Q4 2023 Crinetics Pharmaceuticals Inc Earnings Call

Welcome to the great extra must medical's fourth quarter and full year 2023 financial results Conference call.

Operator: Welcome to the Crinetics Pharmaceuticals fourth quarter and full year 2023 financial results conference. At this time, all participants are in listen-only mode.

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

Operator: Following the management's prepared remarks, we'll hold a question and answer session. I will now turn the call over to Cory Davis of LifeSci Advisors. Please go ahead. Thank you, Sergio. And hello, everyone.

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

I will now turn the call over to Corey Davis.

Please go ahead.

Thank you Sergio and Hello, everyone. Joining me on the call today are Scott Struthers, founder and Chief Executive Officer, Alan Krasner, Chief Endocrinologist, and Mark Wilson, Chief Financial Officer also joining us for the Q&A portion of the call our Dana pursuit, Chief Medical and development Officer, and Jim Hazard Chief Commercial officer.

Corey George Davis: Joining me on the call today are Scott Struthers, Founder and Chief Executive Officer; Alan Krasner, Chief Endocrinologist; and Marc Wilson, Chief Financial Officer. Also joining us for the Q&A portion of the call are Dana Pizzutti, Chief Medical and Development Officer, and Jim Hazzard, Chief Commercial Officer. Such forward-looking statements are not guarantees 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.

A press release announcing our fourth quarter and full year 2023 financial results was issued today and is also available on the kinetics 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.

Corey George Davis: 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, February 28, 2024. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this call. I'll now hand the call over to Scott Struthers.

Refined in their entirety by the cautionary statements contained in today's news release, the Companys other news releases and kinetic 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 the date of this live broadcast February 28, 2024, <unk> takes no obligation to revise or update any forward looking statements to reflect events or circumstances. After the date of this call I'll now hand, the call over to Scott Struthers Scott go ahead.

Scott Struthers: Scott, go ahead. Thanks, Cory. Good afternoon, everyone.

Thanks, Corey and.

Good afternoon, everyone and thank you for joining us for our quarterly results call.

Scott Struthers: And thank you for joining us for our quarterly results call. As the company progresses towards commercialization, it's our intent to expand our investor outreach and provide regular opportunities for interactive dialogue. We appreciate your attendance and look forward to our discussion today and on future quarterly calls.

As the company progresses towards commercialization, it's our intent to expand our investor outreach and provide regular opportunities for interactive dialogue. We appreciate your attendance and look forward to our discussion today and on future quarterly calls.

To begin I'll spend a few moments summarizing our recent accomplishments before turning the call over to Alan Krasner, our chief endocrinologist to discuss our clinical programs and recently reported data in some more detail.

Scott Struthers: To begin, I'll spend a few moments summarizing our recent accomplishments before turning the call over to Alan Krasner, our Chief Endocrinologist, to discuss our clinical programs and recently reported data in some more detail. But before we get started with a review of 2023, I wanted to say how pleased we are to have announced a private placement equity financing of approximately $350 million earlier today. We're very appreciative of the continued support that we've received from new and existing shareholders who share our long-term vision for building the premier endocrine company to help patients suffering from a wide range of different endocrine-related diseases. This financing is simply one more step forward in that strategy.

Before we get started with a review of 2023 I wanted to say how pleased we are to have announced a private placement equity financing of approximately $350 million earlier today.

Very appreciative of the continued support that we've received from new and existing shareholders, who share our long term vision for building the Premier <unk> company to help patients suffering from a wide range of different endocrine related diseases.

This financing is simply one more step forward in that strategy.

Scott Struthers: 2023 was a tremendously successful year for crinetics on many fronts. I'll begin with our lead development candidate, Paltucetine. Paltucetine continues to deliver impressive results in the two indications for which it is being developed, acromegaly, and carcinoid syndrome. In September, we reported clinical results in acromegaly that exceeded expectations. Our Phase III Pathfinder I trial achieved its primary endpoint of maintaining IJF control and met all secondary endpoints with high statistical significance. As a reminder, Pathfinder I was designed to evaluate oral paltucetine in patients with acromegaly who are already controlled on standard of care, which are injected somatostatin receptor-ligand depots or SRL therapies. Our intention for this trial is to support an indication for the maintenance of acromegaly treatment. In other words, to maintain biochemical control in patients switching from standard of care injectables to once-daily oral paltuces.

2023 was a tremendously successful year for kinetics on many fronts.

I'll begin with our lead development candidate toxicity Curtis team continues to deliver impressive results in the two indications for which it is being developed acromegaly in carcinoid syndrome.

In September we reported clinical results and acromegaly that exceeded expectations.

Our phase III Pathfinder, one trial achieved its primary endpoint of maintaining IGF control.

All secondary endpoints with high statistical significance.

As a reminder, pathfinder one was designed to evaluate <unk> in patients with acromegaly.

Already controlled on standard of care, which are injected somatostatin receptor ligand depots, our SRM therapy.

Our intention for this trial is to support an indication for the maintenance of acromegaly treatment.

In other words to maintain biochemical control in patients switching from standard of care Injectables to once daily oral <unk>.

In contrast, our second phase III trial Pathfinder II <unk>.

Scott Struthers: In contrast, our second phase three trial, Pathfinder 2, is evaluating paltucitine in patients with acromegaly who have elevated IGF levels above the normal range. These are patients who are either naive to therapy, untreated for at least four months, or patients who agreed to wash out of the standard of care as part of entering the study. We completed enrollment in Pathfinder 2 last year, and we are on track to unblind and report top-line results in March.

Is evaluating <unk> in patients with acromegaly, who have elevated IGF levels above the normal range.

These are patients who are either naive to therapy untreated for at least four months for patients who agreed to wash out of the standard of care as part of entering the study.

We completed enrollment in Pathfinder to last year, and we are on track to unwind to report topline results in March.

Scott Struthers: If successful, we intend to submit an NDA supported by these results from both studies to the U.S. FDA in the second half of 2024. Overall, our Pathfinder program is intended to provide a broad label for the treatment of acromegaly. Moving now to carcinoid syndrome, our second intended indication for PAL215.

If successful we intend to submit an NDA supporting supported by these results from both studies to the U S. FDA in the second half of 2024.

Overall, our Pathfinder program is intended to provide a broad label for the treatment of acromegaly.

Moving now to carcinoid syndrome, or second intended indication for <unk>.

Scott Struthers: In December, we reported initial results from our ongoing Open Label Phase 2 trial in patients with carcinoid syndrome. From a safety point of view, peltucetine continues to be well tolerated in this patient population, consistent with what we've seen from our other clinical studies to date. With regard to efficacy, to date, we are seeing clear reductions in the two key symptoms of carcinoid syndrome, which are excess bowel movement frequencies and flushing episodes. Results from December were from a subset of patients, and the study is now fully complete with a total of 36 patients. In the profile, we reported the initial results, and what we reported in the initial results is confirmed. Based on the top-line results that we expect in the first half of this year, we're excited to move forward into phase three studies in carcinoid syndrome, pending alignment with the FDA on the study design. Following in the footsteps of Paltusatine, we've built a remarkably deep pipeline. Our second molecule, 4894, is currently being evaluated in an open-label phase 2 trial in patients with congenital adrenal hyperplasia, or CAH, and in a second trial in patients with ACTH-dependent Cushing's disease. People with CAH are unable to make cortisol and instead make excess adrenal androgens.

In December we reported initial results from our ongoing open label Phase II trial in patients with Carcinoid syndrome.

From a safety point of view <unk> team continues to be well tolerated in this patient population consistent with what we've seen from our other clinical studies to date.

With regard to efficacy to date, we are seeing clear reductions and the two key symptoms of carcinoid syndrome, which are excess bowel movement frequency and flushing episodes.

Results from December where from a subset of patients in the study is now fully complete with a total of 36 patients.

And the profile and the profile we reported the initial results.

In that we reported and the initial results is confirmed.

And the topline results that we are expected in the first half of this year. We're excited to move forward into phase III studies in carcinoid syndrome pending alignment with the FDA on the study design.

Following in the footsteps of <unk>, we built a remarkably deep pipeline are.

Our second molecule 494 is currently being evaluated in an open label phase II trial in patients with congenital adrenal hyperplasia CAH.

And a second trial.

Patients with ACTH dependent cushings disease.

People with CAH, you're unable to make cortisol and instead make excess adrenal androgens and four.

Scott Struthers: And 4894 is an oral ACTH antagonist designed to normalize levels of adrenal androgen. Alan will elaborate on this program, and we anticipate reporting initial results from a subset of patients in the second quarter of the year. Beyond 4894, we're also advancing multiple preclinical programs, including a parathyroid hormone, or PTH, receptor antagonist for the treatment of hyperparathyroidism, as a TSH antagonist for the treatment of Graves' disease and thyroiditis, and candidates for metabolic diseases including diabetes and obesity. These are just a few of the many early-stage programs in our pipeline, and we plan to provide you with regular updates on these and In anticipation of a potential 2025 launch of Faltusatine, we also remain focused on building out our commercial organization.

94 is an oral ACTH antagonist designed to normalized levels of adrenal androgens.

Alan will elaborate on this program and we anticipate reporting initial results from a subset of patients in the second quarter of the year.

Beyond 49 core we're also advancing multiple preclinical programs, including a parathyroid hormone or PTH receptor antagonist for the treatment of hyperparathyroidism.

TSH antagonist for the treatment of <unk> disease anti rare disease.

And candidates for metabolic diseases diseases, including diabetes and obesity.

These are just a few of the many early stage programs in our pipeline and we plan to provide you with regular updates on these and other development candidates when appropriate.

In anticipation of a potential 2025 launch of <unk>.

We also remain focused on building out our commercial organization.

Acromegaly in Carcinoid syndrome, together present, a multibillion dollar market opportunity.

