Crinetics Pharmaceuticals, Inc. (CRNX) Earnings Call Transcript & Summary

Greetings, and welcome to the Crinetics Conference Call. [Operator Instructions] As a reminder, this conference is being recorded. It is now my pleasure to introduce Charles Schultz, Vice President of Investor Relations and Corporate Communications. Thank you, you may begin.

Thank you, Doug. Good afternoon, and welcome to the Crinetics Carcinoid Syndrome Phase II Initial Results Conference Call. Joining me today are Dr. Scott Struthers, Crinetics' Founder and Chief Executive Officer; and Dr. Alan Krasner, Crinetics' Chief Endocrinologist. Following the formal presentation, Dr. Dana Pizzuti, our Chief Medical and Development Officer, will join us for the question-and-answer portion of the call. Before we begin, I would like to point out that there is a slide deck that will accompany today's presentation, which can be viewed using the Events and Presentation link provided on the Investors section of the Crinetics Pharmaceuticals website at crinetics.com. In addition, a news release announcing the initial results was issued today and is also available on our corporate website. As a reminder, we will be making forward-looking statements, and I invite you to learn more about the risks and uncertainties associated with these statements as disclosed in our SEC filings. Such forward-looking statements are not a guarantee of performance, and the company's actual results could differ materially from those stated or implied in such statements due to the risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release. The company's other news releases and Crinetics' SEC filings, including its annual report on Form 10-K. I would 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, December 18, 2023. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. I will now hand the call over to Dr. Struthers. Please go ahead, Scott.

Thank you, Charles. Good afternoon, everyone. Thank you for joining us today. We're very excited to present initial results from our ongoing open-label Phase II study of paltusotine, in patients living with carcinoid syndrome. We'll present the top line data set from all enrolled patients in the first half of 2024, but we're extremely pleased with what we're seeing so far. From a safety point of view, paltusotine continues to be well tolerated with no new safety findings compared to what we've seen in our previous clinical trials. Pharmacokinetics in this population of patients with carcinoid syndrome remains consistent with what we expected to see from prior experience in healthy volunteers. We're also seeing meaningful reductions in both frequency and intensity of bowel movements and flushing, these are the key symptoms of carcinoid syndrome. Overall, if the profile we're seeing today is confirmed in the top line results next year, we'll present these data to the FDA to seek alignment on the Phase III study design. We hope to initiate that Phase III study later next year. Just as a reminder, carcinoid syndrome arises from neuroendocrine tumors that typically originate in the intestine. It's the second most common GI malignancy after colon cancer. A good fraction of patients have symptomatic carcinoid syndrome, and that is due to tumor production of serotonin and other factors. Symptoms in this disease are heterogeneous and can present differently in each patient. Patients can experience excess bowel movements or excess and/or excess severe flushing episodes, that are incredibly disruptive to their daily lives. Gastroenterologists consider normal bowel movement frequency to be less than 3 per day, and these patients can be well in excess of that threshold. Flushing is also debilitating and potentially dangerous and the treatment goal is to reduce these episodes to less than one per day. In addition, if not well controlled, carcinoid syndrome can lead to other severe or life-threatening conditions such as carcinoid heart disease. Less common, patients can experience life-threatening carcinoid crisis that need urgent medical attention. Current standard of care for carcinoid syndrome is injected depot somatostatin receptor ligand, or SRL. There is a high burden of care associated with these painful monthly depot injections, and often they are not fully effective for a large portion of patients. As a result, patients often have to dose escalate above the maximum label dose to give themselves additional short-acting octreotide injections to provide better control. Our goal in treating patients with paltusotine is to provide a once-daily oral treatment that is able to reduce their total symptom burden without the high burden of care imposed by the painful injection -- monthly injection. Whether a patient experiences excess bowel movements, flushing episodes or a combination of both symptoms, we want them to be able to live their lives without being forced to focus on their disease or its treatment. With that, I'll hand it over to Dr. Alan Krasner, our Chief Endocrinologist, to talk about our clinical study and the results we're seeing to date. Alan?

