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spk04: Welcome to the Krenetics Pharmacuticals first quarter 2024 earnings conference call. At this time, all participants are in listen-only mode. Following management's prepared remarks, we will hold a question and answer session. I will now turn the call over to Corey Davis of LifeSci Advisors. Please go ahead.
spk12: Thank you, Alan. Hello, everyone, and welcome to Krenetics earnings call.
spk13: Joining me today are Dr. Scott Struthers, Founder and Chief Executive Officer, Dr. Alan Krasner, Chief Endocrinologist, and Mark Wilson, Chief Financial Officer. Also joining us for the Q&A portion of the call are Dr. Dana Pizzuti, Chief Medical and Development Officer, and Jim Hazard, Chief Commercial Officer. The press release announcing the first quarter 2024 financial results was issued today and is also available on the Crenetics corporate website. As a reminder, we'll be making forward-looking statements, and I invite you to learn about the risk and uncertainties associated with these statements as disclosed in our SEC filings. Such forward-looking statements are not a guarantee of performance, and the company's actual results could differ materially from those stated or implied in such statements due to risks and uncertainties associated with the company's businesses. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release, the company's other news releases, and Cronetic's SEC filings, including its annual report on Form 10-K. I'd also like to specify that the content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, May 9th, 2024. Chronetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call.
spk12: With that, I'll hand it over to Scott. Go ahead.
spk14: Thank you, Corey. Good afternoon, everyone, and thank you for joining us on our first quarter 2024 results call. I'll begin by spending a few moments summarizing our recent accomplishments before turning the call over to Dr. Alan Krasner, our chief endocrinologist. He will discuss our clinical programs and recently reported data in more detail. Chronetics had an extremely strong start to 2024. Recently, we reported positive results from two late-stage clinical studies for paltucetine in patients with acromegaly and carcinoid syndrome. Behind palatucetine, we've built a remarkably deep pipeline. This includes our second internally discovered clinical stage compound, CRN4894, which will now be known as atumelnan. At the endoconference 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 in each of the ongoing open-label Phase II studies evaluating the safety and efficacy of Atumelnat in patients with CAH and Cushing's disease. We are also hosting an in-person reception to review data from clinical studies of Atumelnat in CAH and ACTH-dependent Cushing syndrome at 6 p.m. on Monday, June 3rd, for those attending in person. 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 1st. Three posters from the paltucetine acromegaly clinical program will also be presented, highlighting results from Pathfinder 2, 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. Now let me take a few minutes to dive a little deeper into the progress made with the two paltucetine indications. We're extremely pleased to have completed our phase three 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. Pathfinder 2 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 3 studies to support an NDA filing for the treatment of acromegaly in the second half of this year. In anticipation of a potential 2025 launch of Peltucetine, we're continuing to work on important aspects of commercial readiness. We have already held multiple advisory boards and conducted market research with physicians to gather their input on how to optimize the communication of the Peltucetine 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 injection site pain, breakthrough symptoms, and the months-long regimens required to identify the appropriate dosage for their patients receiving injectable depots. An accompanying campaign directed at patients will be launched early next year. Our market access team has also been active dialogue with leading payers to understand the current marketplace and the dynamics for Paltusa team 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's demonstrated meaningful reductions of both frequency and severity of flushing episodes and bowel movements caused by this disease. These effects were rapid, sustained, and consistent with the preliminary data we reported last December. Overall, we believe the safety and efficacy profile of paltucetine in this study supports progressing into a phase three study as soon as we can. We plan to discuss these results with the FDA and align on a phase three study design, which enable us to begin a phase three study by the end of the year. Finally, we strengthened our balance sheet with a $350 million private placement in February from new and existing equity investors. This additional capital has provided us with sufficient runway to fund operations into 2028 based on current projections for our pipeline of product candidates. In summary, Looking to the rest of 2024 and 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 programs.
spk05: Thank you, Scott.
