFNDR to besides meeting our key endpoints.

It was notable that IGF one was reduced from elevated baselines in 93% of patients treated with multicity.

These IGF-1 declines that occurred rapidly with most of the effect occurring in just two to four 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 two 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 trial 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 symptoms and 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 2 Acrobat advanced study.

A number of the participants in this study have now been treated with paltusotine for over four 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.

Notably, rapid IGF-1 response observed in PATHFNDR-2 could allow patients and physicians to reach the fully effective dose of CAL02 sitting 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 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 us take a course and how to self administer acromegaly medication at home.

In short, paltusotine may represent a completely new paradigm for somatostatin receptor based therapy paltusotine second target indication carcinoid syndrome has also shown promising results.

In March, we reported top line results from the open-label Phase 2 trial.

This study enrolled participants with carcinoid syndrome who experienced one of or both of the key symptoms of the disease, diarrhea and flushing.

Participants were either naive to standard of care treatment or untreated and actively symptomatic for or 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 eight-week treatment period.

We intend to discuss the Phase 2 carcinoid syndrome data with the FDA to align on a Phase 3 study design.

We look forward to updating you on the Phase 3 details, including dose registrational endpoint and timing.

Once we've had these discussions, as Scott discussed, our second investigational compound in clinical development is at two measurement, which is a once daily oral ACTH receptor antagonist in development for the treatment of both congenital adrenal hyperplasia or CAH. and Cushing's.

The adrenal glands are the sole source of excessive steroid that caused clinical complications in both disease states.

And this steroid production is driven by excessive exposure to ACTH.

It is natural, therefore, to target the ACTHRMC two 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 agreements.

The lead indication for APT amendment is classic CAH a genetic disorder that affects approximately 27,000 patients in the US these patients lack a critical enzyme in the adrenal cells 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 over stimulation of the adrenal cortex resulting in overproduction of quarters of precursors like 17 hydroxy progesterone and adrenal androgens like interesting down, also known as a for the adrenal paper, androgen anemia causes many serious medical complications beginning in utero, progressing through childhood and into adulthood because CAH patients cannot produce cortisol.

Exogenous glucocorticoids 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 adenoma, bone loss and a host of other serious medical problems.

It's 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 at the moment is the right approach to achieve this balance and look forward to showing initial data from our Phase 2 studies in the coming weeks.

Amylin was designed to reduce or eliminate ACTH stimulation at the level of the adrenal, thereby lowering adrenal androgen output.

Once adrenal paper androgen anemia 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 adrenal is the only means by which ACTH drives the pathologic adrenal androgen output scene and CH and the ACTH receptor is a single choke point at which this over driven system might be turned off.

Our ongoing Phase 2 open label sequential dose cohort study in CH. is evaluating safety and pharmacokinetics of at two milligram dose for three months.

In addition, we are evaluating pharmacodynamics and in CHH this is measured primarily using the androgenic biomarker, Andrew standalone, or A4, as well as the quarters our precursor 17 hydroxy progesterone.

The goal of treatment is to reliably and reproducibly eliminate excess of exposure to adrenal steroids as reflected by these biomarkers.

Patients in our study continue their pre-trial glucocorticoids at unchanged doses.

So we can observe the time course and durability of any response to FDA amendment 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 at two mainland data at the upcoming Endocrine Society meeting in June.

This will not include the full cohort of patients in the CH study, but will comprise initial data from a subset of the first two dose cohorts.

We expect these early results will give us directional information that will help guide developmental plans for at the moment.

In CAH, initial data from the Phase 2 seniors single-center trial in Cushing's disease will also be presented at the same meeting.

With that, I will now hand it over to Mark 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 at Momenta 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 CRN01941 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, Mark.

We will continue to build on the strong progress this quarter throughout the rest of the year.

And beyond.

We look forward to sharing at Tumela data in the coming weeks as well as providing continued updates as we progress how to steam 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.

Thank you.

Ladies and gentlemen, we will now begin the question and answer session.

(Operator Instructions)

Yasmeen Rahimi, Piper Sandler.

Yes, good afternoon, team, and thank you for all your thoughtful words.

Just I know we're going to have quite a bit talk in the Q&A about CA's upcoming readout, but would love to actually I dig into the Cushing's data set.

