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

Good afternoon, ladies and gentlemen, and welcome to the Crinetics Phase II Data conference call. [Operator Instructions] Following the presentation, we will conduct a question-and-answer session. [Operator Instructions] This call is being recorded on Tuesday, the 12th of March 2024. I would now like to turn the conference over to Corey Davis. Please go ahead.

Thanks, John. Good afternoon, everyone, and thanks for joining us to discuss the Phase II top line results with paltusotine for carcinoid syndrome. Joining me today are Dr. Scott Struthers, Founder and CEO; and Dr. Alan Krasner, Chief Endocrinologist. Then also joining for the Q&A section of the call will be Dr. Dana Pizzuti, Chief Medical and Development Officer; and Jim Hassard, Chief Commercial Officer. Before we begin, I'll point out there's a slide deck for today's presentation, which can be viewed with the Events and Presentations link on the Investors page of the Crinetics website. In addition, a news release was issued today and is also available on the 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 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'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, March 12, 2024. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events and circumstances after the date of this call. I'll now hand the call over to Scott. Please go ahead.

Thank you, Corey. Good afternoon, everyone. Thanks for joining us today. Let me cut to the chase. Flushing and diarrhea are the key symptoms experienced by people living with carcinoid syndrome. As you can readily see on Slide 3, paltusotine demonstrated meaningful reductions in both frequency and severity of flushing episodes and bowel movements in our open-label Phase II study. These effects were rapid and they were sustained. Each of the endpoints shown here supports this conclusion. Paltusotine continues to be generally well tolerated with no new safety findings. These results from the full cohort of 36 patients are all consistent with the preliminary data we reported last December. Overall, we believe the safety and efficacy profile of paltusotine in this Phase II carcinoid syndrome study supports progressing into a Phase III study with all due haste. We plan to discuss these results with the FDA and align on a Phase III study design as soon as possible. At the same time, we have launched all of the underlying activities necessary to kick off a global Phase III trial. They are highly experienced Crinetics teams working hard on all aspects of this program. We hope to activate sites and begin enrolling patients by the end of the year. From the very beginning, paltusotine was very much designed with the needs of the patients in mind. The current standard of care for people living with either acromegaly or carcinoid syndrome are painful injections given intramuscularly or deep subcutaneously, most often these require administration by a health care professional. For many, the injections were off too soon, and then the patients experience breakthrough symptoms. So instead of 1 monthly injection, many patients have to take more frequent injections, sometimes every 2 or 3 weeks. Imagine managing all of this in addition to dealing with your disease and the rest of everyday life. Imagine what consistent symptom control with a daily oral tablet could mean to someone living with carcinoid syndrome. Our vision for paltusotine is to help patients focus on living their life, not managing their treatment. I believe we are a major step closer to that vision today. With that, I will hand it over to Dr. Alan Krasner, our Chief Endocrinologist, and he will talk about the results from today's study and how it supports this vision for paltusotine. Alan?