spk17: Today I will provide updates on recently reported clinical programs, starting with peltucetine. 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 peltucetine was shown to be generally well-tolerated. We therefore intend to seek approval for patients who might switch from injected SRLs to peltucetine as studied in Pathfinder 1 and also in those who are not currently treated with medications and might start peltucetine as a first-line treatment as studied in Pathfinder 2. We reported most recently the top-line results from the 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 peltucidine. These IGF-1 declines occurred rapidly, with most of the effect occurring in just two to four weeks. These reductions were durably sustained throughout the treatment period. Significant improvements in acromegaly symptom control associated with peltucetine compared to placebo have now been documented in two major independent controlled trials. As previously discussed, we are very excited to further explore our rich database into which patients reported their symptoms on a daily basis during the trials. 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. 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. 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 peltucetine for over four years. The overall dataset suggests that peltucetine 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. 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 and dealing with the side effects that often occur after these injections. 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. In short, paltucetine may represent a completely new paradigm for somatostatin receptor-based therapy. Paltucetine's second target indication, carcinoid syndrome, has also shown promising results. In March, we reported top-line results from the Open Label Phase II trial. 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. Kaltucetine was generally well tolerated at the doses evaluated in this trial with no severe or serious treatment related adverse events. In addition, pharmacokinetics in this patient population was consistent with what we expected to see from prior experience. We observed significant and meaningful reductions in both the frequency and severity of bowel movements and flushing episodes, consistent with the initial results we reported last December. Importantly, the intensity of these symptoms was also reduced by peltucetine. These reductions occurred quite rapidly and were sustained throughout the eight-week treatment period. We intend to discuss the phase two carcinoid syndrome data with the FDA to align on a phase three 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 etumelnift, which is a once-daily oral ACTH receptor antagonist in development for the treatment of both congenital adrenal hyperplasia, or CAH, and Cushing's disease. The adrenal glands are the sole source of excessive steroid that cause the clinical complications in both disease states, and 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 etumelanin is classic CAH, a genetic disorder that affects approximately 27,000 patients in the U.S. These patients lack a critical enzyme in the adrenals responsible for cortisol production. The hypothalamus and pituitary responds to these low cortisol levels by producing high levels of ACTH. This excess ACTH in turn causes overstimulation of the adrenal cortex, resulting in overproduction of cortisol precursors like 17-hydroxyprogesterone and adrenal androgens like androstenedione, also known as A4. The adrenal hyperandrogenemia causes many serious medical complications beginning in utero, progressing through childhood and into adulthood. Because CAH patients cannot produce cortisol, exogenous glucocorticoid replacement is required for life, but replacement doses should be very low, and these low doses should not cause adverse effects. As a result, many physicians find it necessary to use high 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. It is very difficult to find a dose of glucocorticoid which effectively controls adrenal androgen production without causing these side effects. This highlights the fundamental challenge in treating this disease to strike the right balance between reducing adrenal androgens, yet minimizing the effects of excess glucocorticoids. We believe Etumelment is the right approach to achieve this balance and look forward to showing initial data from our phase two studies in the coming weeks. Etumelment was designed to reduce or eliminate ACTH stimulation at the level of the adrenal, thereby lowering adrenal androgen output. Once adrenal hyperandrogenemia is controlled, patients who are taking excessive doses of glucocorticoid should be able to lower their dose and reduce or even avoid steroid therapy-related adverse effects. Remember, the ACTH receptor in the adrenals is the only means by which ACTH drives the pathologic adrenal androgen output seen in CAH, and the ACTH receptor is a single choke point at which this overdriven system might be turned off. Our ongoing phase two open label sequential dose cohort study in CAH is evaluating safety and pharmacokinetics of F2 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 excess of exposure to adrenal steroids as reflected by these biomarkers. The patients in our study continue their pretrial glucocorticoids at unchanged doses, so we can observe the time course and durability of any response to atrium ailment itself. In future studies, we expect to evaluate glucocorticoid dose reduction once we know that the compound can reduce adrenal androgen output. As Scott mentioned, we will be presenting late-breaking attenuamint data at the upcoming Endocrine Society meeting in June. This will not include the full cohort of patients in the CAH study, but will comprise initial data from a subset of the first two dose cohorts. We expect these early results will give us directional information that will help guide developmental plans for Add to Melanin in CAH. Initial data from the phase two single center trial in Cushing's disease will also be presented at the same meeting. With that, I will now hand it over to Mark to review the financials.
