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

Greetings, and welcome to the Crinetics Pharmaceuticals Conference Call. [Operator Instructions] As a reminder, this conference is being recorded. I would now like to turn the conference over to your host, Mr. Corey Davis. Thank you. You may begin.

Thanks, Melissa, and thank you all for participating in today's call. Earlier this morning, Crinetics issued a news release announcing positive top line data from its Phase II ACROBAT EDGE and EVOLVE trials. If you've not yet seen the release, it's available on the Investors section of the Crinetics Pharmaceuticals website. Before we begin, I'd like to remind you that some of the information contained in the news release and on this call contains forward-looking statements based on current expectations, including statements about the initiation of planned clinical trials. 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 this morning's news release and Crinetics' SEC filings, including its annual report on Form 10-K. I'd also like to point out that the contents of this call contains time-sensitive information that's accurate only as of the date of this live broadcast, October 26, 2020. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. With that, I'd like to turn it over to Dr. Scott Struthers, Founder and CEO of Crinetics. Please go ahead, Scott.

Thanks, Corey, and thanks to all you listening to this call. Today, we will be discussing the results from our Phase II ACROBAT EDGE and EVOLVE trials. Trials evaluated paltusotine, our once-daily oral non-peptide, somatostatin receptor type 2, or SST2 agonist, as a treatment for acromegaly. I'm joined today by Dr. Alan Krasner, our Chief Medical Officer. Before I hand the call over to Alan, I'd like to first discuss the most important high level findings from the program as well as the unmet need and market opportunity for paltusotine. I'm very excited that EDGE -- that the EDGE study met its primary endpoint. Final data demonstrate that once-daily oral paltusotine allows patients in the pre-specified primary analysis group to maintain their IGF levels when switching from injected somatostatin receptor ligands, or SRL's, depot therapy to the standard -- the current standard of care. This result bodes well for our Phase III program as in addition to being the biomarker that physicians use to manage their acromegaly patients. IGF-1 is a Phase III registrational endpoint accepted by regulators around the world. Importantly, after the end of the 13-week treatment period where paltusotine was withdrawn, the data also showed a rise in levels of IGF and growth hormone, another key biomarker. These data characterize the magnitude of the therapeutic activity of oral paltusotine. Post-hoc analysis of data combined from patients in EDGE and EVOLVE show compelling evidence of the dose response. Finally, similar to what we've seen in our healthy volunteer studies, paltusotine was well tolerated in acromegaly patients. With that positive data in mind, I'd like to take a moment to remind our listeners about the high unmet need and large market opportunity for paltusotine. As you can see on this slide, molecules targeting SST2 are currently used to treat both acromegaly and neuroendocrine tumors, an indication that we'll be pursuing in a subsequent clinical trial that I'll discuss at the end of this call. Acromegaly is a rare endocrine disorder, affecting more than 25,000 people in the U.S. As you can see on the left of this slide, acromegaly symptoms are the result of benign pituitary adenomas that secrete excess growth hormone. This growth hormone then acts to the liver to increase IGF-1 levels. Elevations in these hormones, in turn, lead to bone and cartilage overgrowth, organ enlargement, changes in glucose and lipid metabolism as well as a myriad of other symptoms, which the standard of care attempts to address with monthly injections of SRLs, such as octreotide or lanreotide. There are 4 approved injectables that collectively generate about $3.1 billion in revenue in 2019 despite major limitations. Sandostatin, or octreotide, and Somatuline, or lanreotide, are approximately 90% of the market. And in patients on either of these 2 drugs as monotherapy comprise the patients that were the pre-specified primary analysis population in EDGE, i.e. group 1. While these depots are intended to help prevent acromegaly symptoms from interrupting patients' daily life, the therapies themselves are actually quite disruptive. Patients frequently complain about the pain caused by the high-volume viscous injections, which can make even the simple act of sitting down an arduous activity once a month. Because these are intramuscular injections, they usually have to be administered by a healthcare professional, it requires patients to schedule their life around these monthly visits with their healthcare provider. 2 of the newer entrants, pegvisomant, a growth hormone antagonist and pasireotide, a nonselective somatostatin agonist, also has significant limitations. And as a result, comprise only 10% of the market. Patients receiving pegvisomant often have difficulty traveling as the injections are taken daily and require refrigeration. Many of these patients end up buying a separate fridge just for their meds. Pasireotide is also not an ideal therapy as patients taking it are at risk of impaired glucose control and even drug-induced diabetes. It was of these limitations in mind that we designed paltusotine from scratch as a once-daily oral therapy that targets the same receptor as octreotide and lanreotide, but with the obvious benefits that a once-daily oral pill would have, assuming at least equivalent efficacy and safety. Additionally, we think we may be able to further improve patient outcomes simply by switching patients from a monthly depot to daily dosing schedule. Our injected depots are effective at reducing IGF-1 levels, many patients return -- suffer from a return of acromegaly symptoms at the end of each month as the depot wears off. The daily pill could solve this problem as patients would have a consistent exposure throughout the month. Now let's get into the details of the ACROBAT EDGE Phase II study. And for that, I'll hand the call over to our Chief Medical Officer, Dr. Alan Krasner, to go into details about the design and results of this program. Alan, I'll let you take it from here.

