Q1 2024 Crinetics Pharmaceuticals Inc Earnings Call

Operator: Welcome to the Crinetics Pharmaceuticals First Quarter 2024 Earnings Conference Call. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a question and answer session. I will now turn the call over to Cory Davis of Lifesci Advisors. Please go ahead.

Welcome to the <unk> Pharmaceuticals first quarter 2024 earnings conference call.

Corey George Davis: At this time, all participants are in listen only mode.

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

Corey George Davis: I'll now turn the call over to Corey Davis of lifestyle Advisors. Please go ahead.

Corey George Davis: Thank you, Alan. Hello, everyone, and welcome to Crinetics' Earnings Call. Joining me today are Dr. Scott Struthers, Founder and Chief Executive Officer, Dr. Alan Krasner, Chief Endocrinologist, and Marc Wilson, Chief Financial Officer. Also joining us for the Q&A portion of the call are Dr. Dana Pizzuti, Chief Medical and Development Officer, and Jim Hassard, Chief Commercial Officer. 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.

Corey George Davis: Thank you Alan Hello, everyone and welcome to kinetics earnings call. Joining me today are Dr. Scott Struthers, founder and Chief Executive Officer, Dr. Alan Krasner, Chief Endocrinologists, Mark Wilson, Chief Financial Officer.

Corey George Davis: Also joining us for the Q&A portion of the call are Dr. Dana <unk>, Chief Medical and development Officer, and Jim Hazard, Chief Commercial Officer press release announcing our first quarter 2024 financial results was issued today and is also available on the frenetic corporate website. As a reminder, we'll be making forward looking statements and I invite you to learn about the risks and uncertainties.

Corey George Davis: Associated with these statements as disclosed in our SEC filings such forward looking statements are not a guarantee of performance and the company's actual results could differ materially from those stated or implied in such statements due to risks and uncertainties associated with the company's businesses. These forward looking statements are qualified in their entirety by the cautionary statements contained in today's news release the company.

Corey George Davis: Other news releases in <unk> SEC filings, including its annual report on Form 10-K.

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

Corey George Davis: Also I'd like to specify that the contents of this conference call contains time sensitive information that is accurate only as of the date of this live broadcast May nine 2024 kinetics takes no obligation to revise or update any forward looking statements to reflect events.

Corey George Davis: Stances after the date of this conference call with that I'll hand, it over to Scott go ahead.

Unknown Executive: Thank you, Cory. Good afternoon, everyone, and thank you for joining us on our first quarter 2024 results call. I'll begin by spending a few moments summarizing our recent accomplishments before turning the call over to Dr. Alan Krasner, our Chief Endocrinologist, who will discuss our clinical programs and recently reported data in more detail. Crinetics had an extremely strong start to 2024.

Scott: Thank you Corey good afternoon, everyone and thank you for joining us on our first quarter 2020 for our results call.

Unknown Executive: Recently, we reported positive results from two late-stage clinical studies for paltucetine in patients with acromegaly and carcinoid syndrome. Behind paltucetine, we've built a remarkably deep pipeline. This includes our second internally discovered clinical stage compound, CRN4894, which will now be known as Atumelnex. At the ENDO conference this June in Boston, we will present five abstracts from our clinical development programs, including four late-breaking abstracts. Two poster presentations will highlight initial data from each of the ongoing Open Label Phase 2 studies evaluating the safety and efficacy of etumelnat in patients with CAH and Cushing's disease. We are also hosting an in-person reception to review data from clinical studies of Atum Elnat in CAH and ACTH-dependent Cushing syndrome at 6 p.m. on Monday, June 3rd, for those attending in person.

Speaker Change: I'll begin by spending a few moments summarizing our recent accomplishments before turning the call over to Dr. Alan Krasner, our chief Endocrinologist.

Unknown Executive: He will discuss our clinical programs and recently reported data in more detail.

Unknown Executive: Kinetics had an extremely strong start to 2024 recently, we reported positive results from two late stage clinical studies for <unk> in patients with acromegaly in Carcinoid syndrome.

Unknown Executive: Behind Pal Tusa team, we've built and remarkably deep pipeline.

Unknown Executive: This includes our second internally discovered clinical stage compound <unk> hundred 94, which will now be known as asking about that.

Unknown Executive: At the Endo Conference. This June in Boston, We will present, five abstracts from our clinical development programs, including for late breaking abstracts.

Unknown Executive: Poster presentations will highlight initial data in each of the ongoing open label Phase II studies evaluating the safety and efficacy of <unk> and.

Unknown Executive: In patients with CAH and Cushings disease.

Unknown Executive: Were also hosting an in person reception to review data from clinical studies vacuum Telenet and CAH and ACTH dependent Cushing syndrome at six PM on Monday June 3rd for those attending in person.

Unknown Executive: Data from the entire Pathfinder Phase 3 acromegaly program will be featured in a science and innovation theater led by Dr. Kevin Yuen of the Barrow Neurological Institute on Saturday, June 1. Three posters from the Paltucetin-Acromegaly Clinical Program will also be presented, highlighting results from Pathfinder II. The Use of Acromegaly Symptom Diary in Pathfinder-1 and updates on the long-term safety and efficacy data from the ongoing Open Label Extension Study. We've also made excellent progress towards new development candidates this quarter in all of our early stage programs. These include a PTH receptor antagonist for the treatment of hyperparathyroidism, a TSH antagonist for the treatment of Graves' disease, including thyroid eye disease, and our programs for diabetes and obesity.

Unknown Executive: Data from the entire Pathfinder Phase III Acromegaly program will be featured in our science and innovation Theater led by Dr. Kevin you win of the borrow neurological Institute on Saturday June 1st.

Unknown Executive: Three posters from the <unk> clinical program.

Unknown Executive: We will also be presented highlighting results from Pathfinder too.

Unknown Executive: The use of acromegaly symptom diary, and Pathfinder, one and updates on the long term safety and efficacy data from the ongoing open label extension study.

Unknown Executive: We've also made excellent progress towards new development candidates this quarter in all of our early stage programs.

Unknown Executive: These include a PTH receptor antagonist for the treatment of hyperparathyroidism.

Unknown Executive: TSH antagonist for the treatment of graves disease, including thyroid eye disease, and our programs for diabetes and obesity.

Unknown Executive: Now, let me take a few minutes to dive a little deeper into the progress made with the two paltustine indications. We're extremely pleased to have completed our Phase 3 program in Acromegaly with a successful readout of Pathfinder 2 in April. This study evaluated paltucetine in people with acromegaly who were not pharmacologically treated and was the second of two pivotal trials.

Speaker Change: Now, let me take a few minutes to dive a little deeper into the progress made with the two <unk> indications.

Unknown Executive: We are extremely pleased to have completed our phase III program in acromegaly with a successful readout of Pathfinder two in April.

Unknown Executive: This study evaluated <unk> in people with Acromegaly, who were not pharmacologically treated and was the second of two pivotal trials.

Unknown Executive: Pathfinder II achieved its primary endpoint of IGF control and met all secondary endpoints with high levels of statistical significance. Together with the Pathfinder 1 results we reported last year, we now have data from two phase three studies to support an NDA filing for the treatment of acromegaly in the second half of this year. In anticipation of a potential 2025 launch of peltucetine, we're continuing to work on important aspects of commercial readiness

Unknown Executive: <unk> achieved its primary endpoint of IGF control and met all secondary endpoints with high levels of statistical significance.

Unknown Executive: With the Pathfinder one results, we reported last year.

Unknown Executive: We now have data from two phase III studies to support an NDA filing for the treatment of acromegaly in the second half of this year.

Unknown Executive: In anticipation of a potential 2025 March upheld tusa team, we're continuing to work on important aspects of commercial readiness.

Unknown Executive: We have already held multiple advisory boards and conducted market research with physicians to gather their input on how to optimize the communication of the Palitucetine program. We will continue to educate the medical community with data presentations at multiple medical conferences in the coming months. We will launch a campaign later this year directed towards health care providers to increase awareness of the unmet needs with the current standard of care, including injections for pain, breakthrough symptoms, and the months-long regimens required to identify the appropriate dosage for their patients receiving injectable depots.

Unknown Executive: Already held multiple advisory boards and conducted market research with physicians to gather their input on how to optimize the communication of the <unk> program.

Unknown Executive: We will continue to educate the medical community with data presentations at medical card at multiple medical conferences in the coming months.

Unknown Executive: We will launch a campaign later this year directed towards health care providers to increase awareness of the unmet needs with the current standard of care, including injection site pain breakthrough symptoms.

Unknown Executive: In the months long regimens required to identify the appropriate dosage for their patients receiving injectable depots.

Unknown Executive: An accompanying campaign directed at patients will be launched early next year. Our market access team has also been in active dialogue with leading payers to understand the current marketplace and the dynamics for Paltucetine to become a valuable treatment option for patients, if approved. Pathfinder 1 data has already been well received, and we are seeing a similarly enthusiastic response to our early conversations regarding Pathfinder 2. We're also very pleased with the results from the Open Label Phase 2 study in carcinoid syndrome patients that demonstrated meaningful reductions in both frequency and severity of flushing episodes and bowel movements caused by this disease. These effects were rapid.

Unknown Executive: And accompanying campaign directed at patients will be launched early next year.

Unknown Executive: Our Mac our market access team has also been active dialogue with leading payers to understand the current marketplace and the dynamics for Pal tusa team to become a valuable treatment option for patients if approved.

Unknown Executive: Pathfinder, one data has already been well received and we are seeing a similar to the enthusiastic response to our early conversations regarding pathfinder too.

Unknown Executive: We're also very pleased with the results from the open label Phase two study in carcinoid syndrome patients that's demonstrated meaningful reductions of both frequency and severity of Flushing episodes in Belgium bowel movements caused by this disease.

Unknown Executive: These attacks for rapid.

Unknown Executive: Sustained, and consistent with the preliminary data we reported last December. Overall, we believe the safety and efficacy profile of paltucetine in this study, and we will progress into a Phase 3 study as soon as we can. We plan to discuss these results with the FDA and agree on a Phase 3 study design, which should enable us to begin a Phase 3 study by the end of the year. Finally, we strengthened our balance sheet with a $350 million private placement in February from new and existing equity investors.