Scott Struthers: Acromegaly and Carcinoid Syndrome together present a multi-billion dollar market opportunity. We're actively developing commercial capabilities for these markets, identifying key prescribers, and tailoring our launch strategy. We know that Pathfinder 1 data is responding well, creating excitement among acromegaly and carcinoid syndrome prescribers and the patient. Understanding partner perspectives is also crucial, and Jim Hassard and our chief commercial officer, our chief commercial officer, are building a market access team to build relationships with these important stakeholders. We're preparing logistics, finalizing specialty pharmacy agreements, and generally preparing the company for commercial readiness on all fronts. We're looking forward to the rest of 2024 and 2025.

We're actively developing commercial capabilities for these markets identifying key prescribers and tailoring our launch strategy.

We know that Pathfinder, one data is resonating well, creating excitement amongst the acromegaly in carcinoid syndrome prescribers and patients.

Understanding payer perspective is also crucial and Jim hazard and our chief commercial our Chief commercial officer is building a market access team to build relationships with these important stakeholders.

We're preparing logistics finalizing specialty pharmacy agreement and generally preparing the company for commercial readiness on all fronts.

Looking forward to the rest of 2024 and 'twenty five.

Scott Struthers: We anticipate multiple transformative milestones ahead, such as completing Pathfinder II. Completing Phase 2, followed by initiation of a Phase 3 study in carcinoid syndrome. Finishing Phase II and initiating a Phase III study in CAA. Submitting our first NDA and launching paltucetine paracromegaly, if approved. Moreover, continuing to advance our pipeline of promising candidates in high-prevalence indications that are beginning to emerge from discovery. We will also continue to invest in our world-class discovery capabilities, which are the roots of our long-term success. With that, I'll hand it over to Dr. Alan Krasner, our Chief Endocrinologist, to talk about our clinical program and the results we're seeing today. Alan?

We anticipate multiple transformative milestones ahead complete.

Completing pathfinder II.

Completing phase II, followed by initiation of a phase III study in carcinoid syndrome.

<unk> in a phase II and initiating a phase III in CAH submitting our first NDA.

And launching <unk> for Acromegaly if approved.

Moreover, continuing to advance our pipeline of promising candidates in high prevalent indications that are beginning to emerge from discovery.

We were also continue to invest in our world class discovery capabilities.

Routes of our long term success.

With that let me hand, it over to Dr. Alan Krasner, our chief Endocrinologists to talk about our clinical program and the results we're seeing today.

Alan S. Krasner: Thank you, Scott. Today, I will provide a summary of the results we recently reported from our clinical programs and what this means for continued development, starting with peltucetin. As Scott already mentioned, our Phase III Pathfinder I study of oral paltucetine in patients with acromegaly achieved all the goals set out for the study. In September, we reported highly statistically significant results in our primary endpoint and all secondary endpoints. Before I dive into the data, I'd like to reiterate that this trial was designed to evaluate paltucetine in patients who are already biochemically controlled on injectable SRL therapy and switch to paltucetine. In acromegaly, excess growth hormone acts on the liver to secrete excess insulin-like growth factor 1 or IGF-1.

Thank you Scott.

Today I will provide a summary of the results. We recently reported from our clinical programs and what this means for the continued development starting with <unk>.

As Scott already mentioned, our phase III Pathfinder, one study of oral <unk> in patients with acromegaly achieved all the goals set out for this study.

In September we reported highly statistically significant results and our primary endpoint and all secondary endpoints.

Before I dive into the data I'd like to reiterate at this trial was designed to evaluate patients participating in patients who are already biochemically controlled on injectable <unk> therapy and switch to participate.

And acromegaly excess growth hormone access it deliver to secrete excess insulin like growth factor, one or IGF one.

Alan S. Krasner: Participants in the PATHFINDER-1 trial were previously treated with injectable SRL therapy and had IGF-1 levels at baseline of less than or equal to 1 times the upper limit of normal. The goal for peltucetine in this trial was to maintain this level of biochemical control. Therefore, the primary endpoint was the proportion of participants who maintain IGF-1 levels of less than or equal to one times the upper limit of normal on paltucetine compared to placebo. We also pre-specified clinically important metrics as secondary endpoints. The change from baseline in IGF-1, the change in acromegaly symptoms using a fit-for-purpose acromegaly symptom diary, and the proportion of participants able to maintain growth hormone levels of less than one nanogram per milliliter.

Participants in the Pathfinder, one trial were previously treated with injectable <unk> therapy and had IGF one levels at baseline of less than or equal to one times the upper limit of normal.

The Gulf for participating in this trial was to maintain this level of biochemical control.

Therefore, the primary endpoint was the proportion of participants who maintain IGF one levels of less than or equal to one times, the upper limit of normal <unk> compared to placebo.

We also pre specified clinically important metrics as secondary endpoints the change from baseline in IGF, one the change in acromegaly symptoms using a fit for purpose acromegaly symptom diary.

And the proportion of patient participants able to maintain growth hormone levels of less than one nanogram per milliliter.

Alan S. Krasner: In the study, we saw a remarkable 83 percent, or 25 of 30 patients who received peltucidine meet the primary endpoint. This is compared to only 4%, or 1 out of 28 patients receiving placebo. The magnitude of this difference is highly statistically significant, with a p-value of less than 0.0001. In all secondary endpoints, we also achieved statistical significance. Participants in the peltucetine group maintained control of IGF-1 levels, while those on placebo rose markedly.

In this study we saw a remarkable 83% or 25 of 30 patients who received <unk> meet the primary endpoint.

This is compared to only 4% or one out of 28 patients receiving placebo.

<unk> of this difference was highly statistically significant with a P value of less than 0.0001.

And all secondary endpoints, we also achieved statistic statistical significance.

Dissipates in the <unk> group maintained control of IGF, one levels, while those on placebo rose markedly and this difference was statistically significant with a P value of 0.0001.

Alan S. Krasner: And this difference was statistically significant, with a p-value of 0.0001. In addition, overall symptom control was measured using the Acromegaly Symptom Diary, or ASD. Participants receiving peltucetine maintained control of their symptoms, as measured by the total ASD score. This is compared to an overall increase from baseline as reported by the placebo group. This difference was statistically significant, with a p-value of 0.02.

In addition, overall symptom control was measured using the acromegaly symptom diary or ASD score.

Participants receiving <unk> maintain control of their symptoms as measured by the total ASD score.

This is compared to an overall increase from baseline as reported by the placebo group.

This difference was statistically significant with a P value of zero point zero Q.

Finally, 87% of participants receiving <unk> maintained growth hormone levels less than one nanogram per milliliter compared to 28% in placebo.

Alan S. Krasner: Finally, 87% of participants receiving paltucetine maintained growth hormone levels less than one nanogram per milliliter, compared to 28% of those receiving placebo. This difference was also highly statistically significant with a p-value of 0.0003. We are very excited about these results that demonstrate durable symptom and biochemical control through a convenient once-daily oral option for patients who are currently burdened by depo injections. These data are very clear that peltocetine effectively maintains IGF-1 levels in the normal range. In the direct guidance on the development of drugs for the treatment of acromegaly issued in January 2023, the FDA identified two acromegaly patient populations of interest. Firstly, the maintenance population that was evaluated in the PATHFINDER-1 trial, and secondly, the treatment population that we are currently evaluating in our PATHFINDER-2 study.

This difference was also highly statistically significant with a P value of 0.0003.

We are very excited about these results that demonstrate durable symptom and biochemical control.

Through a convenient once daily oral option for patients who are currently burdened by depot injections.

These data are very clear that <unk> effectively maintains IGF one levels in the normal range.

Yes.

In the draft guidance on the development of drugs for the treatment of Acromegaly issued in January 2023 the.

The FDA identified two acromegaly population.

Two acromegaly patient populations of interest.

Firstly, the maintenance population, who are evaluated in the Pathfinder, one trial and secondly, the treatment population that we are currently evaluating in our Pathfinder II study.

Alan S. Krasner: The treatment population includes those with active acromegaly who are not currently on medical therapy and therefore have an IGF-1 level that is greater than the upper limit of normal. The goal here is to show that a new agent can treat active disease as measured by lowering elevated IGF-1 levels. SRLs are currently used in practice as first-line medical therapy for acromegaly because published studies have demonstrated that most untreated patients, when treated with SRL monotherapy, have meaningful lowering of IGF-1.

The treatment population includes those with active acromegaly, who are not who are not currently on medical therapy, and therefore have an IGF one level that is greater than the upper limit abnormal.

The goal here is to show that a new agent can treat active disease as measured by lowering elevated IGF one level.

<unk> are currently used in practice as first line medical therapy for Acromegaly, because published studies have demonstrated that most untreated patients when treated with <unk> monotherapy have meaningful lowering of IGF one.

Alan S. Krasner: Although only a minority of patients, particularly among those who are naive to medical therapy, normalize IGF, it is not possible to predict which untreated patients who start out with a potentially wide range of baseline IGF-1 elevations will actually normalize. But it is known that the majority of patients treated with an SRL in previous studies benefited from therapy. For regulatory purposes, the primary objective of Pathfinder 2 is to demonstrate a statistically greater proportion of subjects on Peltucidine with normal IGF-1 at the end of treatment compared to that achieved with placebo treatment. This was the same primary objective of Pathfinder 1.

Although only a minority of patients, particularly among those who are naive to medical therapy normalized IGF one.

It is not possible to predict which untreated patients who start out with a potentially wide range of baseline IGF one elevations.

Actually normalize, but it is known that the majority of patients treated with <unk> in previous studies benefited from therapy.

For regulatory purposes. The primary objective of Pathfinder II is to demonstrate a statistically greater proportion of subjects on <unk> with normal IGF, one at end of treatment compared to that achieved with placebo treatment.

This was the same primary objective of Pathfinder. One however, it is important to note that the absolute IGF, one normalization rates and Pathfinder too is expected to be lower than that observed in the pathfinder one population.