Thank you, Scott, and good morning, everyone. I'd like to start by describing the design of the EDGE study conducted at 45 sites across 13 countries. The objective of the study was to demonstrate maintenance of IGF-1 levels as patients switched from their previous injectable medications to paltusotine. The pre-specified primary endpoint was the change in IGF-1 at week 13 of paltusotine treatment versus baseline. The baseline values reflecting biochemical control while previously treated with octreotide or lanreotide monotherapy. The primary hypothesis of the study was that there would be no change in median IGF-1 levels from switching patients to oral paltusotine for 13 weeks. The pre-specified primary analysis population consisted of patients who have previously received depot octreotide or lanreotide monotherapy but had not achieved full normalization of IGF-1 levels. These are referred to as group 1 patients and they constitute the majority of acromegaly patients in clinical practice. I want to emphasize that IGF-1 has been and remains a standard biomarker that is accepted by the FDA for pivotal trials in acromegaly, and a key biomarker used by previously approved drugs in their pivotal program. I'd like to bring your attention now to the study diagram. Patients started the study in a 4- to 6-week screening period, during which time the average of 3 measurements were used to establish the baseline IGF-1 value, while on octreotide or lanreotide. After completing the screening period, all patients started on 10 milligrams per day of paltusotine. IGF-1 levels were measured frequently over the course of the 13-week treatment period, based on these measurements, the dose of paltusotine was potentially increased in 10-milligram increments up to a maximum of 40 milligrams per day at weeks 4, 7 and 10. IGF-1 was measured at the end of the 13-week treatment period for assessment of the primary endpoint. After week 13, paltusotine was withdrawn and patients entered a 4-week washout period. This was intended to provide a measure of paltusotine's IGF-1 suppressive activity as IGF-1 levels were expected to rise as paltusotine washed out. Slide 7 shows both the pre-specified primary analysis population, group 1, and the additional exploratory populations. Group 1 consisted of 25 patients that were taking stable doses of long-acting octreotide or lanreotide monotherapy. Their IGF-1 values at screening were above the upper limit of normal and less than or equal to 2.5x the upper limit of normal. The study also included 4 exploratory patient populations, intended to investigate whether paltusotine might contribute to the care of patients receiving more intensive treatment regimens. Groups 2 and 3 were treated with the combination of either depot octreotide or lanreotide plus the dopamine agonist cabergoline. Group 2 having elevated IGF-1 and Group 3 having normal IGF-1 at baseline. Groups 4 and 5 consisted of patients on the non-selective agonist pasireotide in Group 4, or a combination of octreotide, lanreotide plus the growth hormone receptor antagonist, pegvisomant in Group 5. On Slide 8, you will see that we enrolled a total of 47 patients into EDGE with 25 in the group -- in the primary group 1. We had a low number of dropouts in this trial as 89% of patients completed the study. There were no discontinuations due to adverse events. On Slide 9, you'll see a breakdown of the patient demographics in the EDGE trial. I won't go through the demographic data in detail now as the slides are posted on our website for the interested in taking a deeper dive. I will, however, point out that most group 1 patients were receiving what would be considered full doses of octreotide or lanreotide, which are the most commonly used doses in practice. On Slide 10, you'll see that the EDGE trial met its pre-specified primary endpoint. With respect to IGF-1, there was no statistical difference from baseline to the end of treatment. However, when paltusotine was withdrawn, these patients' median IGF-1 levels rose rapidly to approximately 2x the upper limit of normal versus about 1.3x the upper limit of normal on paltusotine and on the prior SRL therapy. This change after paltusotine washout was statistically significant, and the magnitude of the rise reflects the therapeutic activity of paltusotine. The same was true in measuring growth hormone. Again, paltusotine was able to show maintenance of growth hormone levels after 13 weeks, but when it was withdrawn, we see a rapid increase in growth hormone that is statistically significant. The absolute and change from baseline numbers are shown on Slide 11. We won't review these in detail now as the table is available on our website, but these results are clear and consistent. I do want to point out that the median change from baseline in IGF-1 showed no statistical difference from 0. The median was pre-specified for the primary analysis but we show here the means in this table as well. So you can see there was no important differences due to the method of analysis. At both 2 and 4 weeks into the washout period, IGF-1 levels show statistically significant increases with p-values less than 0.0001 when compared to the end of treatment at week 13. On Slide 12, you will see that the statistical analysis of growth hormone mirrors what we see with IGF-1. And this provides further support for the therapeutic activity of paltusotine. Before diving deeper into the EDGE results, I'd like to take a minute to describe in more detail the design of the study's dose titration period as it is a vital concept that allowed us to extract information regarding the dose-response relationship of paltusotine. As you can see on this slide, all patients started at a 10-milligram daily dose of paltusotine. After 2 weeks on the 10-milligram dose, patients had IGF-1 levels measured. This value at 2 weeks was used to determine whether the patient was up titrated to 20 milligrams at 4 weeks. If paltusotine was well tolerated and if IGF-1 was greater than 0.9x the upper limit of normal, the patient moved to 20 milligrams at week 4. IGF-1 was again measured at week 5 for potential titration to 30 milligrams at week 7. IGF-1 levels above 1x the upper limit of normal at week 8 would trigger the last potential up titration at week 10. Patients then remained on their week 10 dose, which would be a maximum of 40 milligrams until the washout period. Designing EDGE in this way afforded us the opportunity to treat individual patients with varying doses of paltusotine throughout the treatment period. It also allowed us to collect IGF-1 data at each of these dose levels. What you can see in this slide is that the majority of patients received each of the doses all the way to 40 milligrams. This was not surprising since these patients were known not to be biochemically normalized on pretrial SRL therapy. Moving on now to Slide 14. We just showed you the end of treatment and baseline IGF-1 values. This figure shows the entire time course. And you can see that paltusotine maintained the median IGF-1 roughly stably through the treatment period. You can see from the bars just above the x-axis, that the majority of group 1 patients eventually titrated up to the maximum 40-milligram dose of paltusotine. By week 10, 20 out of the 23 patients who completed the dosing period were on the higher doses of 30 and 40 milligrams. After cessation of paltusotine therapy, IGF-1 levels rose rapidly and significantly during the washout period. I'd like now to dive a bit deeper into our efficacy data. On Slide 15 is a graph showing the change from baseline in IGF-1 levels for individual patients at the end of treatment and 4 weeks after paltusotine withdrawal. You can see from the individual data that 87% of group 1 patients, completing 13 weeks of paltusotine treatment, maintain IGF-1 levels within 20% of baseline or lower. Additionally, the data show that 82% of the group 1 patients have at least a 20% rise from baseline in IGF-1 4 weeks after withdrawal of paltusotine. These data will be useful in helping to design and power future Phase III studies in which responder analyses will likely be key. We can also see from these individual data that most patients are responding to paltusotine and the means and meetings are not driven by outliers. Now