Unknown Executive: Sustained.

Unknown Executive: And consistent with the preliminary data we reported last December.

Unknown Executive: Overall, we believe the safety and efficacy profile of <unk> in this study.

Unknown Executive: Supports progressing into a phase III study as soon as we can.

Unknown Executive: We plan to discuss these results with the FDA and align on a phase III study design, which enable us to begin a phase III study by the end of the year.

Unknown Executive: Okay.

Unknown Executive: Finally, we strengthened our balance sheet with a $350 million private placement in February from new and existing equity investors.

Unknown Executive: This additional capital has provided us with sufficient runway to fund operations into 2028 based on current projections for our pipeline of product candidates. In summary, looking to the rest of 2024 and 2025, we anticipate multiple upcoming milestones from our clinical candidates and continued advancement of our deep pipeline of emerging candidates that address increasingly higher-prevalence indications. As has been our practice since inception, we continue to invest in our world-class discovery capabilities that provide the roots for our long-term success. With that, I'll hand it over to Dr. Alan Krasner, our Chief Endocrinologist, to talk about our clinical program.

Unknown Executive: This additional capital has provided us with sufficient runway to fund operations into 2028 based on current projections for our pipeline of product candidates.

Speaker Change: In summary, looking to the rest of 'twenty 'twenty, four and 'twenty five we anticipate multiple upcoming milestones from our clinical candidates and continued advancement of our deep pipeline of emerging candidates that address increasingly higher prevalent syndications.

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

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

Alan S. Krasner: Thank you Scott.

Alan S. Krasner: Today I will provide updates on recently reported clinical programs, starting with Peltucci. As a reminder, the Phase III Pathfinder Program was designed to evaluate the safety and efficacy of peltucetine for the treatment of a broad spectrum of patients with acromegaly. Both Pathfinder studies met all pre-specified primary and secondary efficacy endpoints, and pelticitin was shown to be generally well-tolerated We therefore intend to seek approval for patients who might switch from injected SRLs to paltucetine, as studied in Pathfinder 1, and also for those who are not currently treated with medication and might start paltucetine as a first-line treatment, as studied in Pathfinder 2.

Speaker Change: Today I will provide updates on recently reported clinical programs starting with participating.

Alan S. Krasner: We recently reported the top line results from untreated patients in Pathfinder 2. Besides meeting all key endpoints, it was notable that IGF-1 was reduced from elevated baselines in 93% of patients treated with Peltucetine. These IGF-1 declines occurred rapidly, with most of the effect occurring in just two to four weeks. And these reductions were durably sustained throughout the treatment period.

Alan S. Krasner: As a reminder, the phase III Pathfinder program was designed to evaluate the safety and efficacy of <unk> for the treatment of a broad spectrum of patients with acromegaly.

Alan S. Krasner: Both Pathfinder studies met all pre specified primary and secondary efficacy endpoints and participating was shown to be generally well tolerated.

Alan S. Krasner: We therefore intend to seek approval for patients who might switch from injected Srs <unk> S studied and Pathfinder, one and also in those who are not currently treated with medications and might start <unk> as a first line treatment as studied in Pathfinder too.

Alan S. Krasner: We reported most recently at the topline results from the untreated patients Pathfinder too.

Alan S. Krasner: It's meeting all key endpoints. It was notable that IGF, one was reduced from elevated baselines and 93% of patients treated with <unk>.

Alan S. Krasner: These IGF one declines occurred rapidly with most of the effect occurring in just two to four weeks.

Alan S. Krasner: These reductions were durably sustained throughout the treatment period.

Alan S. Krasner: Significant improvements in acromegaly symptom control associated with paltucetine compared to placebo have now been documented in two major independent control trials. As previously discussed, we are very excited to further explore our rich database into which patients reported their symptoms on a daily basis during the trial. With the database from Pathfinder 1, we have already been able to perform additional interesting analyses, which we will be reporting at the Endocrine Society meeting in June.

Alan S. Krasner: Significant improvements in acromegaly symptom control associated with <unk> compared to placebo have now been documented in two major independent control trials.

Alan S. Krasner: As previously discussed we are very excited to further explore a rich database into which patients reported their symptoms on a daily basis during the trials.

Alan S. Krasner: With the database from Pathfinder, one we have already.

Alan S. Krasner: <unk> been able to perform additional interesting analyses, which we will be reporting at the endocrine Society meeting in June.

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

Alan S. Krasner: We have wondered for a long time, whether daily World <unk> might result in a difference in the frequency of day to day symptom exacerbations that plague, many patients with acromegaly treated with long acting injections.

Alan S. Krasner: And we look forward to reporting on this soon at the meeting.

Alan S. Krasner: We will also be presenting late-breaking updated data from our long-term open-label extension cohort from the Phase II Acrobat Advanced Study. A number of the participants in this study have now been treated with paltucetine for over four years. The overall data set suggests that paltucetine represents a lot more than just a user-friendly, convenient oral substitute for an injection. Unlike the current first-line agents, peltucetine has been rigorously demonstrated to control symptoms of acromegaly, as well as biochemical markers of disease activity.

Alan S. Krasner: We will also be presenting late breaking updated data from our long term open label extension cohorts from the phase II Acrobat advanced study.

Alan S. Krasner: A number of the participants in this study have now been treated with participating for over four years.

Alan S. Krasner: The overall data set suggests that toxicity and represents a lot more than just a user friendly convenient oral substitute for an injection.

Alan S. Krasner: Unlike the current first line agents <unk> has been rigorously demonstrated to control symptoms of acromegaly as well as biochemical markers of disease activity.

Alan S. Krasner: The notably rapid IGF-1 response observed in Pathfinder 2 could allow patients and physicians to reach the fully effective dose of peltucetine much faster than is the case for the current standard of care. A simple once-daily oral agent could prevent the pitfalls, pain, and unneeded expense associated with the current standard of care. People already dealing with the burdens of acromegaly might not need to schedule their lives around the next injection or deal with the side effects that often occur after these injections.

Alan S. Krasner: The notably rapid IGF, one response observed in Pathfinder II could allow patients and physicians to reach the fully effective dose of <unk> much faster than is the case for the current standard of care.

Alan S. Krasner: A simple once daily oral agent could prevent the pitfalls pain and unneeded expense associated with the current standard of care.

Alan S. Krasner: People already dealing with the burdens of acromegaly might not need to schedule their lives around the next injection and dealing with the side effects that often occur after these injections.

Alan S. Krasner: With Peltucetine, one would not need to worry if the last injection was administered correctly and whether or not it will last until the next one is due. Nor would one need special equipment or to take a course in how to self-administer acromegaly medication at home.

Alan S. Krasner: With participating one would not need to worry you have to last injection was administered correctly and whether or not it will last until the next one is due.

Alan S. Krasner: Norwood, one need special equipment or to take us take a course and how to self administer acromegaly medication at home.

Alan S. Krasner: In short, paltucetine may represent a completely new paradigm for somatostatin-receptor-based therapy. Teltucetine's second target indication, carcinoid syndrome, has also shown promising results. In March, we reported top-line results from an Open Label Phase II trial.

Alan S. Krasner: In short <unk> may represent a completely new paradigm for somatostatin receptor based therapy.

Alan S. Krasner: <unk> second targeted indication Carcinoid syndrome has also shown promising results.

Alan S. Krasner: In March we reported top line results from the open label Phase II trial.

Alan S. Krasner: This study enrolled participants with carcinoid syndrome who experienced one or both of the key symptoms of the disease, diarrhea and flushing. Participants were either naive to standard of care treatment or untreated and actively symptomatic, or were controlled on SRL therapy and willing to wash out prior to entry. Caltusatine was generally well tolerated at the doses evaluated in this trial, with no severe or serious treatment-related adverse events. In addition, pharmacokinetics in this patient population was consistent with what we expected to see from prior experience.

Alan S. Krasner: This study enrolled participants with carcinoid syndrome, who experienced one or both of the key symptoms of the disease diarrhea and Flushing.

Alan S. Krasner: Participants, who are either naive to standard of care treatment or untreated and actively symptomatic or where controls on SRO therapy and willing to wash out prior to entry.

Alan S. Krasner: <unk> was generally well tolerated at the doses evaluated in this trial with no severe or serious treatment related adverse events.

Alan S. Krasner: In addition, pharmacokinetics in this patient population was consistent with what we expected to see from prior experience.

Alan S. Krasner: We observed significant and meaningful reductions in both the frequency and severity of bowel movements and flushing episodes, consistent with the initial results we reported last December. Importantly, the intensity of these symptoms was also reduced by Peltucetin. These reductions occurred quite rapidly and were sustained throughout the eight-week treatment period.

Alan S. Krasner: We observed significant and meaningful reductions in both the frequency and severity of bulb moments in Flushing episodes consistent with the initial results we reported last December.

Alan S. Krasner: Importantly, the intensity of these symptoms was also reduced by <unk>.

Alan S. Krasner: These reductions occurred quite rapidly and were sustained throughout the eight week treatment period.

Alan S. Krasner: We intend to discuss the phase 2 carcinoid syndrome data with the FDA to align on a phase 3 study design. We look forward to updating you on the Phase III details, including dose, registrational endpoint, and timing, once we've had these discussions. As Scott discussed, our second investigational compound in clinical development is Abtumelnibt, which is a once-daily oral ACTH receptor antagonist in development for the treatment of both congenital adrenal hyperplasia, or CAH, and Cushing's disease.

Alan S. Krasner: We intend to discuss the phase III carcinoid syndrome data with the FDA to align on a phase III study design.

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

Alan S. Krasner: As Scott discussed our second investigational compounds in clinical development is <unk>, which is a once daily oral ACTH receptor antagonist in development for the treatment of both congenital adrenal hyperplasia or CAH and Cushings disease.

Alan S. Krasner: The adrenal glands are the sole source of excessive steroid that causes the clinical complications in both disease states, and this steroid production is driven by excessive exposure to ACTH. It is natural, therefore, to target the ACTH, or MC2, receptor in order to fundamentally interrupt the pathologic progression of these diseases. That is because the receptor is the sole mediator of ACTH signaling, and it is found only in the adrenals. The lead indication for ettumelnant is classic CAH, a genetic disorder that affects approximately 27,000 patients in the U.S.