spk16: Thank you, Alan. Chronetics 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 Peltucetine for Acromegaly, the initiation of multiple later stage clinical trials in additional indications with Peltucetine and Atumelnap, as well as continued investment in our pipeline. With respect to the financial results, research and development expenses were $53.3 million for the quarter end of March 31, 2024, compared to $38.5 million for the same period in 2023. The increase was primarily attributable to higher personnel costs and manufacturing and development activities, both of which were driven by the advancement of our clinical programs and the expansion of our pre-clinical portfolio. For the quarter ended March 31, 2024, general and administrative expenses were 20.8 million compared to 12.2 million for the same period in 2023. These increases were primarily attributable to higher personnel costs to support the growth of the organization. Net loss for the quarter ended March 31, 2024 was 66.9 million compared to a net loss of 46 million for the same period in 2023. Revenues were $0.6 million for the quarter ended March 31, 2024, compared to $2.7 million for the same period in 2023. Revenues during the current year's quarter were primarily derived from our Paltucetin licensing arrangement with our Japanese partner, SKK. And revenues for the prior year were associated with licensing arrangements for Paltucetin and CRN01941, another somatostatin targeted development candidate. Net cash used for operating activities for the quarter end of 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.
spk14: Thank you, Mark. We will continue to build on the strong progress this quarter throughout the rest of the year and beyond. We look forward to sharing that to MelNet data in the coming weeks, as well as providing continued updates as we progress PAL-216 to regulatory submissions, and as we make continued advancements in the exciting new programs beginning to emerge from our discovery efforts. Thank you all for your attention. Operator, we are ready to take questions.
spk04: Thank you. Ladies and gentlemen, we will now begin the question and answer session. If you have a question, please press star one in your touchtone phone. You will hear a three-tone prompt acknowledging your request, and the questions will be pulled in the order they are received. If you would like to withdraw from the question queue, please press star two. If you're using a speakerphone, please lift the handset before pressing any keys. Please be advised that you can ask one question at a time.
spk05: One moment, please, for your first question.
spk04: Your first question comes from Yasmin Rahimi of Piper Sandler. Your line is already open.
spk11: Yes. Good afternoon, team, and thank you for all your thoughtful remarks. I know we're going to have quite a bit of talk in the Q&A about CH upcoming readout, but I would love to actually dig into the Cushing's data set. I guess, you know, it's an interim look. It's been, 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 would potential next steps be in development for Cushing. So, I'll jump back into the queue.
spk14: Thank you, Yaz. Alan, can you take that question?
spk17: Sir, yes. We are collaborating with a leading KOL at the NIH in Cushing's, in our Cushing's disease study. This is a study in which the compound is dosed for 10 days while patients are in the clinical research center. And there is frequent monitoring of many parameters, but especially pharmacodynamically speaking of most interest would be cortisol. These are patients with Cushing's disease who start with high levels of cortisol excretion. And, of course, we'll be interested to see if cortisol is reduced during this 10-day dosing period. That is the information we would get from this study that I think will be of interest. We expect that the data we would present at the Endocrine Society meeting would give us directional kind of information to help guide our future development in Cushing's. Sort of like when we reported carcinoid syndrome data in December, it was directionally of interest. I would expect we would learn a great deal from what we've seen so far. Of course, we'll be a subset of the patients, as we discussed in our remarks. But still, again, I hope we'll have qualitative directional information.
spk05: Thank you.
spk04: Your next question comes from Jessica Fai of J.P. Morgan. Your line is already open.
spk10: Hey, guys. Good afternoon. Thanks for taking my question. What elements of Atsumelman's profile do you think will best differentiate it from CRF antagonists in CAH?