Alan S. Krasner: However, it is important to note that the absolute IGF-1 normalization rate in Pathfinder 2 is expected to be lower than that observed in the Pathfinder 1 population. Remember, the Pathfinder 1 population was all known to have normal IGF-1 levels on SRL monotherapy at baseline. Pathfinder-2 patients would be expected to have a wide range of IGF-1 elevations at baseline. Based on published data, our best estimate of the overall percentage of patients who achieve normal IGF-1 levels on-drug at the end of treatment in Pathfinder 2 should be approximately 30%. And this study has the power to show that this is different than that expected in the placebo group. This normalization rate would indicate that peltucetine is similarly effective to injected SRLs in this patient population and should be able to compete with injections as a first-line therapy. Although IGF-1 normalization is of interest, perhaps even more relevant to clinical practice is the reduction from elevated baselines that can be achieved with PAL-II, and this is a pre-specified key secondary endpoint in Pathfinder 2.

Remember the Pathfinder, one population will all known to have normal IGF, one on Srs monotherapy at baseline.

Kathleen acute patients would be expected to have a wide range of IGF one elevations at baseline.

Based on published data our best estimate of the overall percentage of patients who achieved normal IGF one on drug at the end of treatment and Pathfinder too should be approximately 30% and this study is powered to show that this is different than that expected in the placebo group.

This normalization rate would indicate that <unk> is similarly effective two injected <unk> in this patient population and.

And should be able to compete with the injections as a first line therapy.

Although IGF one normalization is of interest, perhaps even more relevant to clinical practice is the reduction from elevated baseline that can be achieved with <unk>.

And this is a pre specified key secondary endpoint and Pathfinder II.

Alan S. Krasner: Pending results, we hope that Pathfinder 2 will complement Pathfinder 1 and allow us to seek a broad indication for paltucetine in the treatment of acromegaly. Pathfinder 2 completed enrollment with 111 enrolled participants. We look forward to sharing top-line results from Pathfinder II with you in the next phase. Feltucetine's second target indication, carcinoid syndrome, is also showing promising results to date. In December, we reported initial results from the ongoing Open Label Phase 2 trial. As a brief reminder, SRLs are the first-line medical therapy for carcinoid syndrome, and we would expect that oral peltucetine would compete with injections in this patient population as well. Carcinoid syndrome arises from neuroendocrine tumors that most commonly originate in the small intestine. The syndrome is caused by tumor production of serotonin and other factors. The two key symptoms that patients experience in this disease are diarrhea and flushing.

Pending results, we hope that pathfinder to complement Pathfinder, one and allow us to seek a broad indication for <unk> in the treatment of acromegaly.

Pathfinder, two completed enrollment with 111 enrolled participants.

We look forward to sharing top line results from Pathfinder to with you in the next month.

<unk> second target indication Carcinoid syndrome is also showing promising results to date.

In December we reported initial results from the ongoing open label Phase II trial.

As a brief reminder, SRM tools or their first line medical therapy for Carcinoid syndrome, and we would expect that <unk> would compete with injections in this patient population as well.

Carcinoid syndrome arises from neuro endocrine tumors that most commonly originate in the small intestine.

The syndrome is caused by tumor production of serotonin and other factors.

Two key symptoms that patients experience in this disease are diarrhea and flushing.

Our goal in treating carcinoid syndrome patients with <unk> is to reduce their total symptom burden.

Alan S. Krasner: Our goal in treating carcinoid syndrome patients with peltucidine is to reduce their total symptom burden. The ongoing Phase 2 study is an open-label, parallel-group study that enrolls patients who are either nave to SRL treatment or currently treated, untreated, and actively symptomatic, or who are controlled on SRL therapy and willing to wash out prior to entry. The initial results we presented in December included 27 participants. The trial is fully enrolled with a total of 36 participants, and top-line results from the full study are anticipated in the first half of this year. From a safety point of view, peltucetine was well tolerated with no new safety findings, consistent with what we've seen in our previous studies.

The ongoing phase II study is an open label parallel group study that enrolled patients who are either naive to <unk> treatment or are currently treated untreated and actively symptomatic or who are controlled on srs therapy and willing to wash out prior to entry.

The initial results we presented in December included 27 participants.

The trial is fully enrolled with a total of 36 participants and topline results from the full study are anticipated in the first half of this year.

From a safety point of view <unk> was well tolerated with no new safety findings consistent with what we've seen in our previous studies.

Alan S. Krasner: In addition, pharmacokinetics in this patient population remains consistent with what we expected to see from prior experience and healthy volunteers. We are also very pleased to have already observed meaningful reductions in the two key symptoms of carcinoid syndrome, access bowel movements, and flushing episodes, even in the initial look at the data. So far, peltucetine is associated with a 65% reduction in excess bowel movement frequency in patients who enter the study with greater than three bowel movements per day.

In addition, pharmacokinetics in this patient population remains consistent with what we expected to see from prior experience in healthy volunteers.

We are also very pleased to have already observed meaningful reductions in the two key symptoms of carcinoid syndrome, excess bowel movement and Flushing episodes, even in the initial look at the data.

So far <unk> is associated with a 65% reduction in excess power movement frequency in patients who entered the study with greater than three bowel movements per day.

Alan S. Krasner: In patients who experienced one or more flushing events per day at baseline, peltucetine is also associated with a 65% reduction in these. As part of the study design, participants had the opportunity to up-titrate their dose of peltucidine based on pre-specified symptom criteria. However, few patients in the study at the time of the initial analysis required an increase in dose.

In patients, who experienced one or more flushing events per day at baseline <unk> is also associated with a 65% reduction in these episodes.

As part of the study design participants had the opportunity to up titrate their dose of participating based on pre specified symptom criteria.

However, a few patients in the study at the time of the initial analysis required an increase in dose. So we believe we're in the correct range to observe a response.

Alan S. Krasner: So we believe we're in the correct range to observe a response. Results of biomarkers and other supplemental exploratory endpoints will be analyzed and reported with final results. We are excited about this initial data and look forward to reviewing the full top-line results, which are anticipated in the first half of this year. Based on the results thus far, we believe peltucetine is acting like an SRL in terms of its ability to provide symptom relief, and we think the full data set will confirm that.

Results of biomarker and other supplemental exploratory endpoints will be analyzed and reported with final results.

We are excited about this initial data and look forward to reviewing the full top line results, which are anticipated in the first half of this year.

Based on the results. Thus far we believe <unk> is acting like an <unk> out in terms of its ability to provide symptom relief and we think the full dataset will confirm this.

Alan S. Krasner: We will submit the final data to the FDA for discussion at the end of Phase 2 meeting. We look forward to updating you on the Phase 3 trial design details, including dose, registration, NOAA endpoint, and timing, once we've had these discussions. Our second candidate following Paltucetine is CRN 04894. 4894 is an ACTH receptor antagonist in development for the treatment of congenital adrenal hyperplasia, or CAH. Classic CAH is a genetic disorder that affects approximately 27,000 patients in the U.S. These patients have impaired cortisol production, which causes high levels of ACTH. This excess ACTH causes overstimulation of the adrenal cortex, resulting in the overproduction of androgens.

We will submit the final data to the FDA to discuss at an end of phase two meeting.

We look forward to updating you on the phase III trial design details, including dose Registrational endpoint and timing once we've had these discussions.

Our second candidate following <unk> is CRM zero for $8 94.

494 is an ACTH receptor antagonist in development for the treatment of congenital adrenal hyperplasia or CAH.

Classic CAH is a genetic disorder that affects approximately 27000 patients in the U S.

These patients have impaired cortisol production, which causes high levels of ACTH.

This excess ACTH causes overstimulation of the adrenal cortex, resulting an overproduction of androgens.

Alan S. Krasner: As an ACTH antagonist, 4894 is designed to act directly at the adrenal gland to normalize adrenal androgen production. 4894 is currently being studied in a Phase II open-label, sequential-dose study in participants with CAH. At this stage of development, we are primarily interested in evaluating the safety and pharmacokinetics of 4894. However, we're also interested in looking at pharmacodynamics. And in CAH, this is measured primarily using the biomarker androstenediome, or A4. Similar to how we presented the carcinoid syndrome data in December, we plan to report initial data from the Open Label Phase 2 study in the second quarter of 2024. This will not be complete data but initial data from a small number of enrolled participants.

As an ACTH antagonist <unk> 94 is designed to act directly at the adrenal gland to normalized adrenal androgen production.

494 is currently being studied in a phase two open label sequential dose study participants with CAH.

At this stage of development, we are primarily interested in evaluating safety and pharmacokinetics of 494.

However, we're also interested in looking at pharmacodynamics and in CAH. This is measured primarily using the biomarker androstenediol or 84.

Similar to how we presented the carcinoid syndrome data in December we plan to report initial data from the open label Phase II study in the second quarter of 2024.

This will not be full data, but initial data from a small number of enrolled participants.

Alan S. Krasner: We hope it will give us an early picture of how 4894 is acting in CAH patients. With that, I will now hand it over to Marc for a review of the finances. Thank you, Alan. We ended 2023 on a strong financial footing with $558.6 million in cash and investment. In addition, earlier today, we announced a $350 million private placement equity financing. This private placement further strengthened our financial position with approximately $900 million on a pro forma basis.

We hope that will give us an early picture of how 494 is acting in CAH patients.

With that I will now hand, it over to Mark for a review of the financials.

Thank you Alan we.

We ended 2023 on strong financial footing with $558 $6 million in cash and investments.

In addition earlier today, we announced a $350 million private placement equity financing.

This private placement further strengthened our financial position with approximately $900 million on a pro forma basis.

We have a solid financial foundation as we prepare for multiple upcoming data readouts and regulatory milestones.