Alan S. Krasner: The adrenal glands are the sole source of access of steroid that caused the clinical complications in both disease States and this steroid production is driven by excess of exposure to ACTH.

Alan S. Krasner: It is natural and therefore, it to target the ACTH or EMC two receptor in order to fundamentally interrupt the pathologic progression of these diseases.

Alan S. Krasner: That is because the receptor is the sole mediator of ACTH signaling and it is found only in the adrenals.

Alan S. Krasner: The lead indication for <unk> is classic CAH, a genetic disorder that affects approximately 27000 patients in the U S.

Alan S. Krasner: These patients lack a critical enzyme in the adrenals responsible for cortisol production. The hypothalamus and pituitary respond to these low cortisol levels by producing high levels of ACTH. This excess ACTH, in turn, causes overstimulation of the adrenal cortex, resulting in the overproduction of cortisol precursors, like 17-hydroxyprogesterone, and adrenal androgens, like androstenedione, also known as A4. This adrenal hyperandrogenemia causes many serious medical complications, beginning in utero and progressing through childhood and into adulthood.

Alan S. Krasner: These patients lack a critical enzyme in the adrenals responsible for cortisol production.

Alan S. Krasner: The hypothalamus and pituitary responds to these low cortisol levels by producing high levels of ACTH. This.

Alan S. Krasner: This excess ACTH in turn causes overstimulation of the adrenal cortex, resulting in overproduction of cortisol precursors like 17, Hydroxyprogesterone and adrenal androgens like Androstenediol also known as <unk>.

Alan S. Krasner: The adrenal hyper Andrew Genia causes many serious medical complications beginning in utero progressing through childhood and into adulthood.

Alan S. Krasner: Because CAH patients cannot produce cortisol, exogenous glucocorticoid replacement is required for life, but replacement doses should be very low, and these low doses should not cause adverse effects. As a result, many physicians find it necessary to use high supraphysiologic doses of glucocorticoids in an attempt to suppress elevated ACTH levels and thereby lower adrenal androgen production. These elevated glucocorticoid doses are frequently associated with adverse effects, such as weight gain, elevated glucose, edema, bone loss, and a host of other serious medical problems.

Alan S. Krasner: Because CAH patients cannot produce cortisol exogenous glucocorticoid replacement is required for life, but replacement doses should be very low and these low doses should not cause adverse effects.

Alan S. Krasner: As a result, many positions find it necessary to use high Super physiologic doses of glucocorticoids in an attempt to suppress elevated ACTH levels, and thereby lower adrenal androgen production.

Alan S. Krasner: These elevated glucocorticoid doses are frequently associated with adverse effects, such as weight gain elevated glucose edema bone loss and a host of other serious medical problems.

Alan S. Krasner: It is very difficult to find a dose of glucocorticoid that effectively controls adrenal androgen production without causing these side effects. This highlights the fundamental challenge in treating this disease to strike the right balance between reducing adrenal androgens and minimizing the effects of excess glucocorticoids. We believe Atumelment is the right approach to achieve this, and look forward to showing initial data from our Phase 2 studies in the coming weeks.

Alan S. Krasner: It is very difficult to find the dose of glucocorticoid, which effectively controls adrenal androgen production without causing these side effects.

Alan S. Krasner: This highlights the fundamental challenge in treating this disease to strike the right balance between reducing adrenal androgens, yet minimizing the effects of excess glucocorticoids.

Alan S. Krasner: We believe at two Maryland is the right approach to achieve this balance and look forward to showing initial data from our phase II studies in the coming weeks.

Alan S. Krasner: Methumelanin is designed to reduce or eliminate ACTH stimulation at the level of the adrenal, thereby lowering adrenal androgen output. Once adrenal hyperandrogenemia is controlled, patients who are taking excessive doses of glucocorticoids should be able to lower their dose and reduce or even avoid steroid therapy-related adverse effects. Remember, the ACTH receptor in the adrenals is the only means by which ACTH drives the pathologic adrenal androgen output seen in CAH, and the ACTH receptor is a single choke point at which this overdriven system might be turned off.

Alan S. Krasner: <unk> Mellon was designed to reduce or eliminate ACTH stimulation at the level of the adrenal, thereby lowering adrenal androgen output.

Alan S. Krasner: Once the adrenal hyper androgen anemia is controlled patients who are taking excessive doses of glucocorticoid should be able to lower their dose and reduce or even avoid steroid therapy related adverse effects.

Alan S. Krasner: Remember the ACTH receptor in the adrenals as the only means by which ACTH drives the pathologic adrenal androgen output seen in CAH and the ACTH receptor as a single Chokepoint at which this over driven system might be turned off.

Alan S. Krasner: Our ongoing Phase II Open Label Sequential Dose Cohort Study in CAH is evaluating safety and pharmacokinetics at 2-Melanin dosed for three months. In addition, we are evaluating pharmacodynamics, and in CAH, this is measured primarily using the androgenic biomarker androstenedione, or A4, as well as the cortisol precursor, 17-hydroxyprogesterone. The goal of treatment is to reliably and reproducibly eliminate the excess of exposure to adrenal steroids as reflected by these biomarkers. Patients in our study continue their pre-trial glucocorticoids at unchanged doses, so we can observe the time course and durability of any response to the atrium ailment itself.

Alan S. Krasner: Our ongoing phase two open label sequential dose cohort study in CAH is evaluating safety and pharmacokinetics of <unk> Mellon dosed for three months. In addition, we are evaluating pharmacodynamics and didn't see a H. This is measured primarily using the androgenic biomarker.

Alan S. Krasner: Understand iron ore a for as well as the cortisol precursor 17 hydroxy progesterone.

Alan S. Krasner: The goal of treatment is to reliably and reproducible eliminate excess of exposure to adrenal steroids as reflected by these biomarkers.

Alan S. Krasner: The patients in our study continue their pretrial glucocorticoids it unchanged doses. So we can observe the time course and durability of any response to <unk> itself.

Alan S. Krasner: In future studies, we expect to evaluate glucocorticoid dose reduction once we know that the compound can reduce adrenal androgen output. As Scott mentioned, we will be presenting late-breaking ad-to-mail mint data at the upcoming Endocrine Society meeting in June. This will not include the full cohort of patients in the CEH study but will comprise initial data from a subset of the first two dose cohorts. We expect these early results will give us directional information that will help guide the development plans for attenuation in CAH. Initial data from the Phase 2 single-center trial in Cushing's disease will also be presented at the same meeting. With that said, I will now hand it over to Marc to review the financials.

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

Alan S. Krasner: As Scott mentioned, we will be presenting late breaking at two amendment data at the upcoming Endocrine Society meeting in June.

Marc: This will not include the full cohort of patients in the CAH study that will comprise initial data from a subset of the first two dose cohorts.

Marc: We expect these early results, we'll give us directional information that will help guide developmental plans for at two Maryland in CAH.

Marc: Initial data from the phase two singers single Center trial in Cushings disease will also be presented at the same meeting.

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

Marc: Thank you Alan.

Marc J. C. Wilson: Crinetics continues to be in a strong financial position, having ended the first quarter with approximately $900 million in cash and investments. This includes proceeds from the $350 million private placement equity financing we completed in February. Our solid financial foundation is projected to fund our current operating plan into 2028, and this includes plans to commercialize paltucetine for acromegaly, the initiation of multiple later stage clinical trials, and additional indications with paltucetine and atumelanab, as well as continued investment in our pipeline.

Marc: <unk> continues to be in a strong financial position having ended the first quarter was approximately $900 million in cash and investments.

Marc J. C. Wilson: With respect to the financial results, research and development expenses were $53.3 million for the quarter ending March 31, 2024, compared to $38.5 million for the same period in 2023. The increase was primarily attributable to higher personnel costs and manufacturing and development activities. Both of these were driven by the advancement of our clinical programs and the expansion of our preclinical portfolio. For the quarter ended March 31, 2024, general and administrative expenses were $20.8 million compared to $12.2 million for the same period in 2023. These increases were primarily attributable to higher personnel costs to support the growth of the organization.

Marc J. C. Wilson: This includes proceeds from the $350 million private placement equity financing we completed in February.

Marc J. C. Wilson: Our solid financial Foundation is projected to fund our current operating plan into 2028.

Marc J. C. Wilson: This includes plans to commercialize <unk> for acromegaly, the initiation of multiple later stage clinical trials in additional indications with <unk> and <unk> melanoma.

Marc J. C. Wilson: As well as continued investment in our pipeline.

Marc J. C. Wilson: With respect to the financial results research and development expenses were $53 3 million for the quarter ended March 31, 2024, compared to $38 5 million for the same period in 2023.

Marc J. C. Wilson: The increase was primarily attributable to higher personnel costs and manufacturing and development activities.

Marc J. C. Wilson: Both of which were driven by the advancement of our clinical programs and the expansion of our preclinical portfolio.

Marc J. C. Wilson: For the quarter ended March 31, 2020 for general and administrative expenses were $20 8 million compared to $12 2 million for the same period in 2023.

Marc J. C. Wilson: These increases were primarily attributable to higher personnel costs to support the growth of the organization.

Marc J. C. Wilson: The net loss for the quarter ended March 31, 2024 was $66.9 million, compared to a net loss of $46 million for the same period in 2023. Revenues were $0.6 million for the quarter ended March 31, 2024, compared to $2.7 million for the same period in 2020. Revenues during the current year's quarter were primarily derived from our Pelticitin licensing arrangement with our Japanese partner, SKK, and revenues for the prior year were associated with licensing arrangements for Paltusatine and CRM01941, another somatostatin-targeted development candidate.

Marc J. C. Wilson: Net loss for the quarter ended March 31, 2024 was $66 9 million compared to a net loss of $46 million for the same period in 2023.

Marc J. C. Wilson: Revenues were <unk> 6 million for the quarter ended March 31, 2024, compared to $2 7 million for the same period of 2023.

Marc J. C. Wilson: Revenues during the current year's quarter were primarily derived from our <unk> licensing arrangement with our Japanese partner S. J K.

Marc J. C. Wilson: Revenues for the prior year were associated with licensing arrangements for <unk> and CRM zero 194, one.