Thank you, Scott. As you know, today, we're reporting an initial data snapshot from our ongoing Phase II study in patients with carcinoid syndrome. Slide 5 highlights the Phase II study design. This is an open-label parallel group study that enrolled patients who are either naive to SRL treatment or who are currently untreated and actively symptomatic, or who are controlled on SRL therapy and willing to washout of this medication prior to entry. Participants were randomized to receive 1 of 2 initial doses of oral paltusotine, either 40 milligrams or 80 milligrams daily. In the first 4 weeks, patients have an opportunity to uptitrate or starting dose of paltusotine by 40 milligrams based on prespecified criteria for symptom arsenic. In other words, patients randomized to the starting dose of 40 milligrams could be uptitrated to 80 milligrams during the first 4-week treatment. Those randomized to the 80-milligram starting dose would be uptitrated to 120 milligrams. The dose could be downtitrated at any time for tolerability concerns. In the second 4-week period, the participants remained on a stable dose. Patients who completed the randomized treatment phase are eligible to participate in a long-term extension thereafter. Safety is assessed as the primary endpoint. Secondarily, we evaluate the pharmacokinetics of paltusotine in this patient population. We begin to understand the efficacy profile of paltusotine, we included exploratory endpoints such as bowel movement and flushing frequencies measured daily in electronic patient diary. In addition, use of rescue medication, biomarkers and a number of patient reported outcomes will help us best understand the overall patient experience on paltusotine. In today's summary of initial results from this study, we will focus on frequencies of the 2 key symptoms as well as the intensities of these symptoms seen to date. Results of biomarker and other supplemental exploratory endpoints are still being collected and will be analyzed and reported with final results. Please remember, this is an ongoing exploratory study and the numbers presented in this presentation will almost certainly change when we have the final data set. That being said, there are early trends in this open-label study that we believe are important to share. Enrollment is now complete with 36 participants. You can see on Slide 6, that as of the time of this data snapshot, 27 patients were included. Of these, approximately 1/3 came into the study naive to medical therapy or currently untreated, and 2/3 washed out of preexisting SRL therapy. 4 of the 27 patients have not yet had 2 weeks of treatment and therefore, only contribute to the safety set. This leaves 23 subjects evaluated for exploratory measures of efficacy. There was one discontinuation from the study due to the need to undergo chemoembolization for liver tumors. 15 patients completed the 8 weeks of the randomized treatment phase of the study. The table on the right shows the breakdown of initial dose assignment by pretrial treatment status. It is interesting to note that very few patients, only 4 out of 15 completers so far, required a change from their initially assigned paltusotine dose. 13 of the 15 participants have elected to continue into the long-term extension as of the time of this data cut. Slide 7 shows the baseline demographics and disease characteristics observed so far. The mean age of approximately 60 years old is consistent with previous trials in this patient population. Most of the participants in this study are either from North America or Latin America. As expected, those who are naive to treatment have a shorter period of time that has elapsed since their carcinoid syndrome diagnosis compared to those who entered the study already treated. Carcinoid syndrome is caused by well-differentiated neuroendocrine tumors, either grade 1 or 2, which are defined by cell division activity in the patient's tumor. The balance between the 2 tumor grade groups is shown here. Let's start with available data so far on the pharmacokinetics of paltusotine, seen on Slide 8. Intestinal hypermotility is characteristic of carcinoid syndrome. Furthermore, many of these patients have undergone partial bowel resections as part of surgical treatment for their underlying neuroendocrine tumors. Before proceeding to Phase III, we wanted to make sure that the pharmacokinetic exposure in this patient population would be adequate to achieve therapeutic responses. This slide confirms that drug concentrations before and after dosing are at least as robust as those seen in previous studies in healthy volunteers. We are looking at small sample sizes so far, and these data will, of course, be filled in as the study completes. These PK results, which suggests that drug exposure is not diminished by the disease, are consistent with the exploratory efficacy data that we will be reviewing shortly. Slide 9 shows a summary of safety data to date. Overall, paltusotine was well tolerated, with no severe or serious treatment-related adverse events. We are seeing a higher background incidence of nontreatment-related SAEs compared to what we saw in our acromegaly trial, which is not surprising, given that carcinoid syndrome is caused by advanced neuroendocrine tumors usually in the setting of disease metastatic to the liver. 