spk05: Well, thank you, Jess.
spk14: 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 adrenal is controlled, they all converge on ACTH acting at its receptor on the adrenal, which is formed by the MC2 protein. But we'll just call it the ACTH receptor. It's the only way ACTH can act, and it's the only thing that the ACTH receptor does. And so by blocking that, we're blocking the single choke point of action of the whole hypothalamic pituitary adrenal axis on the adrenal. And we've always said we expect to achieve a good blockade of adrenal activity, whether it's measured by adrenal androgens in CAH or by glucocorticoids in Cushing's patients.
spk05: Thank you.
spk04: Your next question comes from Corey Ubenville of LifeSci Capital. Your line is already open.
spk07: Thanks for taking our questions, and I love the new name for 04894, Atumelnat. I'm very intrigued by your endo-abstract title in regard to CAH data. The title is Atumelnat induces rapid and profound reductions of A4 and 17-OHP in participants with CAH. The key word for me there being profound. To the extent you can, can you help us frame expectations on data that we'll see at endo? And I guess if you can't go into granular detail, at a high level, how satisfied are you with the pharmacodynamics you're seeing with Atumelnet in comparison to these 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.
spk14: Yeah, sorry, Corey. I think you'll have to wait until Monday, June 3rd at 12 p.m. Eastern time when the embargo lifts before we can really get too deep into this. But we look forward to seeing you at our poster presentations and welcome everyone to our investor relations event which is at the Omni Hotel on the 3rd at the same day at 6 p.m. In terms of phrasing, sorry, can you repeat the second half of your question if you're still on the line?
spk07: 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 via...
spk14: Yeah, I realize there's been a lot of people wanting to set the bar, and I've always encouraged people to think about treating the whole disease, not defining a bar of one compound or another. In terms of how satisfied we are, again, you'll need to see the data at Endo, and generally, 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 about it.
spk17: Maybe, Scott, I could address the question on what sort of patients are enrolled in this study, if that would be helpful.
spk09: Oh, yeah. Thanks.
spk17: Okay. So these are patients, these are adult patients with classic CAH, which means they have the most severe form of enzyme deficiency. So they're born with this condition and generally throughout life need to take glucocorticoid replacement. So these are all now adults with this condition who are all on glucocorticoid therapy. In general, they will start the study with elevated adrenal androgen levels. There will be a variety of disease severity that we look at. We're trying to be as inclusive as possible. in this study, and it's a three-month dosing period. During the three months, we administer a fixed dose of Etumelment. The background pretrial glucocorticoid therapy has not changed during this study. As I mentioned during my remarks, our first goal is to assess how well 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 glucocorticoid, and they would benefit from being brought down to the floor replacement dose levels.
spk05: That's helpful. Thank you.
spk04: Your next question comes from Joseph Schwartz of LeeRank Partners. Your line is already open.
spk02: Thank you. Congrats on the progress. Given the phase 2 CAH L2 melanin 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'll be reporting at ENDO? Are there additional questions you need to answer before you can advance to phase three? And when will the next look at the CH trial be? Thank you.
spk14: Thanks, Joe. Alan, why don't you take that question?
spk17: 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 the safety, of course, but also pharmacodynamic response at various doses. So this will be a subset. I think we will get good directional information from the doses tested, but we do want to complete the study to make sure we have that complete range of dose response evaluated to help us best design subsequent development for the compound.
spk05: Your next question comes from John of Citizens JMP.
spk04: Your line is already open.
spk09: Thanks for taking the questions. One more for me on 894 and then carcinoma syndrome. When we're thinking about the data at endo, how do you balance the relative importance of a percent reduction in A4 versus achieving normalization as far as clinical development and also management of patients in the real world? And then I'm wondering if you give us some high-level thoughts on the phase three preliminary design of carcinoid syndrome.