Marc J. C. Wilson: Other somatostatin targeted development candidate.

Marc J. C. Wilson: Net cash used for operating activities for the quarter ending March 31, 2024 was $52.9 million. We continue to expect our cash burn to be approximately $50 million to $60 million per quarter for the remainder of 2024. I will now hand it back to Scott for closing remarks before we begin Q&A.

Marc J. C. Wilson: Net cash used for operating activities for the quarter ended March 31, 2024 was $52 9 million.

Scott: We continue to expect our cash burn to be approximately $50 million to $60 million per quarter for the remainder of 2024.

Marc J. C. Wilson: I will now hand, it back to Scott for closing remarks, before we begin Q&A.

Unknown Executive: Thank you, Marc. We will continue to build on the strong progress this quarter throughout the rest of the year and beyond. We look forward to sharing that Tumelnet data in the coming weeks, as well as providing continued updates as we progress Pal 2's team toward regulatory submissions and as we make continued advancements in the exciting new programs beginning to emerge from our discovery effort. Thank you all for your attention. Operator, we are ready to take questions. Thank you.

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

Unknown Executive: We look forward to sharing that to mill net data in the coming weeks as well as providing continued updates as we progress Pal <unk> two regulatory submissions.

Unknown Executive: And as we make continued advancements in the exciting new programs beginning to emerge from our discovery efforts.

Unknown Executive: Thank you all for your attention operator, we are ready to take questions.

Unknown Executive: Okay.

Speaker Change: Thank you.

Operator: Ladies and gentlemen, we will now begin the question and answer session. If you have a question, please press star 1 on your touchtone phone. You will hear a three-tone prompt acknowledging your request, and the questions will be polled in the order they are received. If you would like to withdraw from the question queue, please press star 2. If you're using a speakerphone, please lift the handset before pressing any key.

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

Operator: If you have a question. Please press star one on your Touchtone phone.

Operator: Here are three ton prompt acknowledging your request and the questions will be pulled in the order they are received.

Operator: It feels like to withdraw from the question queue. Please press star two.

Operator: If you are using a speaker phone please lift the handset before pressing any case.

Operator: Please be advised that you can ask one question at a time. One moment, please, for your first question. Your first question comes from Yasmeen Rahimi of Piper's Handler. Your line is already open.

Operator: Please be advised that you can ask one question at a time one moment. Please for your first question.

Yasmeen Rahimi: Your first question comes from Yasmin Rahimi of Piper Sandler Your line is already open.

Yasmeen Rahimi: Yep. Good afternoon, team, and thank you for all your thoughtful remarks.

Operator: Yes.

Yasmeen Rahimi: Good afternoon team and thank you for all your thoughtful remarks.

Yasmeen Rahimi: I know we're going to have quite a bit of talk in the Q&A about CH's upcoming readout, but I would love to actually dig into the Cushing data set. I guess, you know, it's an interim look. It's run by an NIH investigator that's going to share the data. I guess, you know, I think we all understand cortisol reduction is key. We'd love to get your thoughts on what we hope to learn from that study and what potential next steps there might be in development for Cushing's. And I'll jump back into the queue.

Yasmeen Rahimi: And now we're going to have quite a bit talking to Q&A.

Yasmeen Rahimi: Upcoming readout, but would love to actually.

Yasmeen Rahimi: Dig into the Cushing data Scott.

Yasmeen Rahimi: I guess it's in.

Yasmeen Rahimi: Income lock.

Yasmeen Rahimi: It's run by NIH investigator, that's kind of shared the data again.

Yasmeen Rahimi: I think we all understand cortisol reduction of key would love to get your thoughts on what we hope to learn from that study.

Yasmeen Rahimi: And what potential next steps.

Speaker Change: And development for questions and ill jump back into the queue.

Alan S. Krasner: Thank you, Yaz. Alan, can you take that question? Sir, I asked if we are can we are.

Yasmeen Rahimi: Thank you, yes, Alan can you take that question.

Alan S. Krasner: Sir, yes. We are collaborating with a leading KOL at the NIH in our Cushing's disease study. This is a study in which the compound is dosed for 10 days while patients are in the clinical research center, and there is frequent monitoring of many parameters, but especially pharmacodynamically speaking, of most interest would be cortisol. These are patients with Cushing's disease who start with high levels of cortisol excretion. And, of course, we'll be interested to see if cortisol is reduced during this 10-day dosing period.

Alan: Sure Yes.

Alan S. Krasner: We are.

Alan S. Krasner: We are collaborating with a leading kols at the NIH.

Alan S. Krasner: Cushing <unk> in our Cushings disease study. This is a study in which the compound is dose for 10 days while patients are in the clinical research center and there is frequent monitoring.

Alan S. Krasner: Many parameters, but especially pharmacodynamic dynamically speaking of most interest would be cortisol. These are patients with cushings disease, who start with high levels of cortisol excretion and of course, we'll be interested to see if cortisol is reduced during this 10 day dosing period.

Alan S. Krasner: That is the information we would get from this study that I think will be of interest. We expect that the data we would present at the Endocrine Society meeting would give us directional kind of information to help guide our future development in Cushing's, sort of like when we reported carcinoid syndrome data in December. It was of great directionally interest. I would expect we would learn a great deal from what we've seen so far. It, of course, will be a subset of the patients, as we discussed in our remarks. But still, again, I hope we'll have qualitative directional information. Thank you.

Alan S. Krasner: That is the information we would get from this study that I think will be of interest we expect that the data we would present at the endocrine Society meeting would give us.

Alan S. Krasner: Directional kind of information to help guide our future development in Cushings.

Alan S. Krasner: Sort of like when we reported personalized syndrome data in December it was directionally of interest I would expect.

Alan S. Krasner: We would learn a great deal from what we've seen so far of course will be a subset of the patients as is the case.

Alan S. Krasner: As we discussed in our remarks.

Alan S. Krasner: But still again I hope, we'll have qualitative directional information.

Alan S. Krasner: Okay.

Speaker Change: Thank you.

Operator: Your next question comes from Jessica Fye of J.P. Morgan. Your line is already open. Hey guys, good afternoon, and thanks for taking my ques-

Alan S. Krasner: Your next question comes from Jessica Fye of Jpmorgan. Your line is already open.

Jessica Macomber Fye: Hey, guys. Good afternoon, Thanks for taking my question.

Jessica Macomber Fye: What elements.

Jessica Macomber Fye: At some moment profile do you think will differentiate it.

Jessica Macomber Fye: CRF antagonist.

Operator: H.

Operator: Oh.

Alan S. Krasner: Thank you, Jess. You know, as we've said, over the course of discovery and development in this program, that if you look at the mechanisms by which the adrenals are controlled, they all converge on ACTH acting at its receptor on the adrenal medulla, which is formed by the MC2 protein. But we'll just call it the ACTH receptor because it's the only way ACTH can act. And so by blocking that, we're blocking the single choke point of action of the whole hypothalamic pituitary adrenal axis on the adrenal. And we've always said we expect to achieve. Good blockade of adrenal activity, whether it's measured by adrenal androgens and CAH or by glucocorticoids in Cushing's patients.

Jessica Macomber Fye: Thank you Jess.

Alan S. Krasner: As we've said over the course of discovery and development in this program.

Alan S. Krasner: Then if you look at the mechanisms by which the adrenals controlled they all converge on ACTH acting edits receptor on the adrenal.

Alan S. Krasner: Which is formed by the AMC to protein, but I will just call it the ACTH receptor.

Alan S. Krasner: It's the only way ACTH connect and it's the only thing that the ACTH receptor does.

Alan S. Krasner: And so by blocking that we're blocking a single chokepoint of.

Alan S. Krasner: Action of the whole hypothermia pituitary adrenal axis on the adrenal.

Alan S. Krasner: And we've always said we expect to achieve.

Alan S. Krasner: Good blockade of adrenal activity, whether it's measured by.

Alan S. Krasner: Adrenal androgens in CAH or by glucocorticoids in Cushings patients.

Speaker Change: Thank you.

Operator: Your next question comes from Cory Jubinville of Lifesci Capital. Your line is already open.

Speaker Change: Your next question comes from Cory <unk> been Ville of Lifesize capital. Your line is already open.

Cory Jubinville: Thanks for taking our questions, and I love the new name for 04894 HML NAT. I'm very intrigued by your endo abstract title in regard to CAH data. The title is HML NAT induces rapid and profound reductions of A4 and 17 OHP in participants with CAH, the key word for me being profound.

Cory Jubinville: Thanks for taking our questions and loved the new name for <unk> for a moment.

Cory Jubinville: I'm very intrigued by your Endo abstract title in regard to CAH data.

Cory Jubinville: Title is that your melon Dan.

Cory Jubinville: Induces rapid and profound reductions of eight four in 17, OHP and participants with CAH.

Cory Jubinville: The key word for me Theyre being profound to the extent you can can you help us frame expectations on data that we'll see.

Cory Jubinville: To the extent you can, can you help us frame expectations for data that we'll see at endo? And I guess if you can't go into granular detail, at a high level, how satisfied are you with the pharmacodynamics you're seeing with HML NAT in comparison to CRF1 antagonists? And we've also seen some mixed results lately across competitor CAH readouts. Can you help us better understand the types of patients that you've been enrolling in this phase two study? Thank you. Yeah

Speaker Change: I guess.

Cory Jubinville: You can't go into granular detail at a high level, how satisfied are you with the pharmacodynamics youre seeing with at Gmail, a comparison to the Crs one antagonist.

Cory Jubinville: We've also seen some mixed results lately across competitors CAH Readouts can you help us better understand the types of patients that you've been enrolling in this phase II study. Thank you.

Unknown Executive: Yeah, sorry, Cory. I think you'll have to wait until Monday, June 3 at 12 noon Eastern Time, when the embargo lifts, before we can really get too deep into this. But we look forward to seeing you at our poster presentations and welcome everyone to our Investor Relations event, which is at the Omni Hotel on the 3rd of the same day at 6pm. Um, in terms of phrasing, sorry, can you repeat the second half of your question?

Speaker Change: Yes, sorry Corey.

Unknown Executive: I think youll have to wait until Monday June 3rd at 12, a 12 P M Eastern time.