Thank you, Scott. I'll begin by reviewing the carcinoid syndrome and the ongoing unmet needs for patients with this disorder. Roughly 20% of all neuroendocrine tumors result in carcinoid syndrome. The syndrome arises from intestinal neuroendocrine tumors that metastasize to the liver. From the liver, the tumor can secrete serotonin and other factors directly into the systemic circulation. This results in the 2 key symptoms of carcinoid syndrome, flushing and diarrhea. At best, these symptoms are terribly disruptive to a person trying to lead a normal life. At their worst, they can be life threatening due to massive dehydration episodes of hypotension and other medical complications. The current standard of care is injected monthly depot somatostatin receptor ligands or SRLs. SRLs can be quite effective. However, these injections use painful, large gauge needles, and can lead behind subcutaneous nodules and cause other injection site reactions. They often require a health care professional to administer. And even when they are administered by trained professionals, many of these injections are not delivered consistently and accurately despite best efforts. Further, many patients experience unpredictable breakthrough symptoms while taking long-acting depots and a significant number needs to take bolus injections of short-acting octreotide on top of their depot. Our goal for paltusotine in treating people living with carcinoid syndrome is to provide a simple once-daily oral treatment that can alleviate symptoms without the burden imposed by the monthly injections. To achieve this goal, we began by evaluating safety, pharmacokinetics and symptom responses in the Phase II study we will now review. Let's first review the study design, shown on Slide 6. 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 wash out 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 their dose of paltusotine by 40 milligrams based on prespecified criteria for symptom worsening. In other words, patients randomized to the starting dose of 40 milligrams could be uptitrated to 80 milligrams during the first 4 weeks of treatment. Those randomized to the 80-milligram starting dose could be up-titrated to 120 milligrams. The dose could be down titrated at any time for tolerability concerns. In the second 4-week treatment, the participants remained on stable dose. Patients who have 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. To understand the efficacy profile of paltusotine, we included exploratory endpoints such as bowel movement and flushing frequencies measured daily in electronic patient diaries. In addition, biomarkers and supplemental patient-reported outcomes will help us best to understand the overall patient experience on paltusotine. As shown on Slide 7, a total of 36 subjects entered the randomized treatment phase. 18 participants were randomized into each dosing group, 40 or 80 milligrams. You can see the balance between naive untreated patients and those who switched from injections to paltusotine after a brief washout on the 2 different starting doses in the table on the right. After randomization, there were 6 participants who discontinued the study. A total of 9 participants increased their dose at week 2 or 4. Six from the 40-milligram increased to 80 milligrams and 3 from the 80-milligram group increased to 120 milligrams. 30 participants completed the randomized treatment phase, and you can see on the left, the breakdown of doses at the end of the randomized treatment phase. A total of 26 participants or 87% of those eligible to rollover entered into the open-label extension phase. Baseline demographics and disease characteristics were consistent across the patient groups. As you can see on Slide 8, 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 patients in this trial had 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. Moving to the data. I think you'll see that the full 36 subject cohort under discussion today confirms the profile we observed in the initial subset of patients we previously reported in December. I'll begin with the pharmacokinetics of paltusotine in this patient population shown here in Slide 9. Intestinal hyper-motility is characteristic of carcinoid syndrome. Furthermore, many of these patients have undergone partial bowel resections as a part of surgical treatment for their underlying neuroendocrine tumors. Because of this, we were interested to learn about drug exposure specifically in this patient population prior to proceeding to a Phase III study. As you can see, this slide confirms that drug concentrations before and after dosing are at least as robust as those seen in previous studies in healthy volunteers in both the 40-milligram and 80-milligram groups. Slide 10 shows a summary of safety data. Overall, paltusotine was well tolerated with no severe or serious treatment-related adverse events. There were 4 nontreatment-related serious adverse events. Adverse event profiles were similar across the 40- and 80-milligram dosing groups. Slide 11 details the most frequent treatment emergent adverse events, most of which were mild to moderate in intensity. The most common reported adverse events overall were consistent with GI symptoms seen in carcinoid syndrome and are also known side effects of SRL therapy. Most of them occurred early after initiating paltusotine and then self-resolved without the need to discontinue study drug. Let's now look at the impact of paltusotine on reducing key symptoms. The hallmark symptom of carcinoid syndrome is flushing. And as you will see from our data, most patients have it with or without super imposed diarrhea. An individual patient can go through periods where one of the others -- one or the other symptom is most frequent and bothersome. And after some time, the other symptom might predominate. Most patients though suffer from an excess of both symptoms during any given time. Survey research has clearly established that the upper limit of normal for bowel movement frequency is 3 per day. Therefore, in a group of patients with known carcinoid syndrome, it is reasonable to focus on those who clearly have an abnormally elevated bowel movement frequency at baseline to have high confidence that the bowel movement frequency changes on treatment actually represent a reduction in daily bowel movements due to the carcinoid syndrome. On the left side of Slide 12, we see the average daily frequency of excess