that we've given you a detailed look at data from EDGE's pre-specified primary analysis population, I'd like to talk about the data from our exploratory populations. Shown on the next slide, on the left is a graph of IGF-1 levels at baseline after paltusotine treatment and 4 weeks after paltusotine withdrawal in patients from group 2 and 3 of the EDGE study. Patients in these groups were previously treated with injected SRL depots in combination with cabergoline, an orally administered dopamine receptor agonist that is used in conjunction with octreotide or lanreotide in a subset of acromegaly patients. By comparing IGF-1 values at these time points, you can see that paltusotine contributes to IGF on lowering in these patients, and that the effect of paltusotine on IGF-1 levels appears to be greater than the effect of cabergoline. Although these patients will not be included in our Phase III program, these results provide useful information for potential future investigations. Finally, I quickly comment on groups 4 and 5. Patients in these 2 groups were included to explore the relative contribution of an SST2 agonist in the few patients in clinical practice who use more intensive regimens and to expand the safety database in a variety of patient populations. Variable effects were seen in these 2 groups with sample sizes of 4 and 3 patients, respectively. There are not enough data here to draw conclusions, and these exploratory subgroups are not planned for inclusion in Phase III. Shifting gears, I would like now to briefly talk about our second Phase II study, the ACROBAT EVOLVE trial, which will lead to a discussion of the combined analysis of both trials. This was a double-blind global clinical trial with a randomized withdrawal design that enroll patients whose IGF-1 levels were at or below the upper limit of normal on octreotide or lanreotide monotherapy. These patients started the study in a 4- to 6-week screening period, during which time 3 IGF-1 measurements were used to establish the baseline value, similar to the procedures used in EDGE. After completion of the screening period, patients began receiving daily doses of paltusotine for a 9-week dose titration period, during which time IGF-1 levels were frequently measured. At the completion of the dose titration period, those patients who had IGF-1 levels below the upper limit of normal were then randomized to continue receiving paltusotine or to receive placebo for a period of 4 weeks. After this randomized withdrawal period, all patients entered a washout period similar to the EDGE study. Ultimately, we decided to halt enrollment in EVOLVE in April of 2020. Because at that point, we had fully enrolled the EDGE study and we had interim data that were supportive of moving forward into Phase III development for the program. By discontinuing enrollment in EVOLVE, we can now include data from the 13 patients that were enrolled as we prepare for our planned end of Phase II meeting with the FDA. Now before getting into the EVOLVE results, I'll quickly run through the design of the study's dose titration period, which was similar to the design employed in EDGE. As you can see here, patients started at a 10-milligram dose of paltusotine after 2 weeks on the 10-milligram dose, patients had IGF-1 measured. If paltusotine was determined to be well-tolerated and IGF-1 was found to be greater than 0.9x the upper limit of normal, the patient would then be titrated up to a 20-milligram dose of paltusotine at week 4. This process would then repeat itself with an IGF-1 measurement at week 5 and a potential change in dose based on that measurement at week 7. Patients then remained on their week 7 dose, which could be a maximum of 30 milligrams until the washout period, unless, of course, they were randomized to the placebo group at week 10. On Slide 19, you can see the EVOLVE IGF-1 data. Although the sample size is too low to make a meaningful statistical comparison, the results seen during the randomized withdrawal period were generally what was to be expected. We see the median IGF-1 levels of patients randomized to paltusotine were below the upper limit of normal, while the median IGF-1 level for placebo patients rose well above this limit during the withdrawal period. In patients who did not randomize, the median IGF-1 level was slightly above the upper limit of normal. This is not surprising as the reason these patients did not randomize was that their IGF-1 levels were above the upper limit of normal at the end of the dose titration period. You can see from the bars just above the x-axis that the majority of all patients entered the randomized withdrawal period without up titrating to the maximal 30-milligram paltusotine dose. Residual activity of pretrial SRLs at week 2 may have prevented patients from uptitrating at week 4, which would ultimately prevent them from reaching the 30-milligram dose within the timeframe of the study. This would hamper our patient's ability to randomize at week 10 as the patient would be less likely to have an IGF-1 level below the upper limit of normal on a lower dose of paltusotine, as we'll see. Despite this, 7 patients did meet criteria to randomize to EVOLVE. Shown on Slide 20 is a post-hoc analysis of EVOLVE and group 1 EDGE patients that provides evidence of a dose response for paltusotine. Each point on these figures show the median steady state IGF-1 levels at the indicated dose. Data from each patient's IGF-1 response while on the indicated doses are shown. Individual patients are represented at multiple dose levels as they up titrated. These results do not include data from prior to week 7 of dosing in order to avoid potential confounding effects from remnants of pretrial long-acting SRL therapies. In the graph on the left, you can see that patients receiving the higher doses of paltusotine remain at or below IGF-1 levels achieved on baseline SRL therapy. These results are consistent with data from the graph on the right, which show that the magnitude of paltusotine activity as measured by change in IGF-1 from the end of treatment to 4 weeks after withdrawal, increases at higher doses. As mentioned earlier, these data provide evidence of a dose response to paltusotine and acromegaly patients previously receiving injected SRL depots. Slide 21 shows a summary of the safety data we have collected on paltusotine to date. Paltusotine was generally well-tolerated across the EDGE and EVOLVE studies. There were no discontinuations due to adverse events or significant unexpected safety findings. In addition, no treatment-related serious adverse events were reported in either study. The most commonly observed adverse events in EDGE and EVOLVE are consistent with those previously described for SRL depot therapy and also some common symptoms of acromegaly. As you can see on the column on the right, many of these acromegaly symptoms were less common in healthy volunteers that have been studied with paltusotine, suggesting that these symptoms observed in EDGE and EVOLVE were likely related to the underlying acromegaly. It is also interesting to note that the incidence of common SRL side effects such as diarrhea, are more frequently seen in healthy volunteers who have not previously been treated with SRLs compared to the acromegaly patients all of whom had previously been treated with these agents. With that, I'd like to conclude my portion of the call with a brief summary of the ACROBAT results before handing the call back over to Scott. As Scott mentioned earlier, our Phase II EDGE trial met its primary endpoint, as we demonstrated that once-daily oral paltusotine maintained IGF-1 levels in our pre-specified primary analysis population after switching from injected octreotide or lanreotide monotherapy. The results also showed a rise in levels of IGF-1 and growth hormone after withdrawal of paltusotine, which characterize the magnitude of the therapeutic activity of paltusotine. Additionally, exploratory analyses demonstrated evidence of a dose response. Finally, our Phase II study showed that paltusotine is well-tolerated, which is consistent with what was seen in Phase I healthy volunteer trials. I'd now like to hand the call back over to Scott, who will discuss the next steps for paltusotine and for Crinetics. Scott?