Unknown Executive: When the embargo lifts before we can really get too deep into this.

Unknown Executive: But we look forward to seeing you at our poster presentations and welcome everyone to our Investor Relations event, which is at the Omni hotel on the third at the same day at <unk> P. M.

Unknown Executive: In terms of.

Unknown Executive: Phrasing.

Unknown Executive: Sorry can you repeat the second half of your question.

Unknown Executive: If youre still on the line.

Cory Jubinville: Yeah, I guess at a high level, how satisfied are you with the pharmacodynamics you're seeing in comparison to some of the CRF1 antagonists? And we've also seen mixed results in competitor CAH readouts. And can you help us understand the types of patients that you've been enrolling into this phase two study in terms of whether it be compliance or whether it be severity of disease or degree of control?

Speaker Change: Yes, I guess at a high level, how satisfied are you with the pharmacodynamics youre seeing in comparison to some of the Crs one antagonist and we've also seen mixed results in competitors' CAH readouts.

Cory Jubinville: Can you help us understand the.

Cory Jubinville: The types of patients that you've been enrolling into this phase two study in terms of whether it be compliance or whether it be severity of disease or degree of.

Cory Jubinville: Controls.

Unknown Executive: Yeah, I realize there are a lot of people wanting to set the bar, and I've always encouraged people to think about treating the whole disease, not defining a bar for one compound or another. In terms of how satisfied we are, again, you'll need to see the data at ENDO and, generally. Well, maybe I'll just leave it at that. I'll just leave it at, come and see us. We look forward to presenting it and talking to everybody.

Cory Jubinville: Yes, I realize theres been a lot of people wanting to set the bar and I've always encouraged people to think about.

Unknown Executive: Treating the whole disease, not defining a bar of one one compound or another.

Unknown Executive: In terms of how satisfied we are again, you'll need to see the data at endo.

Unknown Executive: And generally.

Unknown Executive: <unk>.

Unknown Executive: Well, maybe I'll just leave it at that I'll, just leave it or to come and see US we look forward to presenting that in talking to everybody about it.

Unknown Executive: Maybe, Scott, I could address the question of what sort of patients are enrolled in this study, if that would be helpful. Okay, so these are patients, these are adult patients with classic CAH, which means they have the most severe form of enzyme deficiency.

Scott: Maybe Scott could address.

Speaker Change: The question on what sort of patients are enrolled in this study if that would be helpful. Thanks.

Unknown Executive: Okay. So these are patients. These are adult patients with classic CAH, which means they are the most severe form of enzyme enzyme deficiency.

Unknown Executive: So they're born with this condition, and generally, throughout life, need to take glucocorticoids replacement. So these are all now adults with this condition, who are all on glucocorticoid therapy. In general, they will start the study with elevated adrenal androgen levels. There will be a variety of disease severity that we look at. We're trying to be as inclusive as possible in this study.

Unknown Executive: So they are born with this condition and generally throughout life need to take glucocorticoid replacement. So these are all now adults with this condition, who are all on glucocorticoid therapy.

Unknown Executive: In general they.

Unknown Executive: We'll start the study with elevated.

Unknown Executive: Adrenal androgen levels.

Unknown Executive: There will be a variety of disease severity that we look at where we're trying to be as inclusive as possible in this study.

Unknown Executive: And it's a three-month dosing period. During those three months, we administer a fixed dose of etumelment. The background pretrial glucocorticoid therapy is not changed during this study. As I mentioned in my remarks, our first goal is to assess how well 4894 reduces adrenal androgen output in and of itself without the additional variable of adjusting glucocorticoid doses. Ultimately, in future studies, assuming 4894 is successful at controlling adrenal hyperandrogenemia, subsequent studies, we would look at glucocorticoid dose reduction as well, because a lot of these patients are on supraphysiologic doses of glucocorticoids, and they would benefit from being brought down to the floor replacement dose level.

Unknown Executive: And it's a three month dosing period during the three months.

Unknown Executive: We administer a fixed dose of <unk>.

Unknown Executive: <unk> background pre trial glucocorticoid therapy has not changed during this study.

Unknown Executive: As I mentioned during my remarks, our first goal is to assess.

Unknown Executive: How well its great 94 reduces adrenal androgen output.

Unknown Executive: In and of itself without the additional variable of adjusting glucocorticoid doses ultimately in future studies, assuming 489 for a successful at controlling adrenal hypersound regionally.

Unknown Executive: Androgen EMEA subsys.

Unknown Executive: Subsequent studies, we would look at glucocorticoid dose reduction as well because a lot of these patients are on super physiologic doses of glucocorticoid and they would benefit from being brought down to the floor replacement dose levels.

Unknown Executive: Okay.

Speaker Change: That's helpful. Thank you.

Operator: Your next question comes from Joseph Schwartz of Learink Partners. Your line is already open.

Operator: Your next question comes from Joseph Schwartz of Leray.

Unknown Executive: Your next question comes from Joseph Schwartz of Leerink Partners. Your line is already open.

Joseph Patrick Schwartz: Thank you congrats on the progress.

Joseph Patrick Schwartz: Given the phase two CH <unk> melanoma study continues to enroll patients I was wondering if you can talk about what more you hope to learn or demonstrate beyond the interim data, which you will be reporting at endo are there additional questions you need to answer before you can advance to phase III and when will the next look.

Operator: At the CH trial.

Joseph Patrick Schwartz: Thank you.

Alan S. Krasner: Thanks, Joe. Alan, why don't you take that question? Yeah, so we will be presenting to a group.

Joseph Patrick Schwartz: Thanks, Joe Alan why don't you take that question.

Alan S. Krasner: Yeah, so we will be presenting, Joe, a subset of the study. The goal of a phase two study is to fully evaluate the relationship between the dose of an experimental agent and safety, of course, but also pharmacodynamic response at various doses. So this will be a subset. I think we will get good directional information from the doses tested, but we do want to complete the study to make sure we have that complete range of dose responses evaluated to help us best design subsequent development for the compound. Your next question comes from John Wolleben of Citizens JMS.

Alan: Yes, so we will be presenting drove a subset of the study.

Alan S. Krasner: The goal of the phase two study is to fully.

Alan S. Krasner: Evaluate the relationship between the dose of an experimental agent and the safety of course, but also pharmacodynamic response to various doses.

Alan S. Krasner: So this will be a subset I think we will get good directional information from the doses tested but we do want to complete the study to make sure. We have that complete range of dose response evaluated to help US best design subsequent development for the compound.

Operator: Your next question comes from John Wolleben of Citizens JMP. Your line is already open.

Jonathan Patrick Wolleben: Your next question comes from John Hello Leben.

Jonathan Patrick Wolleben: Of citizens JMP Your line is already open.

Jonathan Patrick Wolleben: Thanks for taking the questions.

Jonathan Patrick Wolleben: One more for me and for Carcinoid syndrome.

Operator: When we're thinking about the data at Endo.

Jonathan Patrick Wolleben: How do you how do you balance the relative importance of a percent reduction as core versus achieving normalization.

Jonathan Patrick Wolleben: Far as clinical development and then also management of patients in the real World and then I'm wondering if you can give us some high level thoughts on what phase three preliminary design of carcinoid syndrome.

Unknown Executive: All right, we'll let two questions slip by on that one, but I'll take the first part, and Alan, maybe you can take carcinoid syndrome. But generally, you know, percent is always just a shorthand, and it depends on where you start from for the magnitude of the effect that you might see expressed as a percentage. So I do think the goal of therapy is to get people as low as you can on their androgens so that you can adjust, get rid of the androgen effects, and adjust the glucocorticoids to a physiologic level.

Jonathan Patrick Wolleben: Alright, well, let tooth question slipped by on that one, but I'll take the first part and Allen maybe you take carcinoid syndrome.

Unknown Executive: But generally percentage is always just a short hand and it depends on where you start for the magnitude of the effect that you might see expressed as a percentage. So I do think the goal of therapy is to get people as low as you can.

Speaker Change: On androgens.

Unknown Executive: Androgens.

Unknown Executive: So that you can adjust we'll get rid of the androgen effects and adjust the glucocorticoids took physiologic level.

Unknown Executive: No.

Alan S. Krasner: Percent is a good shorthand and perhaps an easy way to make some comparisons. But in the end, it's patients that are the focus. And by the way, it's not just biomarkers. It's the effect of those changes in hormones that may have on the symptoms and expression of the disease in these patients. And Alan, do you want to comment on carcinoid syndrome? Sure, yeah, as we've reported

Alan: Percent is a good short hand, and perhaps an easy way to make some comparisons but in the end its patients.

Alan: Is the focus and by the way, it's not just biomarkers. It's the effect of those changes in hormones that may have on us.

Alan S. Krasner: The.

Alan S. Krasner: Symptoms and expression of the disease in these patients and Alan do you want to comment on Carcinoid syndrome.

Alan S. Krasner: As we've reported in the Phase 2 data, we are actively designing the Phase 3 program for carcinoid syndrome. The plan, of course, is to review with the FDA the full dataset from the Phase 2 study as well as our proposals for Phase 3 and to align with them on the design of Phase 3. I can give you some sort of high-level thoughts about Phase 3.

Alan: Sure Yeah.

Alan S. Krasner: As we reported phase two data where are.

Alan S. Krasner: We are actively designing the phase III program for Carcinoid syndrome. The plan of course is to review with the FDA. The full data set from the phase II study as well as our proposals for phase III and to align with them on the design of phase III.

Alan S. Krasner: I can give you some sort of high level thoughts about phase III again, we have to remember that we haven't had those regulatory discussions. So it's not set in stone, but in general based on regulatory history in this in this disease state.

Alan S. Krasner: Again, we have to remember, though, we haven't had those regulatory discussions yet, so it's not set in stone. But in general, based on regulatory history in this disease state, I would anticipate we're looking at a placebo-controlled trial. The most recent approval for carcinoid syndrome involved a three-month placebo-controlled trial, and I think that's kind of what we're anticipating here, too. Of course, the key endpoints would have to do with the cardinal symptoms of carcinoid syndrome, diarrhea, and flushing.

Alan S. Krasner: I would anticipate we're looking at a placebo controlled trial.