Marc J. C. Wilson: We have a solid financial foundation as we prepare for multiple upcoming data readouts and regulatory milestones, and as we continue investing in the expansion of our deep pipeline. Research and development expenses were $45.6 million and $168.5 million for the quarter and full year ended December 31, 2023, compared to $37 million and $130.2 million for the same periods in 2022. The increases were primarily attributable to higher personnel costs and increased outside services, both of which were driven by the advancement and expansion of our portfolio of programs. General and administrative expenses were $17.1 million and $58.1 million for the quarter and full year ended December 31, 2023, compared to $11.3 million and $42.4 million for the same period in 2021.

And as we continue investing in the expansion of our deep pipeline.

Research and development expenses were $45 6 million and $168 5 million for the quarter and full year ended December 31, 2023, compared to $37 million and $130 2 million for the same periods in 2022.

The increases were primarily attributable to higher personnel costs and increased outside services, both of which were driven by the advancement and expansion of our portfolio of programs.

General and administrative expenses were $17 1 million and $58 1 million for the quarter and full year ended December 31 2023.

Compared to $11 3 million and $42 4 million for the same periods in 2022.

These increases were primarily attributable to higher personnel costs.

Our net loss for the quarter ended December 31, 2023 was $60 1 million compared to a net loss of $45 million for the same period in 2022.

Marc J. C. Wilson: These increases were primarily attributable to higher personnel costs. Our net loss for the quarter ended December 31, 2023 was $60.1 million, compared to a net loss of $45 million for the same period in 2021. For the year ended December 31, 2023, the company's net loss was $214.5 million, compared to a net loss of $163.9 million for the same period in 2022. Revenues were $4 million for the full year ended December 31, 2023, compared to $4.7 million for the same period in 2022. There were no revenues for the quarter ended 2023 compared to 0.7 million for the same period.

For the year ended December 31, 2023, the company's net loss was $214 5 million compared to a net loss of $163 9 million for the same period in 2022.

Revenues were $4 million for the full year ended December 31, 2023, compared to $4 7 million for the same period in 2022.

There were no revenues for the quarter ended 2023 compared to <unk> 7 million for the same period in 2022.

Revenues in both periods were primarily derived from licensing arrangements associated with our <unk> and CRM zero 109 for one product candidates.

Net cash used for operating activities. During the quarter ended December 31, 2023 was $38 5 million.

<unk> was $166 3 million for the year ended December 31 2023.

In 2024, we anticipate our cash burn to be approximately $50 million to $60 million per quarter.

Marc J. C. Wilson: Revenues in both periods were primarily derived from licensing arrangements associated with our Paltusatine and CRN 01941 products. Net cash used for operating activities during the quarter ended December 31, 2023 was $38.5 million, and was $166.3 million for the year ended December 31. In 2024, we anticipate our cash burn to be approximately 50 to $60 million per quarter, and we expect that following the $350 million private placement announced earlier today, our pro forma cash, cash equivalents, and short-term investments of approximately $900 million will be sufficient to fund our current operating plan into 2021. I will now hand it back to Scott for closing remarks before we begin Q&A. Thank you, Marc. We're extremely proud of the progress we've made throughout 2023 and so far in 2024. And 2024 is poised to be a transformative year for chronetics. We look forward to providing continued updates throughout the year as we progress paltucetine through regulatory submissions and commercialization, make continued advancements in our pipeline, and continue to create exciting new drug candidates with our discovery efforts. Thank you all for your attention. Operator, we're ready to take questions.

And we expect that following the $350 million private placement.

<unk> earlier today that our pro forma cash cash equivalents and short term investments of approximately $900 million will be sufficient to fund our current operating plan into 2028.

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

Thank you Mark we're extremely proud of the progress we made throughout 2023 and so far in 2024, and 2024 is poised to be a transformative year for kinetics.

We look forward to providing continued updates throughout the year as we progressed <unk> through regulatory submissions and commercialization may continued advancements in our pipeline and continue to create exciting new drug candidates with our discovery efforts. Thank you all for your attention operator, we're ready to take questions.

Thank you.

Ladies and gentlemen, we will now begin the question and answer session should you have a question. Please press star followed by the number one on your Touchtone phone.

Should you wish to the graph from the polling process. Please press star followed by the numbers.

If you are using a speaker phone please lift the handset before briskly in any case.

One moment. Please for your first question.

Your first question comes from Joseph Schwartz from Leerink Partners. Please go ahead.

Thanks, very much and congrats on all the progress.

So first question on Pathfinder too.

The patients who enrolled in this trial that are not currently receiving medical therapy do you have a sense of how many of them had previously responded to SSR else versus those that didn't.

Operator: Thank you. Ladies and gentlemen, we will now begin the question and answer session. Should you have a question, please press star followed by the number one on your touch-tone phone. Should you wish to decline from the polling process, please press star or the number. If you are using a speakerphone, please lift the handset before pressing any number.

Hello, Joe and thanks, let Alan answer that question.

Hi, Jeff So in the group.

Where patients haven't been recently treated prior to screening for the study.

Operator: One moment, please, for your first question. Your first question comes from Joseph Schwartz from Leering Partners. Please go ahead.

Basically patients who are known not to have responded to as relevant in the past or medical therapy. In the past are not eligible for this study now that is largely left to the discretion of the <unk>.

Joseph Patrick Schwartz: Thanks very much, and congratulations on all the progress. So, first question on Pathfinder 2, for the patients who are enrolled in this trial that are not currently receiving medical therapy, do you have a sense of how many of them had previously responded to SSRLs versus those that didn't? Hello, Joe, and thanks. Let Alan answer that question.

Principal investigator of the Doctor at the research site, but those patients in theory, it's where they are known not to be responsive to medical therapy. They should not really be in a trial.

Which medical therapy is being evaluated.

Right. Okay. That's helpful. Thanks, and then actually another question on Pathfinder two do you have a sense for how the assay you're using to measure IGF one in Ah patients in one or two compares to the assay that was used for the studies that were done many years ago for Octreotide in land rig side.

Alan S. Krasner: So in the group where patients haven't been recently treated prior to screening for this study, basically patients who are known not to have responded to SRLs in the past or medical therapy in the past are not eligible for this study. Now, that is largely left to the discretion of the principal investigator, the doctor at the research site. So for those patients, in theory, if they're known not to be responsive to medical therapy, they should not really be in a trial in which medical therapy is being evaluated. Right, okay, that's helpful. Thanks. And then, actually another question on Pathfinder 2, do you have a sense for how the assay you're using, measuring IGF-1, works in the patient? in Pathfinder 2 compares to the assay that was done many years ago for arctreatite and lanreatite in the same population and could any differences in the assays rigor influence the results, and if so, do you have any estimate for how much that could influence the results?

In the same population could any differences in the assays rigor influence the results and if so do you have any estimate for how.

How much that could.

Translate into.

Yes. So we are using what is currently the gold standard assay for IGF, one measured in our Central Laboratory.

Immunoassay that is very rigorously validated and probably even more important in the assay itself is the update up to date reference ranges by age for IGF. One that's been a major area of research over the last 10 15 years and so we are using the state of the art measurement technique and you're right. The older study.

Alan S. Krasner: Yes, so we are using what is currently the gold standard assay for IGF-1 measured in a central laboratory. It's an immunoassay that is very rigorously validated. And probably even more important than the assay itself is the up-to-date reference ranges by age for IGF-1. That's been a major area of research over the last 10, 15 years. And so we are using state-of-the-art measurement techniques.

<unk> used our previous assays and also previous reference ranges that were available at the time.

However, we have worked with the world world's experts on.

Hey.

Potential assay differences.

And we have taken that into account for our sample size calculations for this study.

Scott Struthers: And you're right, the older studies used previous assays and also previous reference ranges that were available at the time. However, we have worked with the world's experts on potential assay differences, and we have taken that into account for our sample size calculations for this study. There could be minor differences, but in the more recent, I mean, there could be more significant differences with older versions of the assay, but we think we have a good handle on comparing, But Joe, I think also, this is Scott to add that it does get more and more difficult the further back in time you go to compare our data with those earlier studies, and largely because of these assay and perhaps more importantly, the reference ranges for the, Thanks for your questions.

There could be minor differences, but in the more recent.

I mean, there could be more significant differences with older versions of the assay, but we think we have a good handle on comparing two more recently done research, particularly in naive patients with acromegaly.

So Madhu I think also this is scott to add that.

It does get more and more difficult to further back in time, you go to compare our data with those earlier studies.

And largely because of these assay and perhaps more importantly, the reference ranges for the assay.

Thanks for your question.

Thank you.

Your next question comes from Jasmine Rahimi from Piper Sandler. Please go ahead.

Good afternoon, and congrats on all the progress.

The first question that has been submitted to ask all throughout the whole morning has been investors wondering if the pipe investors were previewed any data related to pathfinder too or.

Scott Struthers: Thank you. Your next question comes from Yasmeen Rahimi, from Piper Sandler. Please go ahead. Good afternoon team, and congrats on all the progress. Maybe the first question that has been submitted to us all throughout the whole morning has been investors wondering if the pipe investors have been previewing any data related to Pathfinder 2 or Carcinoid or CEH. Would love to hear your color. And then my second question is for Alan, if you could maybe share, what could be a reasonable sample size for the interim readout for CEH? And also maybe a little bit of a reminder of what is considered a clinically meaningful difference in A4 levels and maybe other key endpoints that we should be looking forward to from the unmet need that exists in these patients. Thank you. Great. Well, you know, I can't answer or discuss the inner workings of that deal process.

Carcinoid or CE would love to hear your color and then my second question is for Alan If you could maybe share.

<unk>.

What could be <unk>.

Bulk sample size for the interim readout for CAH and also maybe a little bit of a reminder of what is considered a clinically meaningful difference in a four level and maybe other key endpoints that we should be looking forward to.

From from unmet need that exists in these patients. Thank you.

Great.

I can't answer or discuss the inner workings of that deal process.