spk14: All right. We'll let two questions slip by on that one. But I'll take the first part. And, Alan, maybe you take carcinoid syndrome. But generally, you know, percent is always just a shorthand. And it depends on, you know, where you start for the magnitude of the effect that you might see expressed as a percentage. So I do think the goal of therapy is to get people as low as you can on their androgens so that you can adjust or get rid of the androgen effects and adjust the glucocorticoids to a physiologic level. So percent is a good shorthand and perhaps an easy way to make some comparisons. But in the end, it's patients that is the focus. And by the way, it's not just biomarkers. It's the effect of those changes in hormones that may have on the symptoms and expression of the disease in these patients. And Alan, you want to comment on carcinoid syndrome? Sure. Yeah.
spk17: As we've reported phase two data, we are actively designing the phase three program for carcinoid syndrome. The plan, of course, is to review with the FDA the full data set from the Phase 2 study as well as our proposals for Phase 3 and to align with them on the design of Phase 3. I can give you some sort of high-level thoughts about Phase 3. Again, we have to remember, 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, and as we already reported in phase two, 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 three 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 size in the Sample sizes in the past have ranged between roughly 80 and 150 patients. And based on our power calculations to date, I think that's right about the range I would expect for our phase three trial as well.
spk05: I hope that's helpful. Let me sneak in, too. Very helpful. Your next question comes from Leyland Gershel of Oppenheimer.
spk04: Your line is already open.
spk18: Hey, good afternoon. Congratulations on the progress, and thanks for taking 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 the Phase II, I wanted to hear of any feedback you've received from physicians with respect to their interest in using peltucetine in patients who are untreated on carcinoid. SRLs given the large population segment who's not currently on therapy? And then I have a follow-up.
spk05: Go ahead, Al.
spk17: Well, 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 themselves usually treat those patients with carcinoid syndrome. A lot of them are our investigators and in our study steering committee and the feedback has been generally very positive from them. They're very excited about the data we have and I would say pleased to be helping us think about what's coming up in phase three and probably many of them would participate in phase three as well. I think it's recognized by many of the physicians who treat this that there are some shortcomings with these injections that are the standard of care for the control of carcinoid syndrome. And we went through many of those limitations in my prepared remarks, but, you know, these are just very burdensome from patients in many ways. They're also technically difficult to deliver in a reproducible way, and this has actually been shown in the literature in this patient population in particular. So I think both the patients and the physicians have expressed to me at least positive thoughts that this would be a real contribution to the field.
spk18: 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 paltisotine. It seems like that was much better than we've seen with the SRLs. Wondering if that particular finding has resonated with respect to maybe longer-term efficacy beyond, I think, the eight weeks that you've shown with the Phase II, you know, for longer-term control of the cardinal symptoms. Thank you.
spk17: Yeah, it's an interesting question. I'm afraid I don't know the answer. I'm not sure the answer is even in the literature. The ability of the biomarker responses to sort of predict longer-term responses with respect to these tumors or the symptoms, 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. 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 program as well.
spk14: 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. It's very surprising to me that There is a significant population of patients with carcinoid syndrome that are not being treated at this point when they clearly should be. And I can only explain it by somebody. They must be making some judgment on the burden of treatment versus the burden of disease and or access to medicines. And it's causing far too many to not have access to medicines that would help them. So we look forward to try and find ways to bring this to more patients than are currently on the injectable depot therapies.
spk18: Thanks so much for the added color.
spk05: Looking forward to hearing more, Dindo.
spk04: Your next question comes from Douglas Sal of AHC Wainwright. Your line is already open.
spk15: Hi. Good afternoon. Thanks for taking the questions. I was just Sirius, maybe, Scott, on the earlier stage pipeline, you have a number of sort of therapeutic areas that you're targeting, many of which you're sort of talking about candidate selection for this year. I think you've talked about sort of diabetes and obesity for something for next year, I guess. What's the, or is there any kind of prioritization within those, and how do you think about sort of you know, the pace that those would go into the clinic and start to read out, you know, with, you know, 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.