And I guess, you know, it's an interim look on it's been it's run by an NIH investigator that's kind of shared the data, I guess, you know, I think we all understand Q4 reduction of key would love to get your thoughts on what we hope to learn from that study and what potential next steps be in development for questions?

And I'll jump back into the queue.

Thank you.

Yes, Alan, can you take that question

?

Yes.

We are collaborating with a leading KOL at the NIH in Cushing's disease in our Cushing's disease study.

This is a study where 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 pharmacodynamic dynamically 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 and 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 and directional kind of information to help guide our future development in Cushing's on 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, will be a subset of the patients, as is the case at?

Yes, as we discussed in our remarks, but still again, I hope we have qualitative directional information.

Yes.

Thank you.

Jessica Fye, JPMorgan.

Good afternoon and thanks for taking my questions.

What elements now men's profile do you think will best differentiate it from CRS ?

Yes, thank you, Jess.

As we've said, over the course of discovery and development in this program and if you look at the mechanisms by which the adrenal controlled, they all converge on ACTH acting at its receptor on the adrenal, which is formed by the MC. two protein, but I will just call it the ACTH receptor, CLEO, ACTH Connect.

And if the only thing that the ACTH receptor does.

And so by blocking that we're blocking the single choke point of action of the whole hypothalamic pituitary adrenal axis on the adrenal and we've always said, we expect to achieve a good blockade of adrenal activity, whether it's measured by the adrenal androgens and CH or buy glucocorticoids and Cushing's patients.

Thank you.

Corey George Davis, LifeSci Advisors.

Thanks for taking the questions.

And I love the new name for oh four, eight nine four at the moment, I'm very intrigued by your Endo abstract title.

In regard to CH data, the title is at Mellon that induces rapid and profound reductions of a four in 17 OHP. in participants with CH. and the key word for me, they're 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 Atmel in comparison to the CRF one antagonist in.

And we've also seen some mixed results lately across competitor CH. readouts.

Can you help us better understand the types of patients that you've been enrolling in this Phase 2 study?

Yes, sorry, Cory, I think you'll have to wait until Monday, June third at 12:PM 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 third at the same day at 6:00 PM on in terms of a phrasing and what sorry, can you repeat the second half of your question?

If you're still on the line.

But yes, I guess at a high level, how satisfied are you with the pharmacodynamics you're seeing in comparison to some of the CRF one antagonist and we've also seen mixed results in competitor CH. readouts.

And can you help us understand of the types of patients that you've been enrolling into this Phase 2 study in terms of whether it be compliance or whether it be severity of disease or degree of control yet for?

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 one compound or another.

In terms of how satisfied we are.

Again, you'll need us to see the data at Endo.

And generally, I'm and maybe I'll just leave it at that.

I'll just leave it at to 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 that would not have full effect from.

Okay.

So these are patients.

These are adult patients with classic CAH, which means they have the most severe form of Enzon 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.

And in general, they will start the study with elevated adrenal androgen levels.

And there will be a variety of disease severity that we look at where we're trying to be as inclusive as possible in this study.

And it's a three month dosing period during the three months and we administer a fixed dose of at the moment.

The background pretrial glucocorticoid therapy has not changed during this study.

As I mentioned during my remarks, our first goal is to assess how well scoring nine four reduces adrenal androgen output in and of itself without the additional variable of adjusting glucocorticoid doses.

Ultimately in future studies, assuming 49 for a successful at controlling adrenal hyper androgen use.

If co-branded anemia subsequent studies, we would look at glucocorticoid dose reduction as well because a lot of these patients are on super physiologic doses of glucocorticoids, and they would benefit from being brought down to the floor replacement dose levels.

That's helpful.

Thank you.

Joseph Schwartz, Leerink Partners.

Thank you.

Congrats on the progress.

Given the Phase 2 CH. two maintenance 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.

Other additional questions you need to answer before you can advance to Phase 3?

And when will the next look at the CH. trial be?

Thank you.

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

Yes.

So I'm we will be presenting a subset of the study.

And the goal of the Phase 2 study is to fully evaluate the relationship between the dose of an experimental agent in the safety, of course, but also pharmacodynamic response to various doses.

And 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 that complete range of dose response evaluated to help us best design subsequent development for the compound.

Jon Wolleben, Citizens GMP.

