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

Greetings. Welcome to Crinetics PATHFNDR-1 top line results conference call. [Operator Instructions] Please note, this conference is being recorded. At this time, I'll turn the conference over to Charles Schultz. Charles, you may now begin.

Thank you, Rob. Good morning, and welcome to the PATHFNDR-1 top line results conference call. Joining me today are Dr. Scott Struthers, the Founder and Chief Executive Officer of Crinetics; Dr. Alan Krasner, our Chief Medical Officer; and Dr. Dana Pizzuti, our Chief Development Officer. Before we begin, I would like to point out that there is a slide deck that will accompany today's presentation, which can be viewed using the Events and Presentation link provided on the Investor page at the Crinetics Pharmaceuticals website at crinetics.com/events. In addition, a news release announcing the top line results was issued yesterday and is also available on our corporate website. As a reminder, we will be making forward-looking statements, and I invite you to learn more about the risks and uncertainties associated with these statements as disclosed in our SEC filings. Such forward-looking statements are not a guarantee of performance, and the company's actual results could differ materially from those stated or implied in such statements due to the risks and uncertainties associated with the company's business. These forward-looking statements are qualified in their entirety by the cautionary statements contained in today's news release, the company's other news releases and Crinetics' SEC filings, including its annual report on Form 10-K. I would also like to specify that the contents of this conference call contains time-sensitive information that is accurate only as of the date of this slide broadcast, September 11, 2023. Crinetics takes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. I will now hand the call over to Dr. Scott Struthers. Please go ahead, Scott.

Thank you, Charles, and good morning, everybody. Today is a great day for Crinetics and for people struggling with acromegaly around the world. Thank you for joining us today as we discuss the impressive positive results from our PATHFNDR-1 study of paltusotine for the treatment of acromegaly. I had the great pleasure of personally getting to know many members of the acromegaly patient community. And it's these people and the many others that I've met -- that I haven't met, that immediately thought of when I saw the data from this study. On behalf of Crinetics, I'd like to express our deep gratitude for so many taking time out of their daily life, participate in this study and help advance the state of medical knowledge for treating acromegaly. I'd also like to thank the many investigators and site staff around the world who participated in the PATHFNDR-1 study as well as the entire Crinetics team. We are pleased to report that the PATHFNDR-1 study met its primary endpoint and all three secondary endpoints. As you will see, 83% of participants receiving paltusotine maintained IGF levels at or below 1.0x the upper limit of normal compared to just 4%, that's one participant in the placebo group. This is highly statistically significant. The study also met all three predefined secondary endpoints showing statistical superiority of paltusotine's placebo on maintenance of IGF levels, maintenance of symptom control and maintenance of growth hormone control. Paltusotine was well tolerated with no severe or serious adverse events and demonstrated no new safety hiccup. Alan will take you through the data in more detail in a moment, but I wanted to emphasize how proud we are of these results. We believe that the results of the PATHFNDR-1 study set a new standard for future acromegaly studies, thanks to its meticulous design and flawless execution conducted at premier endocrinology sites around the world. We hope the success of this study will be an indication of the level of rigor and focus that we put into all of our studies as we continue to build Crinetics into the premier fully integrated endocrine-focused company that can sustainably innovate pioneering therapies across many endocrine diseases. What is acromegaly? For those of you who are new to the story, acromegaly is a condition that is caused by a benign pituitary tumor that secretes excessive growth hormone. That growth hormone acts at the liver to secrete excessive insulin-like growth factor or IGF-1. These above level -- above-normal hormone levels result in a wide range of complications. Somatostatin receptor ligands or SRLs inhibit the excretion of growth hormone and help mitigate the impacts of the disease. People with acromegaly experienced a number of problems with progressive physical changes, including changed facial features, enlarged hands, vision defects, but also bothersome symptoms such as headache, joint pain, sweating, fatigue, weakness in their legs, tissue swelling and numbness or tingling. Acromegaly can also cause more severe complications like cardiovascular disease, respiratory issues and impaired metabolism. These complications not only reduce the quality of life but increase the risk of mortality if acromegaly remains uncontrolled. Paltusotine was designed in our San Diego laboratories to be the preferred treatment option for people living with acromegaly. Every atom in the molecule was optimized for the goal to be taken once daily orally and selectively target the same SST2 receptor as currently available injected peptide SRLs, without introducing new side effects or drug interactions. At Crinetics, we carefully craft each molecule in our drug discovery programs to try to optimize their biological and pharmaceutical properties as best we can for those we hope to -- we may help. Today's robust results for paltusotine are a direct result of that commitment to crafting high-quality small molecule drug candidates. This is an extremely difficult and complicated undertaking. And in my opinion, very few groups in the world are as good as -- good at it as the discovery teams at Crinetics. Our intention in developing paltusotine is to deliver a safe, effective and convenient treatment to help people focus on living their lives rather than living life around a complex healthcare needs. Current first-line standard of care injections are painful and often need to be administered by healthcare providers. Injection therapy can also be associated with breakthrough acromegaly symptoms, particularly towards the end of the monthly injection cycle. In contrast as a once-daily oral tablet, if approved, paltusotine could offer a more convenient non-injectable option that may -- might not only reduce the burden of care on the patient, but also on the healthcare system as a whole. The goal would be to allow the patient to choose such an option without having to pay a price of worsening biochemical or symptomatic control. I'm now pleased to hand the call over to Dr. Alan Krasner, our Chief Medical Officer, to take you through the PATHFNDR-1 results. Alan?