3 participants to date have experienced nontreatment-related serious adverse events. One of the SAEs was heart failure, likely related to carcinoid heart disease, which unfortunately led to a nontreatment-related fatal outcome 26 days after study discontinuation. The most common reported adverse events overall were diarrhea, headache and abdominal pain, all common symptoms in this patient population. At this time, we are not seeing evidence for new drug-related safety concerns or a dose relationship to AE incident. But again, I want to remind you, this is an ongoing study. Now let's look at what we are seeing so far with respect to the frequencies of the key symptoms of carcinoid syndrome on Slide 10. As Scott discussed at the top of the call, it can be normal for adults to have up to 3 bowel movements per day. In this patient population, the number of excess bowel movements can be attributed to the patient's carcinoid syndrome. The reasonable therapeutic goal for this population is to reduce bowel movement frequency to 3 or 0 per day, that is to eliminate the excess bowel movements caused by the syndrome. On the left side of the slide, we are showing the average daily frequency of excess bowel movements in patients who had greater than 3 bowel movements per day at baseline. To orient you, 0 on the Y axis indicates the upper limit of the normal bowel movement frequency range or 3 per day. So far, we are seeing that paltusotine is associated with a 65% reduction in excess bowel movement frequency in these patients. In the case of flushing, every true carcinoid flush is abnormal, however, an average of less than one per day can be considered well controlled. In patients who are -- who experienced flushing one or more events per day at baseline, paltusotine so far is also associated with a reduction of 65% in the 19 patients analyzed. When we look at all the participants on an individual basis, we can see that paltusotine was associated with reductions in bowel movement frequencies for those who need this therapeutic effect and not in those who don't. We see in the left half of Slide 11 that most participants who experienced greater than 3 bowel movements per day at baseline reported reductions in bowel movements of and into the normal range. There was an average reduction of 1.9 bowel movements per day which previous literature would suggest as well into the clinically meaningful range. In contrast, the right side depicts participants who were in the normal range of bowel movement frequency at baseline. As expected for an SRL, there is no evidence that paltusotine will interfere with normal background bowel moments that are not due to carcinoid syndrome. Slide 12 shows individual patient data for flushing episodes. 19 out of 23 participants in the snapshot started with at least one flushing event per day on average, and we can see that paltusotine resulted in improvements, often into the well-controlled range in the majority of these participants. The average reduction of flushing events in this group was 2 per day. Those who are well controlled at baseline remained within the controlled range. On Slide 13, we see that the reductions in carcinoid-related bowel movement frequency occurred quite rapidly and were sustained during this 8-week period of observation in both the untreated patient population on the left and those that are switching off of injected SRL and washing out on the right. You will note that these graphs include all 23 participants for whom we have efficacy data, regardless of their baseline frequency of bowel movement. The mean baselines would be higher if we focused on those with abnormal bowel movement frequencies only. Regardless, the degree of bowel movement controlled on treatment with paltusotine is very comparable to what would be expected with SRL treatment. When we look at flushing frequency over time on Slide 14, we see the same pattern. There is a rapid reduction in flushing episode frequency after 2 weeks on paltusotine, with a sustained effect through 8 weeks. Likewise, the degree of flushing control on treatment with paltusotine is comparable to what would be expected with SRL treatment. Although the number of symptomatic events is an important measure of the burden in the disease, the intensity of the symptoms are also critical to take into account when one assesses the overall control experienced by the patient. On Slide 15, we see that the number of episodes described by participants as associated with the urgent need to have a bowel movement are reduced with paltusotine. Relief from the unpredictable need to run to the bathroom is likely to be enormously important to these patients. We measured the intensity of flushing on a 0- to 10-point numeric scale. You can