spk14: Thanks, Doug. Yeah, the, 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 first. We've been doing some non-GLP tox studies on multiple candidates, and it looks like the team is getting close to selecting the best one. out of several good ones. And then the other programs are successively behind that. Fortunately, we've been in a financial position where we don't need to make difficult prioritization decisions about which good molecule to slow down over the other good molecules. And I do think there's a little bit of just internal prioritization we have to do as we balance workloads between some of the different projects But largely, all projects are moving forward as fast as we can, and I'm optimistic that that's going to leave a whole sequence of upcoming clinical information on these programs over the next 12, 18, 24 months.
spk05: Okay, great. That's really helpful, and congrats on the progress. Thanks. Your next question comes from Catherine Novak of Jones Research.
spk04: Your line is already open.
spk01: Hi. Oh, hi. Thanks for taking my question. I'm just wondering, when it comes to commercialization, what's the overlap in terms of treatment centers and prescriber base for CAH and acromegaly? And then would there be any overlap extended carcinoid syndrome? Is that a completely different institution that you're looking at?
spk14: Thanks, Catherine. It's a high degree of overlap, and maybe, Jim, you could get into some more detail there.
spk00: 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 Salesforce sizing, we see a lot of overlap between acromegaly and carcinoid syndrome. Even in terms of endocrinologists, there's a high degree of overlap with acromegaly and Cushing's disease, of course, because it's pituitary. But we're also seeing the same for congenital adrenal hyperplasia. So a lot of the specialist endocrinologists are seeing all three pituitary or adrenal diseases.
spk14: And I'll just add that that was That was really part of our long-term strategy when we started getting into these indications so that not only from a commercial point of view do we start building into the same centers and same prescribers, but also from a development point of view so that we start using the same investigators and centers again and again and again and trying to find synergies and ways of working well together as those relationships go for the long term.
spk05: Thanks, guys. That's very helpful. Thank you. Your next question comes from Jeffrey Hung of Morgan Stanley.
spk04: Your line is already open.
spk06: Hi, this is Michael Riad. I'm for Jeff Hung. Thank you for taking our question. Circling back to the phase three design for carcinoid syndrome, Is there any ability for the study design to accommodate or potentially show the ability to prevent breakthrough symptoms and the typical waxing and waning versus SRLs, maybe during the initial screen or washout? Just wondering if there's any potential for that analysis. Thanks so much.
spk14: Thanks. I think that's an important question, and we are asking ourselves that. Alan, you might want to comment a bit on it.
spk17: Yeah, it's a very important concept because, you know, that's, as I was talking earlier about the limitations of the current injection therapy for carcinoid syndrome, that is a major issue is you take these long-acting injections sometimes more frequently than once a month, and yet you still have these days where you have active breakthrough of either diarrhea or flushing or both, sometimes more than just a day. And these patients often end up having to take additional medications sometimes anti-diuretals, or sometimes even short-acting subcube boluses of octreotide itself on top of the long-acting octreotide they're already taking. Why that kind of breakthrough occurs is not fully understood, but I suspect that it might be related to some variability in exposure to the drug from month to month. And we do know that there's variability in technique of actually accurately delivering, for example, octreotide to the intramuscular space. So I suspect that contributes to this breakthrough phenomenon. And yes, in our trials, we will be very interested in asking patients every day how they're feeling using an electronic diary, as we did in phase two and as we did in phase three for acromegaly. And I am hoping we will learn interesting things about whether, you know, whether that problem we see with these long-acting injections could potentially be solved with a daily oral dose of a simple oral agent.
spk05: Thank you so much. That's very helpful. I appreciate it. Your next question comes from Brian Scorney. of Baird.
spk04: Your line is already open.
spk08: 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 or assets. Just kind of wanted to ask what from the presentation earlier this year at the Bone and Teeth Corn Research Conference really gave you confidence in the profile of the molecules you're developing and if maybe you could kind of walk us through what excites you about it as well as if this is kind of the profile that you're looking for from the other assets that you're selecting from. Thank you.