Alan S. Krasner: The most recent approval for carcinoid syndrome, and valve to three months placebo controlled trial and I think that's kind of what were anticipating here too.

Alan S. Krasner: Of course, the key endpoints would have to do with the Cardinal symptoms of Carcinoid syndrome, diarrhea, Flushing and as we already reported in phase II, we see reductions in both the frequency of these episodes, but also the severity of diarrhea Flushing to.

Alan S. Krasner: And as we already reported in Phase 2, we see reductions in both the frequency of these episodes but also the severity of diarrhea and flushing, too, with paltucetine therapy. And I think we will very likely, very carefully measure those things in Phase 3 as well. And, you know, in terms of sample size, historically, carcinoid syndrome pivotal trials, first of all, they're generally single pivotal trials for carcinoid syndrome, and the sample sizes in the past have ranged between roughly 80 and 150 patients. And based on our power calculations to date, I think that's about the range I would expect for our Phase III trial as well.

Alan S. Krasner: With <unk> therapy, and I think we.

Alan S. Krasner: We will very likely very carefully measure those things in phase III as well.

Alan S. Krasner: And.

Alan S. Krasner: In terms of sample size historically carcinoid syndrome pivotal trials first of all Theyre generally single pivotal trials for carcinoid syndrome, and the sample size.

Alan S. Krasner: Sample sizes in the past have ranged between roughly 80 and 150 patients.

Alan S. Krasner: And.

Alan S. Krasner: Based on our power calculations to date, I think thats right about the range I would expect for our phase III trial as well.

Speaker Change: Alright, that's helpful. Let me sneak into very helpful.

Alan S. Krasner: Okay.

Operator: Your next question comes from Leland Gershell of Oppenheimer. Your line is already open.

Alan S. Krasner: Your next question comes from Leland crucial.

Leland James Gershell: I'll open hymer.

Leland James Gershell: Your line is already open.

Leland James Gershell: Hey, good afternoon. Congratulations on the progress, and thanks for taking the time to answer my questions. Also, a couple for me on carcinoid, maybe for Alan. You know, with the benefit now of a few months since the reveal from Phase 2, I wanted to hear of any feedback you've received from physicians with respect to their interest in using palticitin in patients who are untreated on SRLs, given the large population segment who is not currently on therapy. And then I have a follow-up question.

Leland James Gershell: Hey, good afternoon, congratulations on the progress and thanks for taking my questions also a couple from me on Carcinoid maybe.

Alan: Maybe for Alan.

Leland James Gershell: With the benefit now of a few months since the reveal from the phase II Wonder here of any feedback you've received from physicians with respect to their interest in <unk>.

Leland James Gershell: Using participating.

Leland James Gershell: In patients who are treated on.

Leland James Gershell: <unk> given the large population segment.

Leland James Gershell: Those are currently on therapy, and then I've a follow up.

Alan S. Krasner: Go ahead, Al. Thanks for the question. We, of course, you know, work closely with a number of specialist physicians, oftentimes oncologists, who specialize in neuroendocrine tumor patient care and also usually treat those patients with carcinoid syndrome. A lot of them are our investigators and on our study steering committee, and the feedback has been generally very positive from them. They're very excited about the data we have and, I would say, pleased to be helping us think about what's coming up in phase 3, and probably, many of them would participate in phase 3 as well.

Speaker Change: Go ahead bill.

Speaker Change: Thanks for the question.

Alan S. Krasner: We of course work closely with a number of specialist physicians oftentimes oncologists, who specialize in neurons consumer or patient care and also themselves usually treat those patients with carcinoid syndrome.

Alan S. Krasner: A lot of them are investigators and in our study steering committee and the.

Alan S. Krasner: The feedback.

Alan S. Krasner: Has been generally very positive from them, they're very excited about the data we have and.

Alan S. Krasner: I would say.

Alan S. Krasner: Im pleased to be helping us think about what's coming up in phase III and probably many of them would participate in phase III as well.

Alan S. Krasner: I think it's.

Speaker Change: It's recognized by many of the physicians, who treat this that there are some shortcomings with these injections that are the standard of care for the control of Carcinoid syndrome.

Alan S. Krasner: I think it's recognized by many of the physicians who treat this that there are some shortcomings with these injections that are the standard of care for the control of carcinoid syndrome, and we went through many of those limitations in my prepared remarks, but you know these are just very burdensome for patients in many ways. They're also technically difficult to deliver in a reproducible way, and this has actually been shown in the literature in this patient population in particular. So I think both the patients and the physicians have expressed to me at least positive thoughts that this would be a real contribution to the field.

Alan S. Krasner: And we went through many of those limitations in my prepared remarks, but these are just.

Alan S. Krasner: Very burdensome from patients in many ways.

Alan S. Krasner: Theyre also technically difficult to deliver.

Alan S. Krasner: And in a reproducible way and this has actually been shown in.

Alan S. Krasner: In the literature in this patient population in particular.

Alan S. Krasner: So I think both the patients and the physicians have expressed to me at least.

Alan S. Krasner: Positive thoughts that this would be a real contribution to the field.

Leland James Gershell: Thanks. And then further to the point of the data you've shown, so the 5-HIAA levels and serotonin were pretty well reduced by paltizotine. Seems like that was much better than we've seen with the SRLs. Wondering if that particular finding has resonated with respect to maybe longer-term efficacy beyond, I think, the eight weeks that you've shown with the Phase 2, you know, for longer-term control of the cardinal symptoms.

Speaker Change: Thanks, and then and then further to the point of the data you've shown so the five HIAA levels and serotonin ware.

Leland James Gershell: Pretty.

Leland James Gershell: Will reduced.

Leland James Gershell: By participating it seems like that was much better than we've seen with Esol's wondering.

Leland James Gershell: If that particular finding has resonated with respect to maybe longer term efficacy beyond I think the eight weeks that you've shown with the phase II.

Speaker Change: For longer term control of the Cardinal symptoms. Thank you.

Alan S. Krasner: Yeah, it's an interesting question. I'm afraid I don't know the answer. I'm not sure if the answer is even in the literature.

Speaker Change: Yes, it's an interesting question.

Alan S. Krasner: I'm afraid I don't know the answer and I'm not sure. The answer is even in the literature that the ability of the biomarker responses to sort of predict longer term responses.

Alan S. Krasner: With respect to these tumors or the symptoms.

Alan S. Krasner: Not really establish these biomarkers are generally used in clinic, primarily to diagnose carcinoid syndrome, but their ability to monitor therapy is not well established but I would thank you for pointing out that we did see some actually pretty nice responses and it is hard to find those in the.

Alan S. Krasner: The ability of the biomarker responses to sort of predict longer-term responses with respect to these tumors or the symptoms is not really established. You know, these biomarkers are generally used in clinic, primarily to diagnose carcinoid syndrome, but their ability to monitor therapy is not well established. But I would thank you for pointing out that we did see some actually pretty nice responses, and it is hard to find those in the older literature.

Alan S. Krasner: Old.

Alan S. Krasner: The older literature, and I suspect that might in part have to do with improvements and then the methodology for measuring these things we're using the latest assays for these biomarkers and.

Alan S. Krasner: Have a feeling that that may have contributed to our pretty clear symptom and biomarker responses that we saw and we of course want to leverage this for our phase III program as well.

Unknown Executive: And I suspect that might in part have to do with improvements in the methodology for measuring these things. We're using the latest assays for these biomarkers, and I have a feeling that that may have contributed to our pretty clear symptom and biomarker responses that we saw. And we, of course, want to leverage this for our phase three.

Unknown Executive: And just to follow up a little bit. This is Scott. Just to follow up a little bit, I did want to note your comment about potentially getting to those patients who currently aren't treated. And I think that is a unique opportunity.

Speaker Change: Yeah, and just to follow up a little.

Unknown Executive: Sorry. This is Scott just to follow up a little bit I did want to note your comment about potentially getting to those patients who currently are treated.

Scott: And I think that is a unique opportunity.

Unknown Executive: It's very surprising to me that there is a significant population of patients with carcinoid syndrome that are not being treated at this point when they clearly should be. And I can only explain it to somebody; they must be making some judgment on the burden of treatment versus the burden of disease and access to medicines. And it's causing far too many to not have access to medicines that would help them. So we look forward to trying to bring this to more patients than are currently on injectable depot therapy.

Scott: That's very surprising to me that.

Unknown Executive: There is a significant population of patients with carcinoid syndrome are not being treated at this point when they clearly should be and.

Unknown Executive: And I can only explain it by somebody they must be making some.

Unknown Executive: Judgment on the burden of treatment versus the burden of disease, and our access to medicines, and it's causing far too many to not have access to medicines that would help them.

Unknown Executive: So we look forward to try and find ways to bring us to more patients than are currently on the injectable depot therapies.

Leland James Gershell: Thanks so much for the Out of Color. Looking forward to hearing more, Dendo.

Speaker Change: Thanks, so much for that color.

Dendo: Forward to hearing more agenda.

Leland James Gershell: Yes.

Operator: Your next question comes from Douglas Tsao of AHC Wainwright.

Leland James Gershell: Your next question comes from Douglas Tsao of H C Wainwright.

Douglas Dylan Tsao: Your line is already open.

Douglas Dylan Tsao: Hi, thanks. Good afternoon.

Douglas Dylan Tsao: Hi, Thanks, good afternoon, and thanks for taking my questions.

Douglas Dylan Tsao: Curious maybe Scott.

Douglas Dylan Tsao: Thanks for taking the questions. I was just curious, maybe, Scott, on the earlier stage pipeline, you have a number of sort of therapeutic areas that you're targeting, many of which you're sort of talking about candidate selection for this year. I think you've talked about sort of diabetes and obesity for something for next year. What's the, or is there any kind of prioritization within those? And how do you think about sort of, you know, the pace that those would go into the clinic and start to read out? You guys have a track record for doing sort of innovative early stage studies that give us pretty good PD data early on in development. And I'm just curious if that's how you anticipate seeing those for those candidates as well. Thank you. Thanks, Doug.

Douglas Dylan Tsao: The earlier stage pipeline you have a number of therapeutic areas that youre targeting on many of what youre sort of talking about candidate selection for this year I think you've talked about sort of diabetes and obesity for something for next year I guess, what's the is there any kind of prioritization with.