see that the severity of flushing episodes is also reduced. What can be lost in reporting the summaries of group data is what somatostatin receptor ligand therapy can mean to individuals living with carcinoid syndrome. I'd like to share the experience of 2 individuals who have participated in this study, which brings this point home for me. The first person, who's symptom burdened, over time is illustrated on Slide 16, was recently diagnosed with carcinoid syndrome and had not been on prior medical therapy. Although bowel movement frequencies are elevated at baseline, in this person, flushing is the dominant symptom with up to 9 episodes per day during the pretreatment period. Flushing is the hallmark symptom of carcinoid syndrome that occurs in 85% of patients. Although other rare diseases and some drugs can cause pathologic flushing, a classic carcinoid flush, which turns the face neck and upper chest deep red, violaceous or purple, is highly distinctive and specific for this condition. Flushes are vasodilatory events, which can be quite symptomatic and associated with falling blood pressure and increasing heart rate. In extreme cases, this process can lead to life-threatening episodes of hypotensive carcinoid crisis. In this case, the day after starting paltusotine, you see bowel movements coming into the normal range of 3 or less per day, and even more impressively, flushing episodes completely dropped to 0 and stay at 0 thereafter. Historically, only SRLs have been able to provide rapid relief of both diarrhea and flushing in a similar manner. The rapid and sometimes dramatic relief in both diarrhea and flushing we saw in participants like this encourages us about the potential of paltusotine in this clinical setting. It is surprising to me that a significant number of patients with carcinoid syndrome who might benefit from SRL therapy are not on the approved therapies now. For an actively symptomatic patient that has not yet started medical therapy, this kind of experience seen in our study excites me about the potential for paltusotine, to someday offer an oral alternative at the time of diagnosis, rather than committing someone to painful depot injections for long-term therapy of indefinite duration. The next example on Slide 17 comes from a participant who is controlled on short-acting octreotide and washed out of the drug prior to starting paltusotine. One can see the rise in both flushing frequency and especially bowel movement frequency during the washout. Secretory diarrhea occurs in 80% of patients with carcinoid syndrome and varies from a few excess bowel movements to over 30 per day. In this case, the patient quickly rose to a peak of 10 bowel movements per day when washing out of the short-acting octreotide. You can imagine for yourselves how disruptive this kind of symptom frequency could be to one's daily life. When paltusotine has started, we see once again rapid symptom responses and by the end of the treatment period, normalization of bowel movement frequency and good control of flushing. I would point out that the initial symptom responses were good, but did not meet protocol criteria for adequate symptom control, and this patient's initial paltusotine dose of 40 milligrams was uptitrated to 80 milligrams. This was the dose that was associated with the excellent results seen in the latter part of the treatment period. Recall current injected SRLs are approved only at the same doses that are effective in acromegaly, whereas clinical literature indicates there are carcinoid syndrome patients who benefit from higher than approved doses of octreotide. The possibility that some patients may benefit from 2x or higher than paltusotine's acromegaly dose was built into the dose range selected for evaluation in this study. We need to evaluate the final data set before proposing a dose or dose range for Phase III. This participant study experience also inspires me because I imagine that a number of patients currently receiving burdensome injection therapy that often achieve only inconsistent control symptoms might be interested someday and switching to a steady, daily oral alternative. To summarize, even in this initial data cut, the goals for this study have already been exceeded. We observed reductions in the frequency and severity of the key symptoms of carcinoid syndrome. Paltusotine was well tolerated and has had no severe or serious treatment-related adverse events to date. The pharmacokinetics was generally consistent with previous studies. The Phase II study has now completed enrollment, with 36 total participants, and we are on track to report the full data in the first half of the next year. We believe the initial data reported here provides a strong foundation to begin preparations for Phase III. Assuming the analysis of all study participants confirms what we're seeing today. We plan to submit the complete data from this study to the FDA in the first half of the year to align on the Phase III design. I will now hand the call back to Scott for final remarks.