Scott Struthers: And Pathfinder 2 remains blinded to you, me, and everyone will know the outcome of that trial next month. But it should be obvious to everybody from the list of great funds that we disclosed in our press release. They were willing to be named and were included in the deal.

And Pathfinder II remains blinded to you me and everyone will know the outcome of that trial next month.

But it should be obvious to everybody from the list of great funds that we disclosed in our press release.

They were willing to be named and were included in the deal.

Scott Struthers: But this isn't a deal, or wasn't a deal about handicapping some single short-term readout. This is a high-quality list of new and existing investors with a long-term view that understand and want to support the long-term growth and vision of our company. Thank you. Thank you, Scott. That was very helpful. And on the ACTH side, Alan?

This isn't a deal or it wasn't a deal about handicapping. Some single short term readout. This.

This is a high quality list of new and existing investors with a long term view that understand and want to support.

The long term growth and vision of our company.

Thank you can I think Scott.

Scott that was very helpful.

And on the ACTH side, yes.

Alan S. Krasner: Yeah. So, those are all great questions about the CAH study. What is an appropriate sample size for us to reach some conclusions about safety, pharmacokinetics, and efficacy? So I'll say right off the bat that this is not a pre-specified statistical exercise. This is more of a qualitative look at directional data, which is exactly what we did recently with carcinoid syndrome. This is a rare disease.

So yes, those are all great questions about the CAH study.

It is.

An appropriate sample size for us to reach some conclusions about.

Safety pharmacokinetics and efficacy.

I'll tell you right off the bat that this is not a.

Pre specified.

Statistical exercise. This is more of a qualitative look at directional data, which is exactly what we did recently with carcinoid syndrome.

This is a rare disease, but in general we are look you asked what's the most what's the clinically meaningful change in the Pharmacodynamic biomarker of most interest and Thats Androstenediol and as we mentioned.

Alan S. Krasner: But in general, you asked what the clinically meaningful change in the pharmacodynamic biomarker of most interest is. And that's androstenedione, as we mentioned. And I think what we'll be looking for, of course, are easily visualized changes from baseline in A4 levels on the pharmacodynamic front. And, in fact

And I think what we'll be looking for of course is <unk>.

Italy.

Our easily visualized changes from baseline in 84 levels on the Pharmacodynamic front and in fact most.

Alan S. Krasner: Most importantly, can we achieve normalization of A4, I think, is probably the most clinically meaningful based on what we know now from elevated baseline. And as you mentioned, there are many other potential endpoints besides 8-4 on the pharmacodynamic front we can look at and that we are exploring a lot of these in this, even this small study in phase 2 for CH. I mean, some examples of things that are also important; there are other biomarkers that are of relevance too, like 17-hydroxyprogesterone, which is another biomarker used by clinicians to assess dose, response to therapy, as well as the diagnosis of the disease, but also things like how are the patients doing clinically.

Most importantly can we achieve normalization of April I think is probably what's most clinically meaningful based on what we know now from elevated baseline.

And as you mentioned there are many other potential endpoints. Besides a four on the Pharmacodynamic front, we can look at and that we are exploring a lot of these in this even this.

Small stub.

Study in phase two for C H.

Some examples of things that are also important there are other biomarkers that are of relevance to like 17 hydroxy progesterone, which is another.

Biomarker used by clinicians to assess dose.

Our response to therapy as well as the diagnosis of the disease, but also things like how are the patients doing clinically a lot of these patients for example of female patients with this disorder have irregular menses and can be in peripheral and we would of course, we monitor menstrual cycling and women very closer.

Alan S. Krasner: A lot of these patients, for example, female patients with this disorder have irregular menses and can be infertile, and we would, of course, monitor menstrual cycling in women very closely. And there are many other clinically important things like that that we will follow carefully, and I hope we have a good directional signal from our interim analysis that we'll be doing and reporting on by the end of the first half. Thank you, Alan, very much. Thank you. Your next question comes from Jessica Fye from JPMorgan Chase. Please go ahead. Hey guys, this is Nassan on for Jess.

Okay.

And there are many other clinically important things like that that we will call them carefully and I hope we have a good directional signals from our interim analysis, there will be doing in reporting on by the end of the first half.

Thank you Alan.

Alright, thank you.

Your next question comes from Jessica Fye from Jpmorgan Chase. Please go ahead.

Hey, guys. This is <unk> on for.

Sure Jess.

So we are very close to.

Operator: So we're very close to bold data for carcinoid. Can you help us set some expectations there? Maybe, like, what would represent a win for that update?

Full data for carcinoid.

Can you help us set some expectations there.

<unk>.

Maybe like what what would represent a win for that update.

Alan S. Krasner: And then, can you provide any updated thoughts on your phase three plans for carcinoid syndrome? Thank you. Yeah, so I was pretty impressed with our interim data reported in December. I thought that was pretty promising stuff already.

And then can you provide any updated thoughts on your phase III plans for carcinoid syndrome.

Yeah, So I mean.

I was pretty impressed with our interim data reported in December I thought that was pretty winning stuff already in some of these very important endpoints kind of reached.

Alan S. Krasner: And some of these very important endpoints kind of reached statistical significance even in this small study, so I would say a win for the final data set is really confirming kind of what we saw in our interim data. And also, we hope to have more information, expanded information on other exploratory endpoints, like key biomarkers, and other sort of supplemental data points. For example, you may recall from our interim data report, we were very excited to see not only the numbers of excess bowel movements and flushing episodes reduced on paltucetine, but also the urgency of those associated bowel movements and also the severity of those flushing episodes were also very meaningfully reduced. That goes beyond just numbers.

Statistical significance, even in this small and its small.

Study, so I would say a win for the final data set is really confirming kind of what we saw.

In our interim data and also we hope to have more information expanded information on other exploratory endpoints like key biomarkers and other sort of supplemental data points. For example, you may recall from our interim data report, we I was very excited to see not only of the numbers of <unk>.

<unk> filed when links and Flushing episodes reduced on <unk>, but also the urgency of those associated Bob moments and also the severity of those Flushing episodes were also very meaningfully reduce that goes beyond just numbers. It goes to the what the patient is actually experiencing and what's most important to patients.

Alan S. Krasner: It goes to what the patient is actually experiencing and what's most important to the patient. So I'm hoping we'll have additional patient-centric information as well. Maybe comment on Phase 3. Oh, I'm sorry.

So I'm, hoping we'll have additional kind of patient centric information as well.

Okay.

And maybe comment on phase III start.

Our phase III. Thank you.

Alan S. Krasner: Phase 3. Thank you. Yes, we are actively designing Phase 3, obviously, and we're using our Phase 2 database to help with that a great deal. In fact, the Phase 2 database is really essential for this process.

Yes, we are actively designing phase III, obviously and we're using our.

Phase II database to help with that a great deal in fact, the phase II database is really essential for this process.

Alan S. Krasner: I do anticipate, based on regulatory history, that we'll be designing a likely a placebo-controlled parallel group phase 3 trial. We are exploring a variety of important potential primary endpoints that we will discuss with the FDA, as well as the key secondary endpoints for the phase 3 trial. Based on historical precedent, we know that the general sample size for phase 3 trials in this area is roughly, say, between 80 and 150 patients, and I think that's the kind of study we will end up proposing to the FDA. And again, we'll report back once we've had those discussions. Thanks, Jeff.

Do anticipate bay.

Based on regulatory history that we will be designing a likely a placebo controlled parallel group phase III trial, we are exploring a variety of important.

Potential primary endpoints that we will discuss with the FDA.

As well as the key secondary endpoints for the phase III trial.

We based on historical precedent, we know that the general sample size for phase III trials. In this area are roughly say between 80 and 150 patients and I think that's the kind of study we will end up proposing to the FDA and again, we will report back once we've had those discussions with them.

Well.

Thanks, Jeff Thank you.

Operator: Thank you. Your next question comes from Jeff Hung from Morgan Stanley. Please go ahead.

Your next question comes from Jeff <unk> from Morgan Stanley. Please go ahead.

Jeff Hung: Thanks for taking my questions. Can you talk about the importance of the acrobatically symptoms diary and your strategy for having that included in the label? And then I have a follow-up. Actually, I think it's important to point out that that's fairly unique amongst the SRLs, and we're very excited about it.

Thanks for taking my questions can you talk about the importance of the acromegaly symptom diary and your strategy for having that included in the label and then I have a follow up.

Actually I think it's important to point out that thats fairly unique amongst <unk> and we're very excited about it and maybe Jim our chief commercial officer could answer a little more in depth.

Scott Struthers: And maybe Jim, our Chief Commercial Officer, could answer a little more in depth. Sure, thanks, Scott. So, as Scott mentioned, symptom diary or quality of life is not a component of the competitive label.

Sure. Thanks, Scott.

As Scott mentioned.

Symptom diary or quality of life has not been a component of the competitive label. So it is something that we.

James Hassard: So, it is something that we do look forward to, and whether it's in the label, or whether it's in publication, it's certainly something that will be communicated to key opinion leaders within the United States and globally. Symptom control among patients with acromegaly is a big deal. There's certainly biochemical control as the regulatory endpoint, but as we speak to patients, it's all about symptoms and how they feel. So, it will be a big part of the conversation from a commercial standpoint, and it certainly will be an important component of how Peltucetine performs for both patients and physicians. Great, thanks. And then what is your latest thinking for the commercial strategy for pilot 16, and what has the pair feedback been so far? Thanks.

We do look forward to and whether it's in the label or whether it's in publication, but certainly something that will be communicated to key opinion leaders within the United States and globally.

Symptom control among patients with acromegaly is a big deal, there's certainly biochemical control as the regulatory endpoint, but as we speak to patients.

All about symptoms on how they feel.

It will be a big part of the conversation.

From a commercial standpoint.

Certainly will be an important component of how Perl tusa team performs for both patients and physicians.

Great. Thanks, and then what is your latest thinking for the commercial strategy for <unk> and what has been the payer feedback been so far.