Thanks, Alan. First, I'm pleased to announce that we'll be hosting a KOL call on November 20 to discuss these results in the context of the current acromegaly treatment landscape. In the near future, we also plan to provide an update on the formulation of paltusotine that we intend to advance towards the market. In parallel, we'll continue to analyze ACROBAT data with the goal of presenting additional data on exposure and response, symptom diaries, patient-reported outcome instruments and all of these at future medical meetings. While this analysis remains ongoing, the top line results we presented today provide us with confidence as we prepare for the end of Phase II meeting with the FDA in the first quarter of next year. After receiving input from regulators, we'll finalize our Phase III development plans with the goal of initiating the registrational study in the first half of next year. As I previously mentioned, we also plan to initiate Phase II trial evaluating paltusotine as the treatment for neuroendocrine tumors, or NETs, in 2021. Today's results from the ACROBAT trials give us additional confidence in this program as the same SRL depot is currently used to treat acromegaly are also used to treat NETs. As we move towards potential regulatory approvals for paltusotine, I want to reiterate that it is covered by a robust IP portfolio, as are all our in-house drug -- discovered drug candidates. We have multiple patents already granted from 2 distinct patent families that extend to 2037 and 2039 without accounting for potential patent term extensions. In addition, we have provisional patent pending for our new formulation with potential term extending into 2041. We also have composition of matter patents for 3 additional classes of non-peptide somatostatin 2 agonist. And finally, paltusotine is eligible for 7 years of market exclusivity in acromegaly upon its approval, which is independent of any patent protection. Briefly, before moving on to the Q&A portion of the call, I'd like to mention that our oral ACTH antagonist and congenital hyperinsulinism programs. Like paltusotine, the lead molecules for these programs target peptide hormone receptors, which is really an extension of the scientific careers of many of us at Crinetics. I myself have been working in this area since I was a fresh and undergrad, which I must have met with a mile -- a little while ago now. This deep organizational experience in endocrinology and peptide receptors and the ability to discover and develop high-quality drugs targeting these receptors is the core competency of Crinetics. Our growing pipeline illustrates one of the truly exciting aspects of endocrinology. Our field is so closely tied to the measurement of blood-based biomarkers that we can significantly derisk clinic programs with clinical proof-of-concept studies and healthy volunteers. This, in turn, translates into value-creating milestones early in clinical development. In both our ACTH and congenital hyperinsulinism programs, we have identified a medical need and an appropriate drug target. For each, our discovery team built what we believe is a best possible candidates. Phase I studies for both programs should initiate shortly. This is particularly exciting because, as you've seen now in the paltusotine development program, both these first-in-human studies will produce key biomarker data in healthy volunteers that should be highly predictive of efficacy in patients. With that, I'd like to extend a big thank you to all our employees, investigators, site staff and especially the patients around the world who have allowed us to make such great progress to date. We'll now open the call to questions. Thank you very much, operator?