bowel movements in the 16 patients who had greater than 3 bowel movements per day at baseline and completed 8 weeks of treatment. Zero on the Y axis indicates the upper limit of the normal bowel movement frequency range or 3 per day. Paltusotine was associated with a 60% reduction in excess bowel movement frequency in these patients, and this is statistically significant with a p-value of 0.02. In the case of flushing, every flush is highly likely to be due to carcinoid syndrome and abnormal. However, an average of less than 1 per day can be considered controlled. In the 24 patients who experienced more than 1 flushing event per day on average at baseline, paltusotine was associated with a reduction of 63%, which is also statistically significant with a p-value of less than 0.001. Slide 13 shows all the participants on an individual basis. For the 19 participants who experienced greater than 3 bowel movements per day at baseline, paltusotine was associated with reductions in bowel movement frequencies, often into the normal range. There was an average reduction of 1.6 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 movements that may not be due to carcinoid syndrome. When we look at flushing episodes on Slide 14, paltusotine resulted in improvements often into the well-controlled range and the majority of these participants. The average reduction of flushing events in this group was 1.9 per day, and those who were well controlled at baseline remained within the controlled range. As you can see on Slide 15, the reductions in carcinoid related bowel movement frequency occurred quite rapidly, beginning within 1 week and reaching an [ idea ] by 2 weeks after paltusotine initiation. These reductions in frequency were sustained during the 8-week period of observation. This rapid and sustained effect is seen in both the untreated patient population on the left, and those that are switching from injected SRL and washing out on the right. Note that these graphs include available data from all 36 participants who entered the study regardless of their baseline frequency of bowel movements. The degree of bowel movement control on treatment with paltusotine is very comparable to what would be expected with SRL treatment. When we look at flushing frequency over time, shown here on Slide 16, we see the same pattern. There is a rapid reduction in flushing episode frequency over 1 to 2 weeks on paltusotine with a sustained effect through 8 weeks of treatment. Again, this is observed in both the untreated population and those switching from prior SRL therapy. The rapid and sustained reductions in bowel movement and flushing frequencies in this study are consistent with what we observed in December in a smaller subset of patients. Although the number of symptomatic events is an important measure of the burden in this disease, the intensity of the symptoms is also critical to take into account when one assesses the overall therapeutic effect experienced by the patient. Slide 17 shows the overall reduction in the severity of both key carcinoid syndrome symptoms and those who completed 8 weeks of treatment. On the left, the number of bowel movement episodes described by patients as urgent is reduced by 64% with paltusotine. The daily diary completed by the participants in the study defined an urgent bowel movement as one in which one feels the need to rush to the toilet in order to avoid having an accident of fecal incontinence. I believe the value of having significant relief from these episodes speaks for itself. For flushing episodes, we measure the intensity of flushing on a 0- to 10-point numeric scale. You can see on the right that the severity of flushing episodes is reduced by 61%. Both of these reductions are statistically significant compared to baseline with p-values of less than 0.0001. We also looked at this reduction in symptom severity over the course of the 8-week treatment period. On Slide 18, you can see that bowel movement urgency follows the same pattern of rapid reduction over 1 to 2 weeks and was sustained through 8 weeks. Again, this pattern is observed in both untreated patients and those switching from prior SRL. On Slide 19, we see that the severity of flushing episodes also rapidly declined over 1 to 2 weeks of treatment and remain low each week throughout the 8-week period. Moving to Slide 20. As previously discussed, neuroendocrine tumors that cause carcinoid syndrome, secrete serotonin and other factors that may cause the symptoms of the disease. Excess serotonin in the circulation is thought to be a key driver of the diarrhea seen in these patients and may contribute to the flushing as well. Measurements of serotonin itself or a metabolite of serotonin called 5 hydroxy indoleacetic acid or 5-HIAA, are used in clinical practice to help physicians confirm the diagnosis of carcinoid syndrome after a patient presents with unexplained diarrhea and/or flushing. After the diagnosis is confirmed and treatment has started, these biomarkers are not used routinely in clinical practice to monitor response to therapy. Unlike another disease state we study at Crinetics, like acromegaly, biomarkers have not served as registrational endpoints for drug approvals in carcinoid syndrome. Although not a primary endpoint in Phase III, biomarker data are likely to serve as information that supports the mechanism of symptom relief just as it did in this study. Here, we use these biomarker results to assess the strength of their association with the clear symptomatic responses to paltusotine that we have already described. The bar graphs show a comparison of the 2 biomarkers performance as measured by the median percent change from baseline at the end of paltusotine treatment for the naive patients in the previously treated washout patients. We can see that most patients had their biomarker data collected per protocol, and that paltusotine reduced serotonin in naive and washout patients and reduced 5-HIAA in naive patients. These results provide objective evidence for the mechanism of the pharmacodynamic response to paltusotine, and that of the 2 biomarkers, serotonin levels appear to better reflect thematic responses that were seen in both the naive and washout patient groups. These data are extremely valuable as we design a Phase III study, and we look forward to reviewing these and all the data from this study with the FDA. I will now hand it back to Scott for final remarks.