Thanks, Alan. In the coming months will be exciting times in paltusotine's development. As you may recall, we anticipate results from our second Phase III study of paltusotine and acromegaly, PATHFNDR-2, in the first quarter of 2024. This study evaluates the safety and efficacy of paltusotine in patients with uncontrolled acromegaly. If positive, these results, together with the successful PATHFNDR-1 study we reported in September, will form the basis of our acromegaly NDA submission in 2024. Finally, our open-label extension studies in acromegaly are ongoing. Over 175 patients have enrolled to date, with some of these patients having now been on paltusotine for more than 3 years. The full results from today's Phase II study in carcinoid syndrome are expected in the first half of next year. This will guide our discussions with the FDA. Pending those discussions, we hope to begin a Phase III study later next year. To conclude, we're very excited about the potential of paltusotine, and today's results bring us another step closer to delivering a much needed therapy to those living with carcinoid syndrome. Let me close by taking a moment to thank all the patients who participated in this study and took time out of their lives to help everyone with carcinoid syndrome. I'd also like to thank all the investigators, site staff and Crinetizens who worked so hard to make this study a success. Thank you all for listening today, and we'll now be happy to take your questions.

[Operator Instructions] Our first question comes from the line of Yasmeen Rahimi with Piper Sandler.

Congratulations to the data. Team, I think, in the last few weeks, as analysts and investors have been bothering you with asking you how do we know this data is going to work or if paltusotine works, and carcinoid syndrome, you have been very clear in saying it's not a function of working or not. It's a function of figuring out what the next steps are. And I think today's presentation made that very clear. Again, with this data on hand, as the purpose of the study is to determine the dose moving forward and potential endpoints to discuss with the agency, could you maybe comment on what your preliminary proposal is based on this interim data. Part 2, what do you need to gain from the totality of the data and the full cohort to maybe inform you more on how those discussions will be with the FDA? And then one last follow-up, if I may ask.

Thanks. Yas, this molecule has been doing everything we've asked about -- asked it for and very excited to get to next steps. Let me let Dana Pizzuti answer that question as we think about regulatory strategy for carcinoid syndrome.

Thanks for the question, Yas. As far as the endpoints, right, and the dose go, we still have a lot to learn. We're pretty excited, though, about what we're seeing so far. As far as the dose goes, as Alan has reflected, we are pretty confident that the 40 or 80 are in the right range for what we need this drug to do. I think as we get the rest of the population through the trial, as you noted in the beginning, only half of them have gone to the complete 8 weeks. We should have much more confidence in that and see whether or not one dose or the other has an advantage. As far as the endpoints go, what is clear is that the most important thing is reducing the symptoms for these patients. And the way that we're configuring our target for this compound is that the drug needs to reduce whatever symptoms these patients have, and some of them have high numbers of bowel movements, in other words, in other patients, it's flushing that really needs to be addressed. And so we'll be looking at the full data set to see what the best way is to describe that and to configure a study that will most clearly sort of [ build ] the efficacy. I think that's -- I think I hit your questions. You said you had a follow-up, though.

Yes. I guess the follow-up is, I think you guys did a nice job to kind of break down the data, and for bowel movement, for example, greater than 3 and then patients who have less than 3. Have you looked at the market in terms of like what percentage of carcinoid patients have greater than 3 movements. And same thing, I think you gave up for flushing, it's greater than one. What percentage of the total market captures that? And is there a thought process to maybe only go after those patients in a larger pivotal study? And I'll jump back into the queue.

Thanks, Yas. So the short answer is I don't think that we've looked carefully at the market per se as to who suffers from flushing and who suffers from bowel movements. But it's a dynamic answer, and it might be that 1 month, it's the bowel movements that are the problem. And the next week, it's the flushing. So I think you have to -- and our goal is to develop therapy than clinical trial design that addresses all of these patients with symptomatic neuroendocrine tumors relieve whatever symptom it is that is facing them in that month.

I agree with that. I have to say though that by definition, I would imagine most patients who are diagnosed with carcinoid syndrome would be either of the criteria, either flushing or bowel movements exceeding 3 at any given time, not mentioning though, that can change over time, the pattern the patients see can change over time.

Congrats again, team.

Thanks, Yas.

Our next question comes from the line of Jessica Fye with JPMorgan.

Congrats on the results. So a couple of questions on the data. On Slide 11, it looks like there are 3 patients who have at least 3 bowel movements per day at baseline who did not experience a decrease on paltusotine. I'm curious if those were switch patients or naive, and in general, if you saw any characteristics that might predict response to drug. And then second, on Slide 13 and 14, the efficacy in the treatment-experienced patients, does it seem like it quite gets back to where it was during the screening period on the SSL -- sorry, SRL. So I'm curious if there's anything you make of that.

Alan, do you want to take that one?

Well, no, we have not identified predictors of response for paltusotine. Again, we're very early in this ongoing study. I'm thinking back to the experience with octreotide and lanreotide. Not all patients are responders to those drugs either, and in fact, in certain cases, patients can respond with respect to their flushing but not so much to their diarrhea and vice versa in some cases. But in general, if you look at the meta-analysis of the carcinoid syndrome literature, 60%, 70% of patients have what are considered meaningful responses to SRL. Is that helpful?

And then she was asking about [ squinting ] hard at bowel movement's time course.

Yes, I would prefer to wait till the final data to make any conclusions about that kind of thing. I would say, though, that the response is there, and it looks a lot like other studies of SRL to me.

Our next question comes from the line of Joseph Schwartz with Leerink Partners.