spk14: Got it. How about, Alan, I'll talk about the preclinical and you can talk about why we're excited about it clinically. But very much this is like many of our programs where the endocrinology in animal model species is almost identical to the endocrinology in humans. And we know that it's very robust way in rats, for example, to induce hyperparathyroidism by infusing excess of parathyroid hormone, and we can watch calcium go up. And then we can introduce one of our antagonists and watch calcium normalize. And also take normal rats and give them PTH antagonist and see their PTH levels rise. So this type of pharmacodynamic response in a model system is very much the same type of thing we would do in a healthy volunteer. And it goes up and down our pipeline. And it's a reason why, from a business perspective, endocrinology is just such a great field because you do so much 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.
spk17: Yeah, sure. You know, this is a novel mechanism of action for that could potentially help a great number of patients who have parathyroid hormone excess for any number of reasons. And by the way, also parathyroid hormone related protein excess. So beginning with hyperparathyroidism, this is a fairly common endocrine disease, primary hyperparathyroidism, in which one of the parathyroid glands in the neck typically overgrows and causes unregulated excess secretion of parathyroid hormone. That results, as Scott mentioned, in hypercalcemia, high calcium levels in the blood, but it's really a multi-organ systemic disease that also damages the bone and the kidneys in particular. And the hypercalcemia itself can cause sometimes very serious symptoms. Now, fortunately for patients with primary hyperparathyroidism, There are very, very effective surgical options available, and many of these patients are cured surgically. However, there is a very important subset of patients who don't get cured by surgery, sometimes because more than one gland actually enlarges in some patients. And there is really a great number of patients who could benefit from having a medical option to control hyperparathyroidism when surgery has not worked. And the other thing I would point out is even with patients who potentially could have surgery, it turns out a lot of them don't have surgery for any number of reasons, including the fact that they may not be surgical candidates. And so therefore, I see a lot of potential for a medical option in this area. That's just one potential, 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. There are treatments available, but they all have limitations, and these patients can be quite ill And I think it's an exciting prospect also potentially for the future for a PTH antagonist. And then there's more, but we don't have time to talk about more.
spk05: Great. Thank you very much.
spk04: Your next question comes from David Lebois from Citi. Your line is already open.
spk19: Thank you for taking my question. With respect to the data being presented for CAH, how should we benchmark it versus what we've seen from other therapies, and what should we expect, and conversely, what should we not expect?
spk14: Alan, maybe you want to reiterate that.
spk17: 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 normal levels of biomarkers. And then there's all the clinical features of the disease we want to carefully assess when we look at our data. So again, our 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 and designs we may want to contemplate for future development beyond phase two.
spk05: Thanks for taking my question. Your next question comes from Dennis Ding of Jefferies. Your line is already open.
spk03: Hi, thanks for taking our questions and congratulations on all the progress. If I can ask on CAH, maybe, you know, just talk about how you're thinking about having to go to the high 160 milligram dose as it was an optional cohort. And I'm just wondering if that cohort has started enrolling or not, or do you even plan to? Thank you very much.
spk14: Alan, do you want to talk about how we think about cohorts and dose selection?
spk17: Yeah. So, this is a sequential dose cohort study. And the first cohort of patients with CAH receive an 80 milligram once per day dose of etumelan. This is based on the 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. That dose, that next cohort could be a higher or a lower dose. We'll certainly share that information at the Endocrine Society meeting as part of the scientific presentation. And I think it's fair to assume we'd have, you know, patients from the first cohort as well as some of the second cohort as well.
spk05: There are no further questions at this time.
spk04: I would hand over the call to Dr. Scott Struthers, Founder and Chief Executive Officer for Closing Comments. Please go ahead.
spk14: Thank you everybody for being with us today and we look forward to seeing many of you in Boston in the beginning of June and throughout the year as more and more interesting things start coming out from the pipeline. Thanks again for your time. Good night.
spk04: Ladies and gentlemen, this concludes today's conference call. Thank you for your participation, and you may now disconnect.
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