Thanks, Alan. I hope it is clear from Alan's review of the data, why we're so enthusiastic about the potential of paltusotine to help people suffering with carcinoid syndrome. We believe these data summarized on Slide 21 provide a strong foundation to proceed to Phase III study. We plan to submit the totality of the data to the FDA as soon as we can to align on the Phase III design. In the meantime, I've instructed our experienced global development team to initiate manufacturing, site selection and all the other activities necessary to begin a Phase III study by the end of the year. Our commercial group has also been working hard to refine our understanding of both the acromegaly and carcinoid syndrome markets. In the case of carcinoid syndrome, this will assist us in planning the Phase III study for maximum impact on patient health. As you can see here on Slide 22, simple oral administration itself is perceived as a significant benefit on several fronts. It's not just for convenience. The HCPs we interviewed told us that an oral option may make a meaningful difference in the effective delivery of medication as well as relief burden of care, not just on patients, but also on physician offices. Physicians seem very comfortable with the level of symptom relief we have demonstrated in this Phase II study. They also predict they would offer it to their patients and think most patients would prefer the oral option if it receives regulatory approval. Our long-term goal is to bring the benefits of paltusotine to patients around the world. Practically, we will focus on the U.S. first. Our strategy for expanding its impact in the U.S. is illustrated here on Slide 23. Success in the U.S. also lays the foundation for success in other regions around the world. We plan to submit the NDA for acromegaly later this year with potential FDA approval in 2025. If approved, this will be followed rapidly by a commercial launch. We hope to reach the majority of what we believe to be the addressable population of 11,000 patients with acromegaly as we build awareness and experience among HCPs and patients on paltusotine. With today's data, we'll be consulting with the FDA to design a Phase III study that will generate data to support a potential approval for the treatment of carcinoid syndrome patients, both those switching from depot injections and those currently not receiving medical therapy. If approved for carcinoid syndrome, we expect the early adopters will be some of the 10,000 patients currently on injected depots switching to paltusotine. After it is approved, we hope that as experience with paltusotine grows, it will be considered a viable treatment option for many of the approximately 23,000 patients with carcinoid syndrome who have opted not to subject themselves to the monthly depot injections. Today, you've seen that paltusotine continues to deliver. First meeting and exceeding our expectations in acromegaly last fall with the PATHFNDR-1 study results, now meeting and exceeding our expectations in calcinoid syndrome. We're eager to see the results of the second Phase III study in acromegaly patients PATHFNDR-2 later this month. Our open-label extension studies of paltusotine remain ongoing. We have over 175 patients enrolled across both carcinoid syndrome and acromegaly. Some of these patients have now been treated with paltusotine for more than 4 years. Today is an important step in our long-range strategy that in the coming years should lead to tremendous growth and value creation. Later in 2024, when we submit our first NDA and continue advancing additional indications and additional drug candidates. 2025 will be one of the most important inflection points in the company's history as we reach an anticipated acromegaly PDUFA date, leading to a potential approval and launch of our first drug. Going into the second half of this decade, we plan -- we expect to launch paltusotine for carcinoid syndrome and as sales of paltusotine grow, we plan to be self-sustaining. We will continue to invest in our discovery and development efforts. We anticipate multiple launches and a continuous stream of clinical milestones throughout the rest of this decade and beyond. Endocrinology has the potential to impact almost all aspects of human health. There are a lot of patients we can help. Crinetics is just getting started. I'd like to close by thanking all the patients who participated in this carcinoid syndrome study and took time out of their lives to help everybody else with carcinoid syndrome. I'd also like to thank all the investigators, site staff and Crinetics team who worked so hard to make this study a success. Thank you all for being here today. We'll now be happy to take your questions.