[Operator Instructions] Our first question comes from the line of Charles Duncan with Cantor Fitzgerald.

Scott and Alan, congrats. And to your team Congrats on these observations and the results of the ACROBAT study so far. So first of all, thanks also for presenting Slide 14 and 15, the time course and individual response data. That's very helpful. When you think about the patient population and, call it, the 20% increase in IGF-1 post drug in that 4 week, do you think that the sample is representative of the broader patient population that you look forward to studying in Phase III and then for the approved label if the drug is approved? And then also, do you believe that you've identified the optimal dose? Or would there be a desire to evaluate more than 1 dose in the pivotal program?

Thanks, Chaz. Alan, I'll let you answer that one.

Yes, Chaz, I do think that the post withdrawal rise in IGF-1 that was observed in EDGE is likely to also occur in the target Phase III patient population. That's based on not only our experience in the EVOLVE study, but also the experience of others in the published literature. The dose range that we've identified in the studies -- in these studies is clearly -- captures a large degree of the dose range that we would target for Phase III, whether we are doing additional analyses to look at both exposure and dose response modeling. So that we will have a thorough understanding of this by the time we meet with the FDA for our end of Phase II meeting. So we don't know yet exactly the final doses that we would propose for Phase III, but we certainly have identified an effective dose range.

Okay. And if I could add -- ask one additional follow-up. With regard to the formulation work that you're doing, I imagine that the dosing that you mentioned -- just mentioned, would you anticipate a bridging study? Or do you think that the exposure response data that you'll have will be sufficient for the Phase III to start in '21? And then with regard to a responder analysis, Scott -- or I believe you mentioned, looking at the individual responses, what kind of levels of response would be interesting to and be clinically meaningful to discern in Phase III?

So the -- in terms of the new formulation, we've been doing extensive work characterizing that recently in healthy volunteers and should be able to provide an update on that in the not-too-distant future. So there won't be additional bridging work because we will -- well, there might be some minor things, but we'll be using the final commercial formulation as part of the Phase III. So after that, there is not additional bridging work required. And then in terms of meaningful responders in the Phase III, I'm not quite sure I understood your question. But I think the important thing to note in the data today is that here we have data that shows both physicians and patients that they can change from a current standard of care first-line depot to a once-a-day oral and not risk loss of control of IGF-1, or at least the vast majority of patients should not risk loss of control with IGF-1. And we find that super encouraging. And that, I think, will be an important component of the Phase III program.

Yes. I guess, Scott, I was asking about a slightly different paradigm, and that is for naive patients to come on to paltusotine, what kind of response rate would you look for to be clinically meaningful? So these are not switching.