One more for me on slide 4, in the car starts syndrome, I'm more thinking about the data at Endo.

How do you how do you balance the relative importance of a percent reduction, a score versus achieving normalization as far as clinical development and also management of patients in the real world?

And then I'm wondering if you give us some high-level thoughts on the Phase 3 preliminary design in carcinoid syndrome.

And we'll have two questions slipped by on that one, but I'll take the first part now and Alan maybe you take carcinoid syndrome, but generally percentage is always just a shorthand and it depends on where you start to 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 get rid of the androgen effects and adjust the glucocorticoids 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 patient.

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 thus the symptoms and expression of the disease in these patients.

And Alan, you want to comment on carcinoid syndrome?

So yes, as we reported Phase 2 data where we are actively designing the Phase 3 program for carcinoid syndrome.

The plan, of course, is to review with the FDA, the full dataset from the Phase 2 study as well as our proposals for Phase 3 and to align with them on the design of Phase 3.

I can give you some sort of high-level thoughts about Phase 3.

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 in this disease state, I would anticipate we're looking at a placebo controlled trial.

The most recent approval for carcinoid syndrome and about a three month placebo-controlled trial.

And I think that's kind of what we're anticipating here to, of course, the key endpoints would have to do with the cardinal symptoms of carcinoid syndrome, diarrhea and flushing.

And as we already reported in Phase 2, 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 3 as well on.

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 size and 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 3 trial as well.

Sorry, I hope that's helpful to let me sneak in two very helpful.

Leland Gershell, Oppenheimer.

Pretty good afternoon.

Congratulations on the progress and thanks for taking my questions.

Also a couple for me on carcinoid, um, maybe for Alan.

With the benefit now of a few months since the Reveal from the Phase 2, what I hear of any feedback you've received from physicians with respect to their interest in using paltusotine in patients who are untreated and on SRLs, given the large population segment who is not currently on therapy.

And then I have a follow-up

Thanks for the question.

I think we, of course, you know, work closely with a number of specialist physicians, oftentimes oncologists who specialize in neuroendocrine tumor patient care and also themselves usually treat those patients with carcinoid syndrome.

And a lot of them are investigators in our study steering committee and the feedback has been generally very positive from them.

They're very excited about the data we have and some I would say, pleased to be helping us think about what's coming up in Phase 3 and probably many of them would participate in Phase 3 as well.

I think it's some 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 you know, 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 a positive thought that this would be a real contribution to the field.

Thanks.Then. And then further to the point of the data, you showed the five HIAA levels when serotonin were pretty well reduced by by paltusotine.

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 the eight weeks that you've shown with the Phase 2 on for longer term control of the cardinal symptoms?

Thank you.

Yes, it's an interesting question, and I'm afraid I don't know the answer and I'm not sure the answer is that even in the literature that the ability of the biomarker responses to sort of predict longer-term responses with respect to these tumors or the symptoms, I'm not really establishing 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 thank you for pointing out that we did see some actually pretty nice responses and it is hard to find those in the old but 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 on We, of course, want to leverage this for our Phase 3 program as well as real up a little.

I'm going to sorry, this is Pat.

Just to follow up a little bit.

I did want to now to your comment about potentially getting to those patients who currently are treated.

And I think that is a unique opportunity.

It'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 our 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.

Thanks so much for the added color look for looking forward to hearing more than that.

Douglas Tsao, H.C. Wainwright.

Thanks or good afternoon.

And thank you for your questions.

I was just curious maybe, Scott, on the earlier-stage pipeline, you have a number of sort of therapeutic areas that you're targeting on, 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 on the pace that those would go into the clinic and start to readout on arm if 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 that's how you anticipate seeing those for those candidates as well?

Thank you.

Thanks, Doug.

Yes, the end 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 a difficult prioritization decisions about which good molecules have slowed 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 lead to a whole sequence of upcoming clinical information on these programs over the next 12, 18, 24 months.

Okay, great.

That's really helpful and congrats on the progress.

Thanks.

Catherine Novack, Jones Research.

Thanks for taking my questions.

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 extend to carcinoid syndrome is, but a completely different in the institutions that you're looking at Safeco turn have a high degree of overlap. and maybe, Jim, you could get into some more detail there.

Thanks, Katherine.