Douglas Dylan Tsao: Within those.

Douglas Dylan Tsao: And how do you think about sort of.

Douglas Dylan Tsao: The pace that those would go into the clinic and start to readout.

Douglas Dylan Tsao: Yes.

Douglas Dylan Tsao: You guys have a track record for doing sort of innovative early stage studies that give us pretty good PD data early on in development and I'm just curious if that's how you anticipate seeing those today.

Speaker Change: For those candidates as well thank you.

Douglas Dylan Tsao: Thanks, Doug.

Douglas Dylan Tsao: <unk>.

Unknown Executive: You know, the emerging pipeline is really super exciting, and we are really committed to what I call the craft of drug discovery. So we want to make sure that these are really the best possible molecules we can make before we invest in development. And so those programs are now really starting to get close to molecules that might be good enough. PTH is probably the first. We've been doing some non-GLP talk studies on multiple candidates, and it looks like the team is getting close to selecting the best one out of several good ones.

Douglas Dylan Tsao: Emerging pipeline is really super exciting and.

Unknown Executive: We are really committed to what I call. The craft of drug discovery. So we want to make sure that these are really the best possible molecules, we can make before we invest in development.

Unknown Executive: And so those programs are now really starting to get close to molecules that might be good enough. PTH is probably first we've been doing some non GOP tox studies on multiple candidates and it looks like the team is getting close to selecting the best one out of several good ones.

Unknown Executive: And then the other programs are successively behind that. Fortunately, we've been in a financial position where we don't need to make difficult prioritization decisions about which good molecule to slow down over the other good molecules. I do think there's a little bit of just internal prioritization we have to do as we balance workloads between some of the different projects. But largely, all projects are moving forward as fast as we can, and I'm optimistic that that's going to leave a whole sequence of upcoming clinical information on these programs over the next 12, 18, 24 months.

Unknown Executive: And then the other programs are successively behind that.

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

Unknown Executive: And.

Unknown Executive: I do think there is a little bit of just internal prioritization, we have to do as we balance workloads between some of the different projects.

Unknown Executive: But largely all projects are moving forward as fast as we can.

Unknown Executive: And I'm optimistic that that's going to lead a whole sequence of upcoming clinical information on these programs over the next two.

Unknown Executive: <unk> 18 24 months.

Unknown Executive: Okay, great. That's really helpful, and congratulations on the progress. Your next question comes from Catherine Novack of Jones Research. Your line is already open.

Speaker Change: Okay, Great that's really helpful and congrats on the progress.

Unknown Executive: Thanks.

Unknown Executive: Your next question comes from Catherine Novack of Jones Research. Your line is already open.

Unknown Executive: Question.

Unknown Executive: Alright.

Catherine Clare Novack: Hi, Thanks for taking my question I, just wondering when it comes to commercialization, what's the overlap in terms of treatment centers and prescriber base for CAH and Acromegaly and then was there any overlap extended carcinoid syndrome is that.

Catherine Clare Novack: Completely different.

Unknown Executive: <unk>.

Catherine Clare Novack: Institutions that youre looking at.

Catherine Clare Novack: Thanks, Catherine. There is a high degree of overlap. And maybe Jim, you could get into some more detail there.

Catherine Clare Novack: Thanks, Catherine is a high degree of overlap and maybe Jim you could get into some more detail there.

James Hassard: Yeah, thanks, Catherine. In terms of acromegaly, and especially carcinoid syndrome, when we look at the 35 to 40 pituitary treatment centers, typically, they are academic centers that also overlap with the National Comprehensive Cancer Center network. So when we're doing some sales force sizing, we see a lot of overlap between acromegaly and carcinoid syndrome. Even, you know, in terms of endocrinologists, there's a high degree of overlap between acromegaly and Cushing's disease, of course, because it's pituitary. And I'll just add that that was really part of our long-term strategy when

Jim: Yeah. Thanks Catherine.

James Hassard: Terms of acromegaly in especially carcinoid syndrome, when we look at the 35% to 40 pituitary treatment centers typically be our academic centers that also overlap with the national comprehensive cancer.

James Hassard: Centered network so.

James Hassard: When we're doing some salesforce sizing, we see a lot of overlap between acromegaly.

James Hassard: In carcinoid syndrome.

James Hassard: In terms of endocrinologists, there's a high degree of overlap with acromegaly in Cushings disease of course because of the pituitary.

James Hassard: But we're also seeing the same for congenital adrenal hyperplasia. So a lot of the specialists endocrinologists are seeing all three.

James Hassard: Pituitary or agreements diseases.

James Hassard: And I'll just add that that was. That was really part of our long-term strategy when we started getting into these indications so that not only from a commercial point of view do we start building relationships with the same centers and same prescribers, but also from a development point of view so that we start using the same investigators and centers again and again and again and try to find synergies and ways of working well together as those relationships go on for the long term.

James Hassard: And I'll just add that that was that was really part of our long term strategy. When we started getting into these indications so that not only from a commercial point of view do we start building into the same centers and same prescribers, but also from a development point of view so that we start using the same investigators in centers.

James Hassard: Again, and again and again and trying to find synergies in <unk>.

James Hassard: Ways of working well together as those relationships go for for the long term.

Operator: Thanks, guys. That's very helpful. Thank you. Your next question comes from

Speaker Change: Thanks, guys Thats very helpful.

Speaker Change: Thank you.

Operator: Your next question comes from Jeffrey Hung of Morgan Stanley. Your line is already open.

Operator: Your next question comes from Jeffrey Hong of Morgan Stanley. Your line is already open.

Operator: Hi, This is Michael <unk> on for Jeff hung. Thank you for taking my question.

Jeff Hung: Circling back to the phase III design for Carcinoid syndrome.

Jeff Hung: Is there any ability for the study designed to accommodate or potentially showed the ability to prevent.

Jeff Hung: Breakthrough symptoms than the typical waxing and waning versus <unk>.

Jeff Hung: Maybe you drink initial screen or washout, just wondering if there's any.

Jeff Hung: Central to that analysis. Thanks, so much.

Jeff Hung: Thanks. I think that's an important question, and we are asking ourselves that. Alan, you might want to comment a bit on that. Yeah, it's a very important concept because

Jeff Hung: Thanks, I think that's an important question and we are asking ourselves that Alan you might want to comment.

Alan S. Krasner: Yeah, it's a very important concept. Because as I was talking earlier about the limitations of the current injection therapy for carcinoid syndrome, that is a major issue is that you take these long-acting injections sometimes more frequently than once a month, and yet you still have these days where you have active breakthrough of either diarrhea or flushing or both, sometimes more than just a day. And these patients often end up having to take additional medication, sometimes antidiuretals, or sometimes even short-acting subcubuloses of octreotide itself, on top of the long-acting octreotide they're already taking. Why? Why do you do that?

Jeff Hung: Yeah, it's a very important concept because.

Alan S. Krasner: As I was talking earlier about the limitations of the current injection therapy for carcinoid syndrome that is a major issue as you take these long acting injections.

Alan S. Krasner: Sometimes more frequently than once a month and you still have these days, where you have active breakthrough of either diarrhea, flushing or both sometimes more than just the day and these patients often end up having to take additional medications, sometimes anti diarrheal holes or sometimes even.

Alan S. Krasner: Short acting sub Q bonuses of Octreotide itself on top of the long acting octreotide, they're already taking.

Alan S. Krasner: Why why that's why that kind of breakthrough occurs in.

Alan S. Krasner: Why that kind of breakthrough occurs is not fully understood, but I suspect that it might be related to some variability in exposure to the drug from month to month. We do know that there is variability in the technique of actually accurately delivering, for example, octreotide to the intramuscular space. So I suspect that contributes to this breakthrough will be very interested in asking patients every day how they're feeling using an electronic diary as we did in phase 2 and as we did in phase 3 for acromegaly, and I am hoping we will learn interesting things about whether that problem we see with these long-acting injections could potentially be solved with a daily oral dose of a simple oral agent.

Alan S. Krasner: Is not fully understood but.

Alan S. Krasner: I suspect that it might be related to some variability and exposure to the drug from month to month and we do know that there are very there is variability in technique of actually accurately delivering for example, octreotide to the intramuscular space. So I suspect.

Alan S. Krasner: So that contributes to this breakthrough phenomenon.

Alan S. Krasner: And yes in our trials, we will be very interested in asking patients everyday how they're feeling using an electronic diary as we did in phase two and as we did in phase III for acromegaly and I am hoping we will learn.

Alan S. Krasner: Interesting things about the weather.

Alan S. Krasner: Whether whether that problem, we see with these long acting injections that could potentially be solved with a daily.

Alan S. Krasner: Oral dose of a simple oral agent.

Alan S. Krasner: Yeah.

Speaker Change: Thank you so much that's very helpful. I appreciate it.

Operator: Your next question comes from Brian Skorney of Baird. Your line is already open.

Alan S. Krasner: Your next question comes from Brian Corny.

Brian Peter Skorney: Baird. Your line is already open.

Brian Peter Skorney: Hey, guys. This is Charlie on for Brian.

Operator: Hey, guys. This is Charlie on for Brian. Thanks for taking our question. So just wanted to switch gears, a little bit towards the PTH asset.

Charlie: Our assets just kind of want to ask what from the presentation earlier this year at the bone and teeth Gordon Research conference.

Brian Peter Skorney: Thanks for taking our question. So I just wanted to switch gears a little bit towards the PTH asset or assets. Just kind of wanted to ask what the presentation earlier this year at the Bone & Teeth Gordon Research Conference really gave you confidence in the profile of the molecules you're developing and if maybe you could kind of walk us through what excites you about them as well as if this is kind of the profile that you're looking for from the other assets that you're selecting from. Thank you.

Brian Peter Skorney: <unk> gave you confidence in the profile of the molecules are developing and if.

Brian Peter Skorney: Maybe you could kind of walk us through what excites you about it as well as if this is kind of the profile that you're looking for.

Brian Peter Skorney: From the other assets that you're selecting from thank you.