Yes. Misunderstood that at 5:30 in Pacific Time. Sorry. Yes. So when a newly diagnosed patient or somebody new to medical therapy first goes on somatostatin analogs, 90%, 95% of them show reductions in IGF. And to almost any extent, a reduction in IGF is a good thing. And so I think most of those patients benefit from somatostatin analog therapy like paltusotine. Now unfortunately, with the mechanism, only about 30% of diagnosed -- newly diagnosed patients will all -- get all the way down to normal levels of IGF-1. And that's where the EDGE population that we studied here today represents the other 70% or so. So while there's not a particular number that one should focus on for a percent reduction, reducing IGF levels is generally beneficial to both quality of life and morbidity and mortality.

And can we assume that you'll be presenting patient-reported outcome information at the upcoming KOL event?

I'm not sure if we're going to have it done by then; we're digging through. That's a ton of data, but we'll get that out as soon as we can.

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

This is Joori dialing for Joe. I guess my first one is on the data that you presented today. Could you talk a little bit about the patients who receive the different doses of paltusotine? Were you able to characterize them or speak to any differences you may have found from patients who received 40 migs over the other doses?

Alan, do you want to answer that?

Thank you for the question. We don't have evidence of baseline characteristics, which are predictive of their dose need. Of course, we have a lot of additional analyses and data mining to do. Most patients, as you saw, based on the titration paradigm did require the full dose or the maximal doses in the EDGE study. Again, these were patients who came in with elevated IGF-1 levels on their previous SRL therapy. But no, we will explore baseline and baseline characteristics of patients and their relationship to dose requirement, of course. But as of now, I'm not aware of predictive characteristics.

Okay. That's helpful. And then could you talk a little bit more about how you're likely to design Phase III? If you're only enrolling partially controlled patients like those in EDGE, do you think you'll be able to get uptake or get a label when patients were fully controlled like those in EVOLVE? And do the FDA view these 2 patient population discretely? And will we get any -- I guess, will we get any insight from with -- from your upcoming meeting with the FDA? Or is there any reason why you wouldn't run a Phase III in both partial and full control patients in order to make -- to maximize the pace of Phase III and the impact in the marketplace?

Yes. We do intend to have full discussions with the FDA on the Phase III program. Based on precedent and recent precedents that we do anticipate looking as the core Phase III population, the well-controlled patient population at baseline. That is because the Phase III program would depend on a responder analysis, responder being defined as normal IGF-1 and in treatment. But in addition to that core, well-controlled population in Phase III, we would like to study other patients as well, including those that are not optimally controlled, as you suggest. So we already have data in both controlled and partially controlled patients from our Phase II program. I would expect that our Phase III would expand our safety and efficacy database in both patient populations. Again, though, we anticipate the core group in Phase III being the well-controlled patient population so that we can do a responder analysis.

Our next question comes from the line of Tyler Van Buren with Piper Sandler.

Congrats on the data. Great to see a nice control with paltusotine during the study. I guess the first question is, in Phase III, when you guys look at treating patients who are biologically controlled, this -- which will be the majority of the patients, as you just noted, does it not make sense to try to push the dose a little bit higher than 20 milligrams in most patients, just given the dose response and maybe have some sort of kind of numerical superiority to standard of care, especially considering the fact that standard of care does consider -- does require rescue injections sometimes in the real world, even though it's maybe not terribly obvious from these IGF-1 graphs in the screening? And then second question was on groups 2 and 3 in the EDGE trial cabergoline patients. I mean, those are more difficult-to-treat patients, right? So is it pretty -- can you guys essentially say that you guys appear to be seeing better control in more difficult-to-treat patients, which could serve as a low-hanging fruit?

Thanks, Tyler. I think your instincts on the dose question are right on. If you look at that dose response data, what you really see is the 30 and 40 milligrams seem to be performing better than the 10 and 20 milligrams for the bulk of patients. And now we need to translate that into exposure response data and begin to finalize the arguments for dose selection in Phase III. But based on this data, I'd estimate that we'd be working at the higher end of that dose range in Phase III and potentially even going above 40 milligrams. But that's something we need to finish the modeling on and have discussion with the regulators. And then the second part of the question, can you remind me how you phrased that, please?

Yes. It was just on the groups 2 and 3, the cabergoline patients and EDGE. I'm assuming those are clearly more difficult-to-treat patients. So is it fair to say that you guys think that paltu might be able to provide better control for the more difficult-to-treat patients?

Yes. I think the way to look at the cabergoline data is that cabergoline is a dopamine agonist. And it's used sometimes by people around at different places around the world to add an extra bit of control on top of a somatostatin receptor ligand, to try and get their IGF levels down just a bit more. And I think that's what you see in our data that the cabergoline provides a small benefit, less significant -- less than the paltusotine benefit. But we would imagine in the long run that cabergoline might be used together with paltusotine as a full oral combination therapy for those patients that need it.

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

Scott, you sort of preceded me a little bit with -- or foreshadowed, in terms of going above the 30 milligram, I'm just curious have you established a maximum tolerated dose for paltusotine?