[Operator Instructions] Your first question comes from the line of Yas Rahimi from Piper Sandler.

Congrats on the consistent and strong data. Again, I would love to get your insight now that you have the totality of data on hand, and really thoughtful design around the 2 endpoints that you have chosen. If your proposal to the FDA is a co-primary endpoint or we have to choose between one versus another. And then also maybe if you could talk about, given that you will be approved in acromegaly while carcinoid is ongoing, how much of the safety requirement in carcinoid is already covered through acromegaly and what a potential size looks like? And I'm happy to jump back in the queue. Sorry for the little nuance multiple parts to one question.

Yes. And let me ask Dana, our Chief Development Officer to answer.

Yes, sure, Yasmeen. Thanks for the question. With respect to the endpoint for the Phase III, we're still going through the nuances of the data. And what we're seeing, though, is that we provide significant benefit to patients, both with flushing and with elevated bowel movements. And so what we are going to sort of propose to the FDA would be to try to optimize our ability to be able to capture as many of the patients that are affected by the disease as possible. Of course, what we propose will need to be reviewed and approved by them in the Phase III. So right now, it looks like a combination of those 2 end points. But in terms of the statistical hierarchy and things like that, that will have to be sorted out after discussion with the agency. With respect to the size of the study, we are anticipating a -- at this point, placebo-controlled trial between 100 and 150 patients. And to the other part of your question, which was around the size of the safety database, I think that -- again, this is another topic that we'll discuss with the FDA. But the overall safety population will encompass both the carcinoid syndrome patients and the acromegaly patients. So I think that we'll be able to support the safety database in carcinoid with the acromegaly findings too.

Your next question comes from the line of Jessica Fye from JPMorgan.

A couple on the commercial side. I know you described some patient numbers, but how do you think about the relative commercial opportunity for paltusotine in carcinoid relative to acromegaly. And related to that, why do you think 23,000 carcinoid patients are currently untreated? Is that cost a factor? Is it solely the pain from the injections?

Let me ask Jim Hassard, our Chief Commercial Officer, to answer and if Alan needs to follow up, he can.

Thank you, Scott. Thank you, Jessica, for the question. So I think as we showed on Slide #22, 23 the relative opportunity in acromegaly is about 10,000 patients and ironically similar number of patients are treated in carcinoid syndrome. So the one difference there is going to be and likely will be the price. We know already as a benchmark within the marketplace that SRLs are used at a higher dose, and we saw probably similar findings from our Phase II in carcinoid syndrome. And as Scott mentioned, they're oftentimes used more frequently just because of the relative efficacy of the SRL. So that will -- as we have shown and communicated will likely increase the dollar value of carcinoid syndrome versus acromegaly. In terms of the 23,000 patients that are suggested by epidemiology that are not treated, we are currently doing market research, and we discussed this a little bit. We are finding the mild patients, mild carcinoid syndrome patients because of the convenience, because these oncology patients are typically treated either in the hospital outpatient setting or in the community oncology setting. The relative burden in terms of travel and need to go to a health care practitioner is limiting the patients treatment, especially in the mild case. So this is an opportunity that we see, especially with paltusotine as a once-daily oral treatment that we actually see a great opportunity to penetrate that and serve those patients that are among that 23,000.

Your next question comes from the line of Cory Jubinville from LifeSci Capital.