Congrats on another nice win. I was wondering, I found it interesting and maybe even counterintuitive that patients with CS had numerically higher exposure to paltusotine than healthy volunteers. So why do you think that is? And then I have a follow-up.

Well, I think it's a little early and perhaps that's the danger of presenting data that's part of a study. So I think those [ error bars ] say that it's completely overlapping. And in the footnote of Slide 8, you'll notice the number of patients that are available at each of those samples. And of course, we're collecting the rest of the data now, and we'll see it in the big data set. But it's too early to say whether there's a difference per se or not. I think we were trying with the study to rule out a problem because of the increased gastric motility or surgical alterations and that seems to be pretty much off the table.

Okay. That's fair. And then I noticed that there were some patients who were naive to SRLs in the study. So I was wondering if you could talk about whether there's any read through from the experience for the naive patients with CS in this trial and what that could mean for the PATHFNDR-2 study of naive patients with acromegaly.

Yes, that's interesting. I mean, to me, naive patients with acromegaly respond by lowering IGF-1 to SRLs in general. And I would hope and expect to see the same thing with paltusotine. The response in carcinoid syndrome patients tends to be a reduction in these symptoms, sometimes dramatic reductions, which really can only be seen with SRL. It goes through the same receptor mechanism in both cases, however, the -- and if the endpoints are different. The other difference between the 2 populations might be the effective dose range for these agents. As I mentioned during my presentation, acromegaly kind of has a peak response at the top of the approved dose levels for the SRL. In the case of carcinoid syndrome, it's been shown in the literature that if you go above the approved dose range, you can actually get improved symptom responses in carcinoid syndrome. And that's what we're beginning to evaluate in this study with paltusotine. As I mentioned, we're harboring the dose range that starts at the paltusotine dose -- at the acromegaly dose for paltusotine, which is 40 milligrams. And we're going 2x above that, if necessary, or above that, if necessary. So I think we're going to capture what's optimal for carcinoid syndrome patients in this study.

Our next question comes from the line of Brian Skorney with Robert W. Baird.

I guess my question is really, if you could kind of walk through, I know there was a titration step in the study to get upsell 120 mg. I wonder if you could just kind of walk us through what the criteria were for up-dosing down dosing again? And what do you see, if any, difference in terms of efficacy or safety as you titrate up?

Thanks, Brian. Alan, why don't you take that one?

Yes. So, so far, it's too early to comment on whether we see increased efficacy in the small number of patients who have titrated. But I must say I'm impressed by the fact that very few seem to need to uptitrate during this 8-week core portion of the study, I mean, that's actually quite encouraging. The criteria for uptitration are based on numbers of bowel movements and/or flushing episodes that are defined in the protocol. These criteria are actually fairly complex to go through in detail. However, they are based on published papers, particularly the registrational trial for the approval of octreotide. Our criteria are quite similar.

I do think, Brian that one thing that to me was really remarkable is how fast some of these symptoms respond. It is essentially the next day in those 2 examples we showed, which is why we wanted to show them.

Our next question comes from the line of Gavin Clark-Gartner with Evercore.

Congrats on the data. Just one question on your Phase III plans. Is your base case to do a placebo-controlled trial or a head-to-head versus injectable trial? Maybe regardless of what the FDA may or may not tell you, what would be your preference for carcinoid?

Well, I can start off here. So it is correct that the most recent approval in carcinoid syndrome was a 3-month placebo-controlled trial. It is also correct in our experience, at least that the FDA tends to -- for placebo-controlled trials, I suspect that's where we're headed. But we are not yet complete with our Phase III proposal. We need our data from this study to kind of finalize that plan. And then as we mentioned, we'll be having those discussions with the FDA next year to finalize the plans for Phase III.

Sounds good. Congrats on the data.

Thanks, Gavin.

Our next question comes from the line of Catherine Novack with Jones Research.

Congrats on the data. I was wondering those patients, I know it's a small sample size, but who responded well with regard to bowel movements, are they the same who had improvement in flushing? And if it's not the case, how can you balance these 2 endpoints in the Phase III design? Is there one symptom that is potentially more meaningful if they're not highly correlated?