In our preclinical studies, the toxicology studies we have not established a toxic level of the drug. And so our tox program went to a maximum feasible dose in both rats and dogs. So we do have tox coverage to go higher in patients, we just need to understand what that means from the exposure response data.

And then I'm just curious, in terms of the data on Slide 19, I think it is. When we look at patients who ultimately were not randomized because -- not achieving the certain control because they necessarily weren't titrated not enough, when they were washed out, did we see the same amount of increase that -- in EVOLVE that we saw, in terms of EDGE, in terms of their IGF levels rebounding and in the same timeframe?

Yes, roughly. I'm not quite sure what you're trying to get at with that. But what we saw in both studies, and you see it in the individual data in EDGE is that there are a few patients, like it's been reported previously, who, even at the end of this 3-month period did not see a rise in IGF, but there are very few. It's like 15%, maybe 20% of the patients. The remainder did show a significant rise in the IGF growth hormone as was seen in the EDGE study as well. So those are the patients that truly need therapy. Is that what you're asking?

Yes. I mean, I'm just curious, I mean, did it seem that patients in the sort of controlled in SRL were less prone to necessarily as quick a rebound or as a sort of by the same order of magnitude as what we saw in the EDGE population where was quite dramatic. Just looking at the chart on Slide 19, to your point, I think, it seems like they don't quite go back as quickly or to the same order of magnitude. But I was just curious if you had been able -- when you look at the data itself, you're able to see that to some extent.

Alan, do you have any insights into that question?

Well, I would say that we do see individual patients in this small EVOLVE trial rebounding, and there are some, as Scott mentioned, who don't seem to rebound as much. It's such a small sample size that I would say in this trial alone, it's variable. But I do -- I think what you may be getting, and this is also relevant for future planning, of course, is that in the controlled population, they start out with low IGF-1. And then when you wash them out of their therapy, is it possible this patient population has a few more patients that take a while for their IGF-1 to wake up. And that is possible. We can't -- we don't have enough patients in EVOLVE to answer that question definitively. But we're certainly planning for that in our Phase III when we power for showing, for example, superiority to placebo, we would take into account anticipated cases where patients who go on placebo seem to not have a rise in IGF-1. And that's been described -- well described prior to us, and we will certainly take that into account as we do our statistical sample size calculations.

Okay. Great. Thanks. Maybe just one final question. Sorry, go ahead.

No, I was just going to say, Doug, just to follow-up a little bit. I think the way to look at the EVOLVE results because the numbers are so small. Notice that really only 3 randomized to paltusotine or to placebo. It's not really appropriately digging into those responder numbers or the behavior of any of those individuals. But what is appropriate is to take that IGF data and the exposure data that we have across the titration period and blend that into the overall dose response study. And it gives us more information about the lower end of the dose response -- lower end of the dose range, as you noted. So I just wanted to clarify how we view that data.

No, and that's helpful. And then just one final. I mean, when you look at this in the dose response data that you generated across both studies, when you think about a Phase III, would it be more likely or maybe a little bit of both, just to start patients at the 20 or 30 or just to have a longer dose titration period?

I think both of those are options. And certainly, we have much more time to do the dose titration. We expect the Phase III to be on the order of 9 months. So a slower titration is possible in that setting. And your idea about starting at a higher dose level makes a lot of sense. We just have to finish the exposure response analysis to decide that.

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

You talked about how 87% of the trial completers had at end of treatment IGF-1 levels within 20% of baseline or lower however, because the population enrolled, the baseline in EDGE was above the upper limit of normal. But you sort of alluded to this data informing a future trial that would involve a responder analysis. So I'm hoping you could just elaborate on what the take-home is from this result as it relates to future responder analyses in a pivotal population where presumably baseline would be under the upper limit of normal?

Yes. I think -- let me just make a comment and I'll let Alan finish up. But I think the way to think about all these patients is that they have some level of responsiveness to the existing SRLs. And what these data show is that when you switch them to an oral, you don't have a change in the vast majority, you don't have a change in IGF levels. Therefore, independent of where they start, if your population starts below 1 and you have no change in IGF, you should stay below 1. And so then the translation into responder analysis simply has to do with the variability around that lack of change. And I think the way to think about it the most is that we're seeing here with the 87% that people's -- 87% stayed within 20%, which is the normal variability of IGF or they were lower. And if we were to think about doing a non-inferiority study, for example, 20% would be a very reasonable margin to assume, especially given that the most recent entrant into this field showed a 21% rise in IGF on average upon switching. So Alan, maybe I'll let you try and touch on this one more because, Jess, I think it is a really important question to think through.