Yes.

James Hassard: Yeah, so the commercial strategy is, I think, as Alan and Scott have mentioned, Pathfinder I and Pathfinder II will provide us with, we hope, the broadest possible label that will allow us to treat and market to both naive patients and patients that are currently going under therapy. In terms of, we've had a number of advisory boards with physicians and also market research with payers, and I will tell you that, based on the Pathfinder I data, the response has been very, very enthusiastic. In terms of a value proposition, we also have been speaking with payers about the relative pricing within the marketplace, both for the standard of care, injectables, and depending on channel as well. And within the hospital segment, there is a markup system that occurs where the average markup for payers and for patients in terms of their co-pay for injectable somatostatin analogs that are delivered within the hospital outpatient setting can be as high as, or on average, about 300%, as high as, in some cases, 700%.

<unk> strategy is I think as elements Scott have mentioned.

101, and Pathfinder too will provide us with we hope the broadest possible label that will allow us to treat them market to both naive patients and patients that are currently going under under therapy in terms of we've had a number of.

Advisory boards with physicians.

<unk> and also market research with payers and I will tell you that based on the on the pathway to one data. The response has been very very enthusiastic.

In terms of our value proposition.

We also have been speaking with payers just to both the relative pricing within the marketplace. Both for the standard of care Injectables and depending on channel as well and within the hospital segment. There is a markup system that occurs where the.

The average mark up for payers and for patients in terms of their copay within injectable somatostatin analogs that are delivered within the Haas low patient setting the markup can be as high as on average about 300% as high as in some cases, 700%.

James Hassard: So this is certainly a savings that oral peltucetine delivered through specialty pharmacy can offer to the payer community and something that we're having continued discussions with payers on that level. Thank you. Thank you. Your next question comes from Yuri Jubinville from Anomalies.

This is certainly a savings that an oral pill tusa team delivered through specialty pharmacy can offer to the payer community and something that we're having continued discussions with payers on that on that level.

Thank you.

Okay.

Thank you.

Your next question comes from jewelry Julian Beil Frank Please.

Operator: Please go ahead. Thanks for taking our questions, and congratulations on all the progress you've made in the last year. A quick question on acromegaly.

Please go ahead.

Thanks for taking our questions and congrats on all the progress you've made last year.

Question quick question on the Acromegaly.

Operator: So, taking a look across all the historical data sets, naive acromegaly, there's a strong correlation between treatment response and certain baseline characteristics, such as age or whether a patient entered the study with a macro versus a microadenoma. Can you give us a better understanding or insight more broadly into how these patient demographics for the past year align across the spectrum of previous studies in this group? I think the simple answer is we haven't done that analysis yet.

Taking a look across all of the historical data.

E Acromegaly really strong correlation between treatment response, certain baseline characteristics, such as age or whether patients entered the study with a macro versus micro adenoma can you give us a better.

Understanding or insight more broadly into how these patient demographics for paths to align across the spectrum of previous studies in this group.

Yes.

I think the simple answer is we haven't done that analysis yet.

Scott Struthers: And some of the sensitivity and subsets will be part of the phase three workup. But broadly, this is a global study with acromegaly patients that we think are representative of the general population. I think in the literature... from previous studies done over the years, it is not easy to identify a clear predictor of response to treatment in acromegaly. Probably, if one thing is most useful, it's just looking at the baseline IGF-1 level. If it's very high, it's gonna take more lowering to get it to normal.

Some of the sensitivity in subsets will be part of the phase III workup.

But broadly this is a global study with.

Acromegaly patients that we think are representative of the general population.

I think in the literature.

From previous.

The study is done over the years.

It is not easy to identify a clear predictor of response to treatment and acromegaly, probably a fun thing is most useful it's just looking at the baseline IGF one level if it's if.

It's very high it's.

I'm going to take more lowering to get to normal and that's why we reiterate that in this kind of study where patients and pathfinder to where patients can start out sometimes with very high IGF one levels.

Alan S. Krasner: And that's why we reiterate that in this kind of study where patients, in Pathfinder-2, where patients can start out sometimes with very high IGF-1 levels, we should expect a lower rate of IGF-1 normalization compared to what we saw in Pathfinder-1, where we knew everybody there was controlled at baseline on medication. Yeah, and we've been trying, Cory, as you've been telling other folks, to be sure and remind people that this is not the same population that we studied in Pathfinder 1 and that overall, our blended estimate for the study is the response rate in the low-30s ballpark. And you've previously, you know, building off of that, you previously mentioned that you've used the head-to-head pass-a-reatide versus octa-reatide study in your assumptions for at least the STRATUM-1 group.

We should expect a lower rate of IGF one normalization.

To what we saw in Pathfinder, one where we knew everybody there was controlled at baseline.

On medication.

We've been trying inquiry.

Then telling other folks to be sure and remind people that this is not the same population that we studied and pathfinder, one and that overall, our blended estimate for this study as a risk.

Our response rate in the low Thirty's ballpark.

Okay.

Mhm.

Previously building off of that you previously mentioned that you would use the head to head passenger it's hybris Octreotide study in your assumptions for at least the stratum. One group can you walk us through that rationale behind looking at that study to inform potential paths to outcomes.

Scott Struthers: Can you walk us through the rationale behind looking at that study to inform potential Pathfinder 2 outcomes? Especially given when you look across these studies historically, that's probably one of the more conservative response rates we've seen. But, it's also one of the most modern and comprehensive studies in the naive population, using the same assay with a close to modern reference range. So I think it's actually a pretty good analog.

Especially given when you look across these studies historically, that's probably one of the more conservative response rates we've seen.

Well, it's also one of the most modern and comprehensive studies in the naive population.

And using the same assay.

Close to modern reference range. So I think it's actually a pretty good analogue and we did use that in our powering assumptions and in that study.

Scott Struthers: And we did use that in our powering assumption. And in that study, the control arm was octreotide, and there were a large number of naive patients, and octreotide reduced IGF levels in the vast majority of patients, but only 24% achieved IGF levels within the normal range. And so that's where we had the powering for that, group or stratum one of Pathfinder 2.

The control arm was octreotide.

And it was the large number of naive patients and octreotide reduced IGF levels.

The vast majority of patients.

But only 24%.

Cheap IGF levels within the normal range and so that's where we have the power rating for that.

Group, our strategy one of Pathfinder II study.

Operator: Thank you. Your next question comes from Brian Skorney from Bird. Please go ahead. Hey, good afternoon, everyone.

Okay.

Sure.

Alright. Thank you. Your next question comes from Brian <unk> from Baird. Please go ahead Sir.

Okay.

Hey, good afternoon, everyone. Thanks for taking my questions.

Brian Peter Skorney: Thanks for taking my questions. I guess just following on from that last question, can you say anything about the baseline characteristics in terms of what the baseline IGF levels were in the Pathfinder 2 study? And I mean, it sounds like there's a reasonable, is it fair to say that there's sort of a trade-off between the primary and secondary endpoints where a lower baseline IGF-1 would mean a better response rate, but lower IGF production and higher baseline sort of mean the reverse? Yeah, I think we'll just have to wait another month. Sorry, Brian. It's coming. I know everybody wants to see it, but nobody wants it more than me.

Just following on on that last question can you say anything about the baseline characteristics in terms of what the baseline IGF level what those are.

The pathfinder to Saudi and I mean, it sounds like it was reasonable.

Fair to say that there is sort of a trade off between the primary and secondary endpoint.

A lower baseline IGF, one would mean better response rate, but lower IGF production on higher baseline.

And the reverse.

Yes, I think.

We'll just have to wait another month alright, Brian.

I know everybody wants to see it but nobody works for me.

Scott Struthers: So, soon, soon is the answer, and was there a part of that that I could really answer? I kind of lost it at the end. Oh, just if you could say anything about sort of the baseline IGF-1 level. Yeah, not at this time. And then maybe as a follow-up to ask something more at the pipeline stage. Seems like your thyroid-stimulating hormone antagonist is moving along nicely. I guess, do you think you have the capability to get an oral agent here? And I was just wondering about the specific target. Is it the TSH receptor? Is it the IGF-1 receptor? I'm just trying to think about how comparable this could be to taprotumumab and any differences between where it's binding to think about. Oh, yeah, no, great.

So soon soon is the answer was there a part of that that I could really answer I kind of lost it yet.

Just if you could say anything about sort of the baseline IGF one level.

Yes, not at this time.

Okay and then.

As a follow up path.

More in the pipeline it seems like Youre thyroid stimulating hormone and Clark.

Moving along nicely I guess do you think you have the capability to get Anoro.

Jim here.

Just wondering about the specific target is at the peak.

<unk> receptors.

<unk> asked one receptor I'm, just trying to think about how to get a handle on on how comparable this could be the conference will be available on any any differences between where it's fine that you can think about.

Scott Struthers: And yeah, I just bumped into one of the chemists in the hall who is really excited about the latest batch of molecules. And we already have good molecules that are oral and are polishing the last few. I think we're getting pretty close with this program.

Oh, Yeah no great.

Yes, just bumped into one of the chemists in the hall, who is really excited about the latest batch of molecules that we already have good molecules that are orally available.

Polishing the last few I think we're getting pretty close in this program.

Scott Struthers: The target is the TSH receptor, and just to remind people, because this isn't something we talked a ton about in our pipeline. Graves' disease is caused by antibodies that people develop that activate this TSH receptor, and so the notion is to block that. And Graves Eye Disease, or thyroid eye disease as it's been branded; the more formal name is Graves Ophthalmopathy, but it's such a mouthful that people call it thyroid eye disease.

The target is the TSH receptor and just to remind people because this isn't something we've talked about in our pipeline.

Graves disease.

It is caused by antibodies that people develop that activate this TSH receptor.

And so the notion is to block that.

And graves eye disease, or thyroid eye disease is it's been branded the more formal name is greatest off the market, but it's such a mouthful that people call it thyroid eye disease.