Congrats on yet another strong readout. It's a little surprising to me to see how few patients required dose escalation, especially given how often high-dose injectable SRLs are used in the real-world setting. So curious on your plans about dose selection moving forward into a Phase III study with only 3 patients escalating to the 120 mg dose. Seems like you're hitting a pretty good window within the 40 to 80 mg range. Do you anticipate carrying the 120 mg forward as well? And can you walk us through your algorithm on what specifically determines when a patient dose escalates and to what degree is that defined by symptoms-only versus investigator or patient decisions?

Thanks, Cory, for the question. So I mean, I agree with you. When I look at these results, I'm struck by the fact that we are probably in the therapeutic refectory dose range that we studied -- that we used in the study, the 40 to 80-milligram dose range seems pretty good for most of the patients to me. But underway is a thorough investigation of dose response and exposure response and these analyses will be used to help us make final recommendations in our Phase III trial design. And of course, that will have to be reviewed with the FDA. The criteria used in this study for dose escalation were all written out in the protocol, and they all were based on the frequency of either bowel movements or flushes. So there were very quantitative criteria used to assess whether the patients needed a dose increase.

And if I can just repeat. It's also important to remember that, that dose increase did not -- may or may not have resulted in an improvement in the symptoms. We have yet to do that analysis. So in some part, the dose increase itself was driven by the protocol similar to what we did in the acromegaly studies.

Your next question comes from the line of Jeff Hung from Morgan Stanley.

Just a follow-up on the last question. I know it's a small number of patients, and you said that you haven't looked at the additional analyses to see whether patients have resulted in improvement in symptoms, but anything else notable about the patients' experiences who went to 120 milligrams versus when they were on 80?

Jeff, no, not that I'm aware of actually. We had very few go to 120 so far. And -- but I can't identify any particular either safety or efficacy finding at this time. But I do think that, certainly, it's nice -- even if we don't use the 120 dose someday, it's nice to have safety data in that kind of range from this study.

Maybe a follow-up on the reverse. How many patients had their dose lowered? And then was there any consistency on when this happened?

So dose lowering was always an option based on tolerability. I've only heard of one transient situation where a patient temporarily went down on their dose, but they went back up. And nobody finished the study, as you can see, the 8-week period, I should say, on a lower dose than initiated -- than 40 milligrams. So I don't see an issue with tolerability of the starting dose in this patient population.

Your next question comes from the line of Brian Skorney from Baird.

This is Luke on for Brian. We were just wondering if the AE seeming fairly consistent across arms. Can you speak to the cause of the higher discontinuation rate in the 80 mg arm. Was it due to these patients not having an adequate response at the higher dose? Or was it more related to side effects?

So the discontinuations due to AEs were at least unrelated. And I'm not aware that there's a dose relationship with the AEs, we've looked at this. And so, no, I think this is what you're -- probably just occurred by chance. We did look carefully at all the AEs, including those non-related that resulted in treatment discontinuation.

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

I was just curious -- and congrats on the data. Just when we think about sort of the dosing and what you saw, what was the sort of reason that we saw sort of the down titration? And just given what we saw, did you see a really strong dose response effect that you saw with paltusotine?

No, we really didn't see any dose response with respect to AE occurrence of significance. There was -- generally, when there's a transient down titration in our studies, it's due to the typical GI AEs that you see with SRLs. And as is the case with acromegaly, down-titrations generally are short-lived and patients come back up to the full dose and do well.

But I guess, Alan, was there an interest or was there anything -- reason why some patients -- more patients didn't necessarily titrate up further to perhaps get even more control of symptoms. I mean because I think we saw a 60% reduction in terms of the bowel movements. Some seems to still stay above that 3 sort of normal number. Were those patients given the option to titrate up? And were there some who stayed above and could have but didn't choose to titrate up?

No, no, they did not have the option to further uptitrate beyond the protocol specifications during the 8-week period. However, those who roll over into the long-term extension, there the investigators have control over titrating the dose as they see fit based on tolerability and efficacy. But no, if they were uptitrated per protocol in the 8 weeks, they had to stay at that dose.