And equally, in terms of acromegaly and maybe, Jim, you could get into some more detail there.

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 when we're doing some sales force sizing.

We see a lot of overlap between acromegaly and <unk> and carcinoid syndrome.

Stephen, you know what in terms of endocrinologists, there's a high degree of overlap with acromegaly and Cushing's disease, of course, because it's proprietary, but we're also seeing the same for congenital adrenal hyperplasia.

So a lot of the on the specialists, endocrinologists are seeing all three pituitary or dreaming diseases.

And I'll just add that, that was 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 for the long term.

Thanks, guys, very helpful.

Thank you.

Jeffrey Hung, Morgan Stanley.

Your line is already open.

Hi, this is Mike Reid on for Geoff on.

Thank you for taking our question.

Circling back to the Phase 3 design for carcinoid syndrome on, is there any ability for the study design to accommodate or potentially show the ability to prevent breakthrough symptoms and the typical waxing and waning versus SRLs on maybe during the initial screen or washout.

Just wondering if there's any central for that analysis.

Thanks so much.

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, that is a very important concept because you know that 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 you still have these days where you have active breakthrough of either diarrhea, flushing or both sometimes more than just the day.

And these patients often end up having to take additional medications sometimes anti-diarrheal tools or sometimes even short-acting subcu boluses of octreotide itself on top of the long-acting octreotide, they're already taking out.

Why why?

That's why that kind of breakthrough occurs and is not fully understood, but I I suspect that it might be related to some variability in exposure to the drug from month to month.

And we do know that there are very, there's variability in technique of actually accurately delivering, for example, octreotide to the intramuscular space, I suspect, and that contributes to this breakthrough phenomenon.

And yes, in our trials, we will be very interested in asking patients every day how they feeling using electronic diary as we did in Phase 2 and as we did in Phase 3 for acromegaly and I am hoping we will learn interesting things about whether whether that problem we see with these long acting injections could potentially be solved with a daily oral dose of I have a simple oral agent.

Thank you so much.

That's very helpful.

I appreciate.

Brian Skorney, Baird.

This is Charlie on for Brian.

Thanks for taking our questions.

So just wanted to switch gears a little bit towards VPTH. asset or assets.

Just kind of wanted to ask what from the presentation earlier this year at the burn in Q4 in research conference really gave you confidence in the profile of the molecules are developing and is and 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.

Thank you.

Added about 10.

And 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 models.

Species is almost identical to the endocrinology in humans.

And we know that it's a 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, can also take normal routes and 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 me 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 it's 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 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 access.

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 overgrowth 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 bone in the kidneys in particular and the hypercalcemia itself can cause sometimes very serious symptoms.

And 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 can benefit from having a medical option to control hyperparathyroidism when surgery has not worked.

And the other thing I would point out is even and 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.

That'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 and there are treatments available but they all have limitations and these patients can be quite ill.

And I think that's an exciting prospect also potentially for the future for IPTH. antagonist.

And then there's more, but we don't have time to talk about more.

Great.

Thank you very much.

David [Vos], Citi.

Thank you for taking my question with respect to the data being presented for CAH, how should we benchmark that versus what we've seen from other therapies and what should we expect?

Conversely what should we not expect?

And Alan, maybe you want to reiterate that?

Yes.

I mean, I think, again, we're expecting directional information in the biomarker responses.

And 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 at normal levels and biomarkers.

And then there's all the clinical features of the disease.

We want to carefully assess when we when we looked at our data.

So again, it's this our Phase 2 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 at doses we and designs we may want to contemplate for future development beyond Phase 2.

Thanks for taking my question.

Dennis Ding, Jefferies.

Thanks for taking our questions and 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.

There was an optional cohort?

And just wondering if that goes outside that cohort has started enrolling or not, or do you even plan to?

Thank you very much.

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 and our add receive an 80 milligram once per day dose of two amendment.

This is based on the Phase 1 healthy volunteer data showing that that does look like it should be effective.

And 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 then the dose for the next cohort.

And at that dose that next cohort could be a higher or a lower dose.

We'll 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,of 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 beginning of June and throughout the year as more and more interesting things start coming up from the pipeline.

Thanks again for your time.

Ladies and gentlemen, this concludes today's conference call.

Thank you for your participation, and you may now disconnect.