Right. I agree with what Scott just said. I think that we don't have reason to believe that the almost arbitrary threshold of normal IGF-1 by definition of a particular assay, that being a little bit above that or below that would affect the ability of a drug to control IGF-1. I think what we're seeing is, as Scott said, maintenance on this compound. It is a somatostatin agonist. It has the same mechanism of action as the previously used drugs in these patients, and we're seeing kind of what you would expect maintenance of control. Whether their baseline IGF-1 is a little lower than this patient population, I would be surprised if that translated into some sort of different property of the drug on the system. The other piece of the story, of course, is not just the maintenance, but also understanding what we should expect when patients go on placebo, for example, in a placebo-controlled trial. We dealt with that issue a little bit earlier, there is a certain amount of, what is called a placebo control rate. In other words, patients who get randomized to placebo who seem to stay with normal IGF-1 for extended periods of time. We also learn from our data, what that might look like, and its sort of is consistent with what others have described. So those 2 pieces of information can be helpful as we design a responder analysis trial in any population.

Okay. Great. And then when I look at Slide 20 on the dose response data, the inter-quartile ranges seem to show a little more, call it, variability or skewed to the upside of IGF-1 than to the downside. Do you think there are any differences in exposure that might be at play there? And do you think this sort of pattern is what we should expect going forward?

Alan, do you want to take that?

It's an excellent question about exposure. Those analyses are ongoing. This is the initial dose response analysis we've done across the 2 studies. But as -- during the studies, we did collect drug concentration data, and we're in the process of doing modeling for exposure and dose response. So that -- I can't answer that question yet. But by the time, again, we meet with the FDA, we hope to have that model in place to help project the appropriate doses for Phase III.

Okay. Great. And maybe just a last one on dose, kind of following up on some of the comments throughout the call just to make sure I understand. Do you think you found the doses to take forward? I think earlier on, you said maybe thinking about the higher end of the dose range here, say, 30 or 40 milligrams? Or do you anticipate exploring doses even higher than 40 milligrams in Phase III?

Go ahead, Alan.

Well, we certainly will be using this exposure and dose response modeling that I referred to, to help guide us on that question. I think these data do not yet answer the question, is there a possible further benefit from increased dose/exposure. It's possible. And I hope the modeling will help us project whether we should explore higher doses and exposure. If -- we are prepared to do that. And as Scott mentioned, we have the safety coverage to go higher on dose in Phase III and beyond, if there is good evidence that, that could be helpful.

Our next question is a follow-up from the line of Charles Duncan with Cantor Fitzgerald.

I think that some of these questions reflect questions from investors. That may be coming in. And I guess I'm wondering if I could get a little bit of color on, call it, a response rate, if you will, or target product profile that you'd look for. I know that ACROBAT EVOLVE is very small sample size, but what would you like to see? And then can you compare, call it, looking at the IGF-1 increase, can you compare to other recent entrants in the field such as the oral octreotide?

So I think what this data shows is that very high proportion of patients should be able to maintain their IGF-1 levels upon switching away from the depots. We see 87% in this -- according to this analysis, and with a 0 net change in IGF levels. And that 0 net change is -- that change in either the mean or the median, is really important. Because, as I mentioned earlier, and as Alan mentioned, this 1x upper limit of normal is a fairly arbitrary line in the sand that the regulators draw. But in practice, what you really want to do is keep IGF levels as low as possible. So if you then look at the recent entrants that you mentioned, the oral octreotide, for example, in their Phase III study, they did show a responder rate of about 60% upon switching. And more importantly, on switching, there was a rise in IGF of about 20% -- 21%, sorry, I calculated it. And yet here, we're showing a potentially much higher responder rate and 0 change in IGF. So I think that bodes really well for both the prospects of approval and the prospects for differentiation in the marketplace.

For sure. And do you think, Scott, if you just think about comparing the 2 products, and I know we're asking you to speculate it because you're comparing across studies, but do you think that, that difference could be due to absorption characteristics or pharmacology? I know a while back, we did a lot of diligence on this, and there could be slightly different, call it, biased agonism out of paltusotine. So is this pharmacological? Or is it dose? Or is it absorption? What do you think? Is that...

Well, we don't -- we really have the data to tease that apart formally. But I'd just come back to when we -- when our discovery group made this molecule, we optimized it to be a highly orally available, well-behaved, small molecule traditional drug. And you see that playing out now, both in the healthy volunteer studies and in the patient studies. And I think it's a property both of high -- relatively high absorption. We've seen 70% oral bioavailability in our healthy volunteer studies. But it's also a property of the long half-life, which is about 2 days. So that if there is some variability in 1 day's absorption, that's kind of evened out with time. So I think these characteristics of paltusotine all contribute to this very, very strong IGF control that we see. And you also noticed a very nice safety profile with patients completing the study and showing good tolerability. So I think all of that bodes well for the long-term prospects of the molecule.

Ladies and gentlemen, that concludes our question-and-answer session. I'll turn the floor back to Dr. Struthers for any final comments.

I just wanted to thank everyone for joining us on the call today. And again, especially the team from Crinetics and our investigators and patients around the world who put this study together during what are arguably some relatively difficult times to do clinical work. We're very happy at the quality of the data and the quality of the people that helped us get there. So thank you all very much and look forward to talking to many of you at future dates.

Thank you. This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.