Scott Struthers: That's caused by the binding of these antibodies to TSH receptors in the cells at the back of the eye. Those receptors then act on those cells and on the IGF receptors on those cells to cause the hypertrophy that results in the protrusion and other problems in the back of the eye. So we're going to the root of the problem. There hasn't been a new drug for Graves' disease itself since the 1940s

That's caused by the binding of these antibodies to TSA to receptors in the cells at the back of the eye.

Those receptors then act.

On the other cells and on the IGF receptors on those cells to cause the hypertrophy that results in the protrusion and other problems in the back of the eye.

So we're going to the root of the problem there hasn't been a new drug for graves disease itself since the 19 forties.

Scott Struthers: And the TSH receptor is the root problem. If you block that, and you have an effective drug for Graves itself, we think you won't get Graves' eye disease. And if you block that receptor for patients who already have Graves' eye disease, we think we can treat it. That's the hypothesis. And, you know, this is yet another peptide hormone receptor that we're trying to replace or block with a small molecule. And maybe I'm tooting our horn a little bit, but I think the guys in the next labs down the hall here are some of the best in the world. Guys and gals, sorry, are some of the best in the world at making drugs like that.

And the TSH receptor as the root problem. If you block that and you have an effective drug for Greece itself. We think you won't be getting graves disease, and if you block that receptor for patients who already have graves eye disease. We think we can treat it that's.

That's the hypothesis.

This is yet another peptide hormone receptor that we're trying to replace or trying to block with a small molecule.

And.

Maybe I'm.

Toot, our horn, a little bit, but I think the guys in the next labs down the hall here are some of the best in the World guys and Gals, sorry for some of the best in the world that making drugs like that so yes, we're going to get.

Scott Struthers: So yeah, we're going to get it. Thank you. Your next question comes from Douglas Tsao from HC Wainwright. Please go ahead. Hi, good afternoon, and thanks for taking the questions.

Alright. Thank you. Your next question comes from Douglas Tsao from H C. Wainwright. Please go ahead.

Hi, good afternoon, and thanks for taking the questions.

Okay.

Maybe as a starting point.

Operator: Maybe as a starting point, I'm just curious, with the CAH readout on the interim look that we'll get, I'm just curious, sort of, is there an operational decision that you make from getting that versus the full readout? I mean, is it sort of similar to carcinoid syndrome, where it sort of really helps you jumpstart thinking about the phase 3 study, or are there potential changes that you would make to the CAH study itself that, you know, sort of midcourse adjustments that would help you sort of better understand how the molecules behave? Yeah, Doug.

I'm just curious.

With the CAH readout on the interim look that will get Im just curious sort of is there.

An operational decision that you make from getting that versus the full readout I mean is it.

Sort of similar to carcinoid syndrome, where it sort of really helps you jump start thinking about the phase III study or are there potential changes that you would make to that.

The CAH study itself that.

Sort of midcourse adjustments.

Is that would help you sort of better understand how the molecules behavior.

Yes, Doug.

Scott Struthers: You know, it's like all the core endocrinology studies, including the phase one we did with paltucetine, where in the earliest cohorts of our SAD study, we knew the drug was working, and we knew the pharmacology that was coming out through these changes in hormonal biomarkers. And as this CAH study progresses, and we begin to get that type of information, it's, you know, it's an open-label study. So we're looking at it all the time.

It's like all the core endocrinology studies, including the phase one we did with <unk>.

We're in the earliest cohorts of our Sad study we knew the drug was working and we knew the pharmacology that was coming out by these changes in hormonal biomarkers.

As this CAH study progresses, and we begin to get that type of information.

It's an open label study so we're looking at it all the time and we're getting all this information to guide our phase III designs.

Scott Struthers: And we're getting all this information to guide our phase three design. But until we start to, until we disclose it, we can't be talking about it publicly, either with our investors or with a broader group of physicians outside of our investigators and our advisory board. So, we want to be able to talk to a broader community about how we advance this program forward, and it's been moving well, so that's why we decided that our current estimate is we'll be able to start talking about it next quarter. Okay, great. And then just a quick follow-up on the TSH antagonist. I'm just curious, what are you looking at, I guess, in a preclinical setting, to determine or select your molecule?

But until we start to instill a until we disclosed that we can't be talking about it publicly either with our investors or with a broader group of physicians outside of our investigators and our advisory boards.

So we want to be able to talk to a broader community about how we advance this program forward.

And it's been moving well so that's why we decided that.

Our current estimate is we'll be able to start talking about it next quarter.

Okay, Great and then just a quick follow up on the TSH antagonist I'm just curious.

What are you looking at.

I guess in a preclinical setting to determine our select your molecule I'm just curious what sort of you're most focused on in terms of lead candidate selection ahead of obviously going into the clinic and seeing.

Scott Struthers: I'm just curious what you're most focused on in terms of lead candidate selection ahead of obviously going into the clinic and seeing, you know, the sort of the impact on thyroid levels, etc. Yeah, so it's it's very much like our other programs. In finding the right molecule, you're trying to optimize 2030 different characteristics.

The impact on thyroid levels.

Et cetera.

Yes.

Very much like our other programs and finding the right molecule youre trying to optimize 2030 different characteristics and we've had molecules for a long time that we're potent at the receptor enable to normalize hormone levels.

Scott Struthers: And we've had molecules for a long time that were potent at the receptor and able to normalize hormone levels in a mouse bottle. But we're really working on all those other little polishing touches to make a good molecule to make sure it's highly orally absorbed, doesn't have drug interactions, you know, has a good toxicology profile. But if you're interested in efficacy, I'll point you towards our corporate deck, where there's a slide towards the back where we give mice an antibody just like the humans have that causes activation of their TSH receptor. Their thyroid hormone levels go up remarkably.

Mouse model.

But we're really working on all of those other little polishing to make a good molecule to make sure. It's highly orally absorbed it doesn't have drug interactions.

It has good toxicology profile.

But if youre interested in efficacy.

You towards our corporate deck, where theres a slide towards the back where we give mice and antibody just like the humans have.

Cause activation of their TSH receptor <unk>.

Thyroid hormone levels go up remarkably.

Scott Struthers: And then we start treating them with one of our oral candidates, and those hormone levels go back to normal. So we'll do that same type of study in patients with Graves' disease. So I think it's quite relevant as an efficacy model. But like I said, in many of our programs, it's not about efficacy.

And then we start treating them with one of our all candidates and those hormone levels to go back to normal.

So we'll do that same type of the study.

<unk> with grades disease, So I think it's quite relevant.

As an efficacy model.

But like I said in many of our programs, it's not about the efficacy its about finding the great drug that also has the great efficacy.

Scott Struthers: It's about finding the great drug that also has the best effects. Thank you. Your next question comes from John Wolleben from Citi Defense A&P. Please go ahead. Hey, thanks for taking the question. Two for me.

Okay. Thank you.

Next question comes from Jon <unk> from CJS from JMP. Please go ahead.

Hey, Thanks for taking the question two for me just wondering if you could give some context about how you think the opportunity for power to sustain changes in agro medically. If you just have a maintenance label versus maintenance and treatment label.

Operator: Just wondering if you could give some context about how you think the opportunity for palatucetine changes in agromaggaly if you just have a maintenance label versus a maintenance and treatment label? And then there seems like a lot of excitement for 894 and CAH, and you know, Cushing's has been a difficult indication, and the dynamics are changing there. You know, are you still thinking about moving forward in Cushing's as well? Or is 894 going to be focused on CAH moving forward? Thanks. Well, let me address 4894. And then I'll hand it over to Jim to think about the commercial opportunity and talk about the commercial opportunity, but, You know, 4894 addresses the ACTH receptor, which is the heart of the body's or the center of the body's endocrine response. When things go wrong in that pathway, bad things happen. So in Cushing's disease with excess glucocorticoids, or in CAH patients with excess glucocorticoids It's a big problem.

And then it seems like a lot of excitement for <unk> four in CAH in Cushing has been a difficult.

Indication and the dynamics are changing there.

Okay.

Or are you still thinking about moving forward in Cushing is as well or is 894 going to be focused on CAH moving forward. Thanks.

Well, let me address <unk> 94, and then I'll hand, it over to Jim to think about.

The commercial opportunity to talk about the commercial opportunity but.

Nine four addresses the ACTH receptor, which is the heart of the bodies for the center of the body's undercurrent response to stressors and when things go wrong in that pathway bad things happen. So cushings disease with excess glucocorticoids are in CAH patients with excess glucocorticoids.

You are adding you are adding too much at a paucity are increasing blood pressure.

Sure.

You are damaging bone.

It's a problem so we.

Upfront in CAH, we have an exciting ongoing study with the NIH in Cushings disease, and we're continuing to work on that.

Scott Struthers: So we were out front in CAH. We have an exciting ongoing study with the NIH on Cushing's disease, and we're continuing to work on that. And we're thinking about what else we might do down the road with an ACTH antagonist. This is something nobody else in the world has ever evaluated in humans, and we're going to learn a lot about the pathway in these studies. So, Jim, maybe you want to comment on the indications and expectations for palchocetine and acromegaly. Sure, thanks Scott. And I think the question was specifically kind of maintenance versus naive.

And we're thinking about what else we might do down the road with an ACTH antagonist. This is something nobody else in the world has ever evaluated in humans and we're going to learn a lot about the pathway in these studies.

So Jim maybe you want to comment on.

Indications and expectations for <unk> and acromegaly.

Sure. Thanks, Scott and I think the question was specifically kind of maintenance versus naive.

James Hassard: I mean, from an addressable patient population standpoint, the majority of the patients are currently on treatment. So in any given year, we estimate maybe 500 new patients or naive patients enter the marketplace. So that gives you, you know, approximately 10,000 patients that are maintenance patients. And that's the importance of the Pathfinder 1 data already in hand, that group of approximately 10,000 patients. However, we don't want to minimize the value of Pathfinder 2 because again, Pathfinder 2 gives us the broadest possible label to really address patients across the continuum. It's differentiated from several products that are in the marketplace.