Unknown Executive: Got it. How about, Alan? I'll talk about the preclinical studies, and you can talk about why we're excited about it clinically. But very much, this is like many of our programs where the endocrinology in animal model species is almost identical to the endocrinology in humans. And we know that it's a very robust way in rats, for example, to induce hyperparathyroidism by infusing an excess of parathyroid hormone, and we can watch calcium go up.

Speaker Change: Got it how about Alan ill talk about the preclinical and you can talk about why we're excited about it clinically.

Alan: But very much this is like many of our programs were.

Alan: The endocrinology and animal model species as well.

Unknown Executive: Almost identical to the endocrinology in humans.

Unknown Executive: And we know that it's very robust way in rats for example to induce hyperparathyroidism by infusing excess of parathyroid hormone and we can watch calcium go up.

Alan: And then we can introduce one of our antagonist and watch calcium normalized.

Alan: Also take normal rats, and give them PTH and tagging and see their PTH levels rise.

Alan: So this type of Pharmacodynamic response in a model system is very much the same type of thing we would do in a healthy volunteer.

Alan: And it goes up and down our pipeline and it's a reason why from a.

Alan: Business perspective, endocrinology is just such a great field because you do so much de risking so early on whether it's an animal models, which closely mimic humans.

Alan: Or it's early healthy volunteers, our early patient studies, where you're measuring biomarkers that are completely objective and well defined.

Unknown Executive: And then we can introduce one of our antagonists and watch calcium normalize, and we can also take normal rats and give them a PTH antagonist and see their PTH levels rise. So this type of pharmacodynamic response in a model system is very much the same type of thing we would do in a healthy volunteer. And it goes up and down our pipeline. And it's a reason why, from a business perspective, endocrinology is just such a great field because you do so much de-risking so early on, whether it's in animal models, which closely mimic humans, or it's early healthy volunteers or early patient studies where you're measuring biomarkers that are completely objective and well-defined. But maybe, Alan, you can comment on the clinical need and why we're excited about a PTH antagonist for these different patient populations.

Unknown Executive: But maybe Alan you can comment on.

Alan: Clinical need and why we're excited about PTH antagonist for these different patient populations.

Alan S. Krasner: Yeah, sure. This is a novel mechanism of action that could potentially help a great number of patients who have parathyroid hormone excess for any number of reasons, and, by the way, also parathyroid hormone-related protein excess. So beginning with hyperparathyroidism, this is a fairly common endocrine disease, primary hyperparathyroidism, in which one of the parathyroid glands in the neck typically overgrows and causes an unregulated excess secretion of parathyroid hormone.

Alan: Yeah sure you know.

Alan S. Krasner: This is a.

Alan S. Krasner: This is a novel mechanism of action for.

Alan S. Krasner: That could potentially help a great number of patients who have parathyroid hormone excess for any number of reasons and by the way also parathyroid hormone related protein excess.

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

Alan S. Krasner: So beginning with hyperparathyroidism Mrs.

Alan S. Krasner: A fairly common endocrine disease primary hyperparathyroidism in which the one of the parathyroid glands in the neck typically over grows in <unk>.

Alan S. Krasner: Cause is.

Alan S. Krasner: Regulated excess accretion of parathyroid hormone that results as Scott mentioned and hypercalcemia high calcium levels in the blood, but it's really a multi oregon systemic disease that also damages the bone in the kidneys in particular.

Alan S. Krasner: And the hypercalcemia itself can cause sometimes for a serious symptoms.

Alan S. Krasner: Now, fortunately, for patients with primary hyperparathyroidism, there are very, very effective surgical options available, and many of these patients are cured surgically. However, there is a very important subset of patients who don't get cured by surgery, sometimes because more than one gland actually enlarges in some patients, and there is really a great number of patients who could benefit from having a medical option to control hyperparathyroidis And the other thing I would point out is even with patients who potentially could have surgery, it turns out a lot of them don't have surgery for any number of reasons, including the fact that they may not be surgical candidates.

Alan S. Krasner: Now Fortunately for patients with primary and prepare with artisan.

Alan S. Krasner: There are very very effective surgical.

Alan S. Krasner: Options available in many of these patients are cured surgically. However, there is a very important subset of patients who don't get cured by surgery, sometimes because more than one gland actually enlarges in some patients and.

Alan S. Krasner: There is really a great number of patients who could benefit from.

Alan S. Krasner: Having a medical option to control hyperparathyroidism when surgery has not worked.

Alan S. Krasner: And the other thing I would point out is even.

Alan S. Krasner: With Ah patients, who potentially could have surgery. It turns out a lot of them don't have surgery for any number of reasons, including the.

Alan S. Krasner: And so therefore, I see a lot of potential for a medical option in this area. That's just one potential, that's probably the most straightforward indication, but there's also something called hypercalcemia malignancy, which is caused by a parathyroid hormone-related protein that also binds to the PTH receptor. Those patients could also use a new option. There are treatments available, but they all have limitations, and these patients can be quite ill, and I think it's an exciting prospect also for the future for a PTH antagonist. And then there's more, but we don't have time to talk about them all.

Alan S. Krasner: The fact that they may not be surgical candidates and so therefore, I see a lot of potential for a medical option in this area.

Operator: Great

Operator: That's just one potential that's probably the most straightforward indication, but there's also something called hypercalcemia malignancy, which is caused by parathyroid hormone related protein, which also binds to the PTH receptor. Those patients could also use a new option and there are treatments available, but they all have.

Operator: Limitations.

Operator: And these patients can be quite ill and I think it's an exciting prospect also potentially for the future for PTH antagonist, and then theres more but we don't have time to talk about it.

Speaker Change: Great. Thank you very much.

David Neil Lebowitz: Your next question comes from David Lebowitz from Citi. Your line is already open.

Operator: Great. Thank you very much. Your next question comes from David Lebowitz from Citi.

Operator: Your next question comes from David <unk>.

David Neil Lebowitz: Citi. Your line is already open.

David Neil Lebowitz: Thank you for taking my question with respect to the data being presented for CAH.

David Neil Lebowitz: How should we benchmark versus.

David Neil Lebowitz: What we've seen from other therapies and what should we expect.

David Neil Lebowitz: Conversely, what should we not expect.

David Neil Lebowitz: Hi, Alan maybe you want to reiterate that.

David Neil Lebowitz: Alan, maybe you want to reiterate that. Yeah, I mean, I think, again, we're

Alan S. Krasner: Yeah, I mean, I think again we're expecting directional information in the biomarker responses. Again, as we discussed, it's more than just what's the percentage reduction in the biomarkers. It's also about how many patients actually get into get normal levels of biomarkers. And then there are all the clinical features of the disease we want to carefully assess when we look at our data. So again, this phase two interim data will not be a statistical exercise, but I'm hoping we'll get good directional guidance in terms of what doses may or may not be effective and what doses we and designs we may want to contemplate for future development beyond phase two. Thanks for taking my question. Your next question comes from Dennis Ding of Jeffries.

David Neil Lebowitz: Yeah, I mean, I think again, we're expecting directional information in the biomarker responses.

Unknown Executive: Again, as we discussed it's more than just what's the percentage reduction and the Biomarkers. So it's also about how many patients actually.

Unknown Executive: Get into get get normal levels of Biomarkers, and then Theres all the clinical features of the disease, we want to carefully assess when we when we look at our data.

Unknown Executive: So again, it's this our phase two interim data will not be a statistical exercise, but I am hoping we will get good directional guidance in terms of what doses.

Unknown Executive: May or may not be effective and what.

Unknown Executive: Doses, we and designs, we may want to contemplate for future development beyond phase II.

Unknown Executive: Thanks for taking my question.

Unknown Executive: Your next question comes from Dennis King.

Alan S. Krasner: Your next question comes from Dennis Ding of Jeffries. Your line is already open.

Unknown Executive: Of Jefferies. Your line is already open.

Unknown Executive: Alright, thanks for taking our questions and congratulations on all the progress.

Unknown Executive: I can ask on CAH maybe.

Unknown Executive: Just talk about how you're thinking about having to go to the high <unk>.

Unknown Executive: <unk> hundred 60 milligram dose with an optional cohort and I'm just wondering if that that cohort has started enrolling or not.

Unknown Executive: Do you plan to thank you very much.

Unknown Executive: Alan, do you want to talk about how we think about cohorts and selection? Yeah. So, this is a...

Alan S. Krasner: Alan do you want to talk about how we think about cohorts in dose selection.

Alan S. Krasner: That dose, that next cohort could be a higher or a lower dose. We'll certainly share that information at the endocrine society meeting as part of the scientific presentation. And I think it's fair to assume we would have patients from the first cohort as well as some of the second cohort as well.

Alan S. Krasner: So, this is a sequential dose cohort study, and the first cohort of patients with CEH will receive an 80 milligram once-per-day dose of etumelamine. This is based on phase one healthy volunteer data showing that that dose looked like it should be effective. After we complete the first cohort of dosing, all the data from that cohort is reviewed by a safety review committee, and that committee then recommends the dose for the next cohort.

Unknown Executive: So.

Alan: This is a sequential dose cohort study and the first cohort of patients with CAH.

Alan S. Krasner: Our.

Alan S. Krasner: Receive an 80 milligram once per day dose of <unk>.

Alan S. Krasner: This is based on the phase one healthy volunteer data showing that that dose looked like it should be effective.

Alan S. Krasner: After we complete the first cohort of dosing are.

Alan S. Krasner: All of the data from that cohort is reviewed by a safety Review Committee and that Committee then recommend the dose for the next cohort.

Alan S. Krasner: Deb dose that next cohort could be higher or a lower dose we will certainly share that information at the endocrine Society meeting as part of the scientific presentation.

Alan S. Krasner: And I think it's fair to assume we would have.

Alan S. Krasner: Patients from the first cohort as well as some of the second cohort as well.

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

Alan S. Krasner: There are no further questions at this time I would hand over the call to Doctor, Scott Struthers, founder and Chief Executive Officer for closing comments. Please go ahead.

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

Unknown Executive: Thank you everybody for being with US today, and we look forward to seeing many of you in Boston in beginning of June.

Speaker Change: And throughout the year as more and more interesting things start coming up from the pipeline. Thanks.

Speaker Change: Thanks again for your time.

Unknown Executive: Right.

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

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