Okay. And then just final one for me. I'm sorry if I missed it. So do you anticipate advancing the 120 into the Phase III?

Well, we are doing evaluations to determine if 120 is necessary. And that's, again, that dose response, exposure response, modeling that is an ongoing effort here. So I don't know quite yet whether we would recommend bringing 120 forward into Phase III. But we will certainly have those evaluations to guide us in that decision.

And maybe because I know this is a common question. It might help clarify. Remember, it's not just frequency of these events. It's also severity, and we see a very nice correlation between decreased frequency and decreased severity. So it may be that on overall, people are satisfied and don't think they need to dose escalate. That may be one reason. It's not just to try and get it down to hit some arbitrary number of bowel movements.

Your next question comes from the line of Leland Gershell from Oppenheimer.

My congratulations, great to see another set of compelling data. I wanted to ask with respect to seeing efficacy in the dose ranges between 40 and 80 and similar, as you mentioned, to what we've seen with acromegaly, maybe speak to the potency of the compound. I wanted to ask your thoughts at this point on dosing in the Phase III. Would you also look to be offering 40, 80 milligram? Might it be different? I know you're still pending further analyses of the data in response, but I just wanted to ask about your view today on that.

Yes. This is Dana. As Alan mentioned before, we're still conducting some of the exposure response and dose response analyses as we get the complete data set. But from the results of this trial, both 40 and 80 seem to do quite well. And so right now, we're sort of thinking that as long as there's not a -- any problem in terms of those patients that initiated at 80, we could start there. But I can't say that we have any strong preference for one or the other. We think it will be one of the two or both. We may offer both or they can titrate up according to the protocol as well.

Your next question comes from the line of Jon Wolleben from Citizens JMP.

Congrats on the data. Just a couple for me. Wondering if you think you have a maximum response at 8 weeks? Or do you think this could improve over time? And then how do you think the flushing and bowel movement reductions compare to the injectable SRLs?

That's almost 2 questions, but we'll let it slip for now. So Alan, do you want to address that?

So the first question was, have we seen the maximal reduction in the symptoms? And when I look at the 8-week curve, I see this very rapid decline to any [indiscernible] that persists for 8 weeks. But -- so my prediction is -- and this, by the way, is largely the case with the SRLs, too, the same kind of pattern of response with the injected SRLs. And so I don't have any reason to believe that there would be continued reduction in the symptom occurrence with time, but only longer-term studies would be able to answer that question. Overall, to answer your second question, I believe the kinds of -- first of all, the time course, the tempo of response as well as the magnitude of response when measuring frequency of events is very comparable to what has been described with the injected SRLs.

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

I was wondering if you look to see whether or not there were any differences in response amongst the patients who are naive or untreated versus those that switched from SRLs? And if so, if there might be any insights or read through to the PATHFNDR-2 study in naive patients.

Yes. So just to put some boundaries on this, we're not talking about PATHFNDR in any way today. But we did present some good data here on the washout versus the untreated patients as groups. And I think maybe the most important thing to remember is that we did not fully wash out those patients to see what the full flurried effect of their disease would be completely untreated. That just isn't something anybody would sign up for and it wouldn't be ethical. So to some extent, the patients who would have washed out are starting at a little bit more controlled state of disease. And therefore, I think you see some less magnitudes of benefits in some of the different dimensions. But be that as it may, even as you pull the whole group, the trends are clear, the effects are clear. And that's why we tried to be so transparent, including individual patient data. And that's a standard we set for ourselves almost all the time.

Your next question comes from the line of David Lebowitz from Citi.

I'm curious, looking at the flushing data, why is it that a disproportion number of the early dropouts actually come from the mean baseline flushing group of less than 1 as opposed to the higher group?