From a from an addressable patient population standpoint, the majority of the patients are currently on treatment. So in any given year, we estimate maybe 500, new patients or naive patients enter.

And so the marketplace. So that gives you approximately 10000 patients that are maintenance piece.

Patients and that's the importance of the tough one to one data already in hand.

Is that group of approximately 10000 patients however, don't want to minimize the value of our pathfinder too because again the two gives us the broadest possible label to really address patients across the continuum. It's differentiated from several products that are in the marketplace. So it will be an important readout for.

James Hassard: So it will be an important readout for us as we move forward, and I think we hope to glean more than just an indication from Pathfinder 2. We hope that there's some important data that will differentiate palchocetine from the injectable somatostatin receptor ligands. Additionally, if I can just add to that a little bit, you know, as amazing as the data was from Pathfinder 1, it was all about maintaining a level of control in patients who were controlled. In Pathfinder 2, we're starting with patients who are sick and demonstrating, if all goes well, that paltucetine can help them lower their IGF levels, lower their symptoms, and make them feel better.

As we move forward and I think we hope to glean more than just an indication from pathfinder to what we hope that there are some important data that will differentiate <unk> from the injectable <unk>.

Amount of Sutton.

Except for ligand.

Additionally.

And then if I can just add to that a little bit.

As amazing as the data was from Pathfinder one.

It was all about maintaining a level of control in patients who were control.

In past senior too, we're starting with patients who are sick and demonstrating Chicago as well.

<unk> can help them lower their IGF levels lower their symptoms makes them feel better.

Scott Struthers: And there's something visceral about being able to communicate an improvement in a disease condition, rather than just the maintenance of that disease condition. And so we're very excited to see how this plays out next month. Thank you. Your next question comes from Dennis Dean from Jefferies. Please go ahead.

And theres, something visceral about being able to communicate an improvement and a disease condition, rather than just the maintenance and the disease condition and so we're very excited to see how this plays out next month.

Yeah.

Thank you your.

Your next question comes from Dennis.

From Jefferies. Please go ahead.

Hi, good afternoon, thanks for taking our questions.

Operator: Thanks for taking our questions. We have two for CAH, if I may. So number one, just around A4 reductions at week 12. You know, there's actually surprisingly not a lot of data out at week 12, and most are for weeks two to four.

Two for CAH.

If I may so number one.

Just around <unk> reductions at week 12, there is actually surprising.

Frankly, not a lot of data out at week 12, and most of it for weeks two to four so I'm curious to hear what level of percentage equal reduction do you think will be competitive.

Dennis Dean: So I'm curious to hear what level of percentage A4 reduction you think will be competitive at week two, given we already have some of the data out there from others, but those are from earlier. And then question two is around a CRF1 competitor who will obviously have some phase 2b data in March. How do you frame that update, given you will report data soon after in Q2, and maybe if I can be a little bit more specific, can you comment on how we should think about percentage A4 change versus the absolute magnitude of A4 change? You know, which people? Thank you.

To Kevin.

Already have some of the data out there from others, but those are from earlier time points and then question two is.

A round a CRF one competitor, who will obviously have some phase <unk> data in March how do you frame that update given you will report data soon after in Q2, and maybe if I can be a little bit more specific can you comment on how we should think about percentage pay for change versus the app.

Luke magnitude of April change.

Which with people focus on thank you so much.

Scott Struthers: Yeah, thanks, Dennis. Let's see what the best way to answer that is. First off, in our study, we're measuring time courses of A4 and other adrenal markers throughout the treatment period, so they'll be comparator time points at different times. One of the other really innovative things that Alan's doing in that study, and we'd like to make our studies, you know, as informative as possible, is we have an option for patients to enroll in what we call the circadian arm, where we measure A4 and other markers throughout the day, because, as you know, those fluctuate. And so understanding the timing of measurements in the day, not just in the weeks, is also important.

Thanks Dennis.

Let's see how the best way to answer that is.

First off in our study, we're measuring time courses of AP or in other.

Adrenal markers.

Throughout the treatment period, so there'll be comparator time points at different places.

One of the other really innovative things that Alan is doing in that study and we'd like to make our studies.

As informative as possible.

We have an option for patients to enroll in what we call the circadian arm, where we measure a four and other markers throughout the day because as you know those fluctuate and so understanding the timing of measurements in the day not just in the weeks is also important.

Scott Struthers: You know, I think you know, but I've been around the center consistent since the earliest days of my career. And CRF is a very exciting molecule that has some wonderful interesting biology. But at the pituitary, it is only a portion of the signal that goes into the corticotroph cells that make ACTH. And we now have an estimate from the recent data on Cronestrophon that by blocking that signal, you can reduce 45% of the A4 output by the adrenal. So that says there's another 65% of signal going into the pituitary from probably vasopressin or some other. However, mechanistically, at the adrenal, there's only one way that ACTH can act, and that's through its receptor, which is called MC2, melanocortin receptor 2. And that's a word block.

I think you know, but I've been around the center can system since the earliest days of my career.

Crs is a very exciting molecule that has some wonderfully interesting biology.

But at the pituitary it is only a portion.

Of the signal that goes into the corticotropin cells that make ACTH.

And we now have an estimate from the recent data on <unk>.

That by blocking that signal.

You can reduce 45%.

The four output by the Dream.

So that says there is another 65% of signal going into the pituitary from probably Vasopressor and Theres some other things.

However, mechanistically at the adrenal Theres only one way that ACTH can act and that is true its receptor which is called <unk> two.

Montana Court receptor two.

And that's what we're blocking.

I would expect an ACTH antagonist to have a much more.

Scott Struthers: So I would expect an ACTH antagonist to have a much larger effect on adrenal A4 output, and we'll know what that effect is, you know, in the coming months. So I'm super excited to see that. And, you know, I think the community is as well. We've known about ACTH and Cushing's disease since 1910. But nobody's ever had an antagonist at that receptor before.

If you can fully block the receptor to have a much larger effect on adrenal eight four output.

And we'll know what that effect is in the coming months, so super excited to see that in.

I think the community is as well, we've known about ACTH in Cushings disease.

Cushings disease since $19 10.

But nobody has ever had an antagonist receptor before so it's a very exciting advancement in the field.

Scott Struthers: So it's a very exciting advancement in the field. Thank you. Your next question comes from Leland Gershell from Oppenheimer.

Thank you.

Your next question comes from Leland <unk> from Oppenheimer. Please go ahead.

Operator: Please go ahead. Thanks, and my congratulations on all the updates. Board.

Thanks, and congratulations on all the accomplishments.

They made.

And thank you for the updates.

Scott Struthers: Just curious, Scott, as we look forward to the annual meeting of the Endocrine Society, too long for now, I want to know if you might be able to give us indication of any updates, perhaps on some of the earlier pipeline programs. Moving forward. Yeah, thanks. You know, that's an annual pilgrimage of endocrinologists from around the world to get together and talk about the latest in endocrinology. And I've been going since the 1980s.

Across the board.

Curious Scott as we look forward to the annual meeting of the Endocrine Society.

Too long for now I want to note you might.

We'll be able to give us indication of.

Any updates perhaps on some of the earlier pipeline programs.

We're moving forward.

Thank you.

Yes. Thanks.

The annual pilgrimage of endocrinologists from around the world to get together and talk about the latest in endocrinology and <unk>.

I've been going since the 19 eighties I love that meeting.

Scott Struthers: I love that meeting. We will be sending, as usual, a large contingent. We're submitting many abstracts. I, frankly, don't know the final list of abstracts, but that'll be coming out as we see the acceptances. I think you can look for a strong presence from us there in Boston this June.

We will be sending as usual a large contingent.

We're submitting many abstracts.

Frankly don't know the final list of abstracts, but that'll be coming out as we see the acceptances.

I think you can look for a strong presence from there from US there in Boston This June.

Scott Struthers: Great. And then just a question, just to clarify and go forward going forward between Cushing's and CH, do you, the press release mentioned the CAH. I think you had indicated previously that we may see quick-shrink data, a huge few, but that wasn't mentioned.

Great and then just a question just to clarify on <unk>.

For you going forward between Cushing and CAH.

Your press release had mentioned the CAH.

To me that would be next quarter. I think you had indicated previously that we may see Cushing data in Q2, but that wasn't mentioned so.

Scott Struthers: So we'll... You're going to perhaps move to Q3 or just wondering if you might have any, No, I think we just didn't do a difference between the two discussions and maybe didn't spend enough time talking about Cushing's. So let's see how it plays out. I think there's a chance we'll hear about both, but 4894 is certainly something of great interest on many fronts, but don't interpret any subtlety in the way we phrase things as any loss of interest in Cushing's.

With machines.

Youre going to be perhaps move to Q3 or.

Just wondering if you have any indication thank you.

No I think we just didn't do a diff between the two discussions and maybe you didn't spend enough time talking about Cushing. So.

Let's see how it plays out I think theres a chance we'll hear about both.

494 is certainly something of great interest on many fronts, but don't interpret any subtlety in the way we phrase things as any loss of interest in Cushings disease.

Okay. Thank you that's all the time, we have for questions today, So I will turn it back to Scott for closing remarks.

Scott Struthers: Thank you. That's all the time we have for questions today, so I will turn it back to Scott for closing remarks. Thank you everybody for joining us today. We appreciate your attention, your support, and look forward to talking to you more in the future. Thank you. Ladies and gentlemen, this concludes your conference call for today. We thank you for participating and ask that you please disconnect your line.

Thank you everybody for joining us today, we appreciate your attention and your support and look forward to talking to you more in the future.

Thank you.

Ladies and gentlemen, this concludes your conference call for today, we thank you for participating and ask Scott to please disconnect your lines.