Thanks for the question. Well, we're still looking at the correlation between the responses for one symptom and the other one. And so as far as our thinking, it's still evolving along those lines. But I think that definitely our approach will be that we want this drug to be useful for patients that have either one or the other symptoms, right, or both. But that we will try to put together a study design where the most troublesome symptom or the most important symptom for the patient would be one we look at in particular. But then we'll keep tabs on everything that's happening with the patient as well. But because of the nature of this disease, with its sort of waxing and waning and then the presence of both of these symptoms at different times in patients, we need to be as thorough as possible in terms of how we keep track of everything. I don't know if that answers your question.

And I might add too, Catherine, it's not just about capturing the primary endpoint. I mean that's obviously important. But I think it's about capturing the impact on the overall health and well-being of these patients. So it's a number of the frequency of bowel movements or the frequency of flushing is obviously very important, but in many ways, the urgency or the severity is also really important in these. One of our consultants said urgency may only be steps away from incontinent, and we need to find ways to capture that. We're measuring many more things than we showed today, and we'll be diving through that, figuring out the best set of primary and secondary endpoints to manage both our statistical requirements in a pivotal study as well as building a label that will provide the best guidance for patients and their physicians about how to use this drug.

Our next question comes from the line of Leland Gershell with Oppenheimer & Co.

Great to see these terrific carcinoid data. Just a question for me. Just to clarify, Alan, had you actually titrated -- were there patients who were actually titrated up to 120 during the 8 weeks, it seemed like your earlier comments indicated there were, but in the slides, it wasn't clear.

No. Actually, in this data cut, no. But again, the study is still ongoing, and we also have patients rolling over into the long-term extension study. And in that part of the study, physicians -- the investigators, the physicians have complete control over titration of the drug. But we have very little information right now on the 120-milligram dose, so far, in this group of patients, it doesn't seem to be needed too much.

Got it. So are you able to comment on in the open label, how many need to go up to 120, or should we wait for that to come out later?

I'm aware of 2 that have gone to the dose, but this is anecdotal information, it's not official results. And I can't tell you yet how that's done, but I can tell you that we have a very talented team watching over these patients, and I haven't heard of any safety signals so far.

Our next question comes from the line of Douglas Tsao with H.C. Wainwright.

And congrats on the data. So just maybe following up, Alan, quickly on that last point. I mean would you anticipate bringing forward all 3 doses into the Phase III? I mean just given the safety profile, it would seem potentially that you could just simply advance the 80 milligram, but it sounds like a couple of patients at least benefited from the 120. So just curious how you're thinking about that.

I think it's a little too early to tell, Doug. We're going to see when everybody gets through the 8 weeks, what we needed to do or what the investigators decided to do in terms of uptitration. But so far, in this initial group of the 15 that went through 8 weeks, most of them stayed on the original dose that they were assigned to in the randomization. So in our mind, we don't see the necessity to go up to 120 very often.

Yes. And I'll remind -- thanks, Doug, by the way. And I'll also remind the audience that dose uptitration is in response to not adequately getting the control you want. And that's true both in the PATHFNDR studies for acromegaly and here. But there very well may be some patients who you just can't get to an improved response and going up from 40 to 80 or going up from 80 to 120 may not result in an improvement. So we have to look at what actually the effect of that was on the individual patients, just like we have to in acromegaly, to really get a better sense of the dose range, dose response characteristics of paltusotine.

Okay. Great. And then just as a follow-up, I mean there isn't, I don't believe, FDA guidance on carcinoid syndrome and obviously, there are fewer clear precedents in terms of Phase III trials right now. But would you anticipate trying to enroll a study with 2 different stratums of both treatment naive as well as untreated patients or treatment naive in untreated patients as well as switches to just be able to have as much of the patient population covered as you could and for the commercial opportunity?

Thanks, Doug. Yes, I mean, and that's exactly what we did here. So I do think we want to make sure and cover as broad a population in our Phase III study as we can. And our expectation is that it should only be a single Phase III study. You have to confirm this, but that would be our expectation. So I want to make sure we get the most out of it. And that means looking at patients with both switching from existing therapy and who may be newly diagnosed or for some reason have not been on therapy for a while.

There are no further questions in the queue. I'd like to hand the call back to management for closing remarks.

Thank you, everybody, and especially our East Coast friends. Thanks for staying into the evening to talk to us, and we're very happy with these results. Look forward to Phase III as soon as possible and have a nice evening.

Ladies and gentlemen, this does conclude today's teleconference. Thank you for your participation. You may disconnect your lines at this time, and have a wonderful day.