Well, I can't answer that question. What I can say is that most patients with real carcinoid syndrome have flushing. And patients who don't have flushing or have very little flushing, I think the question arises how much underlying carcinoid syndrome do they actually have? And whether that -- whether the discontinuations in those cases were related to kind of the sense of having a benefit from an SRL when they have very mild carcinoid syndrome is a question that comes to my mind, but I can't explain it in this particular case in this study.

Your next question comes from the line of Dennis Ding from Jefferies.

Congrats on the data, the symptom control data looks compelling and very promising. But can you remind us your thinking about not having to run a PFS study and what is your level of confidence going into your end of Phase II meeting that the FDA will require a longer PFS study to kind of assess tumor control.

So I'll take that one. This is Scott. A couple of points. One, we are monitoring PFS as part of this in the open-label program because it's important for the baseline management of these patients to see how their tumors are progressing or not. We should all remember this is generally a very slowly progressing disease, unlike many of the other cancers you're used to looking at. And lifespans now, especially after the introduction of the radiopharmaceuticals have been extending greatly, making this a chronic disease for most. So then practically doing a PFS study with paltusotine would be large and difficult and probably not the best use of our funds. Instead, we think that people deserve options beyond just the new radiotherapies. And there's always something going on in our discovery kitchen and one of those things is to find a better approach for all those other patients with NETs that don't have symptomatic disease. So look for that in the -- sometime in the not far distant future, but not right away.

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

Good to see another positive data readout. I'm wondering since FDA doesn't have draft guidance specific to carcinoid syndrome. If you can talk about potential design of proprietary PRO or other novel endpoints that you might need to come up with. What is the process? How long does it take? What kind of data are required? And when will we get an update?

Thanks, Catherine. I'll let maybe both Dana and Alan comment on some of our efforts there.

Yes, sure. Well, from the part of the high level, in terms of the sort of the design of the Phase III study, it will really be about the frequency of the flushing and bowel movement symptoms, right? So it's pretty straightforward that way. And so we expect that it will be fairly straightforward to be able to satisfy the FDA that we are efficacious with those endpoints alone mainly. We, right now, haven't been looking at any other scales, right, that are related to carcinoid in contrast to what we're doing with acromegaly. But we're pretty confident that we won't really need any additional symptomatic efforts to establish the efficacy.

For the primary endpoint.

Yes. And -- but we are -- and even in this study, we have a lot of interesting supplemental questions that I think are on our current electronic patient diary that the patients complete. And they get it very important issues like we discussed -- we showed you the data, for example, on the severity of the symptoms, the urgency of the bowel movements, for example. I see that very much carrying forward into Phase III because I think that whole patient experience package of information is going to be critical. And I expect it to be differentiating as well because if you look at group products, you don't see in their labels, much information other than just numbers of bowel movements or flushing episodes. And so I think there's a lot more to the story than that.

Your next question comes from the line of Gavin Clark-Gartner from Evercore ISI.

Just wondering what your level of confidence is that the FDA will sign off on a placebo-controlled trial? I mean there is the XERMELO precedent that you referenced, 1,000 patients who were not well controlled on somatostatin analog. So I'm just wondering how the FDA thinks about the use of a true placebo here.

Well, we'll find out, obviously, when we go talk with them. But we really feel that the best way to demonstrate efficacy would be against placebo. And there is no guidance, as you're aware, in terms of how they'd like to see the studies designed. I think that one of the important things that we are concerned about with the sort of nature of this disease is that you really can't afford to keep people off of therapy for too long. And therefore, that factors into our considerations for the duration of the trial, too. But in terms of being able to demonstrate efficacy, it really would be much quicker, right, and more straightforward to be able to use the placebo as the control group.

And just as a quick follow-up. It's very problematic to think of what an active control might be blinding an injection versus an oral study would be quite problematic.

Yes, you could indeed wind it unless you gave sham injections to...

Right, and then you'd have to match viscosity and things.

There are no further questions at this time. I will now hand over to Scott Struthers for closing remarks.

Thank you, everybody, for taking time out of your evening to speak with us. I look forward to talking with you all again sometime in the near future. As we've said in the past, PATHFNDR-2 information will be released this month. Thanks again.

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