Thank you, Scott. Let's start with a brief review of the design of the PATHFNDR-1 study on Slide 7. This study was designed in accordance with FDA guidance to evaluate paltusotine for a maintenance of treatment indication in patients who are already treated with injected SRL and switching to paltusotine. The goal in these patients would be to maintain baseline levels of biochemical and symptom control. This study enrolled 58 adult participants with acromegaly who had IGF-1 levels less than or equal to 1x the upper limit of normal, well treated with octreotide or lanreotide depot monotherapy. The procedure for switching to paltusotine used in the trial was quite simple. Participants started their once-daily oral study drug when due for their next injection, which, in most cases, is 4 weeks after the last injection. Participants were randomized 1 to 1 to receive either placebo or an initial dose of 40 milligrams of paltusotine for 9 months. Dose up-titration to 60 milligrams occurred if IGF-1 was greater than 0.9x the upper limit of normal. Down titration to as low as 20 milligrams per day was also allowed based on study drug toleration. 30 participants were randomized to the paltusotine arm and 28 to the placebo arm. Also consistent with FDA guidance, the primary endpoint was the proportion of participants who maintained IGF-1 levels of less than or equal to 1x the upper limit of normal on paltusotine compared to placebo. Endpoint IGF-1 levels were based on the mean of IGF-1 measurements from weeks 34 and 36. During the course of the study, IGF-1 levels were measured at least monthly, and if two consecutive measurements were greater than or equal to 1.3x the upper limit of normal and there was an exacerbation of symptoms as determined by the investigator, participants received rescue injections of either octreotide or lanreotide and were considered nonresponders. We prespecified additional metrics that are clinically important as secondary endpoints. The change from baseline in IGF-1, the ability to maintain growth hormone levels at the target of less than 1 nanogram per milliliter and change in acromegaly symptom scores using a fit-for-purpose acromegaly symptom diary. Slide 8 shows participant disposition. We were pleased that over 98% of enrolled participants completed the randomized controlled portion of the study. Out of the enrolled population, only one participant in the placebo group withdrew consent from the study prior to study completion. We are also pleased to report that 91% of total participants chose to enroll in the open-label extension. This is very similar to our previous high rate of enrollment in the Phase II open-label extension study called ACROBAT Advance. Participant demographics for the two treatment arms are summarized in Slide 9. Age and geographic distribution were well balanced between the two treatment arms. There was a slightly higher proportion of males in the paltusotine arm, which likely resulted in an increased mean weight and BMI in this arm of the study. Slide 10 shows disease characteristics of the population study. The randomization was stratified based on the most important disease characteristics, namely baseline IGF-1 and prior treatment. As you can see, this succeeded in achieving nice balance in mean baseline IGF-1 and a prior treatment with either octreotide or lanreotide between the treatment arms. Typical of trials evaluating stable well-controlled acromegaly, these participants had long-standing disease prior to enrollment, which was somewhat longer in the paltusotine. As Scott noted at the top of the call, PATHFNDR-1 met the primary and all secondary endpoints. The primary endpoint is shown here. 83% or 25 out of 30 participants receiving paltusotine maintained IGF-1 levels of less than 1x the upper limit of normal at the end of the randomized control phase. This is compared to 4% or 1 out of 28 participants on placebo. The magnitude of this difference is highly statistically significant with a p-value of less than 0.0001. On Slide 12, we see that the first of the prespecified secondary endpoints was change from baseline in IGF-1 level. In this analysis, the paltusotine group as a whole demonstrated maintenance of average IGF-1 levels, while those on placebo rose markedly with a p-value for the difference of less than 0.0001. Please recall that our protocol required rescue of any participants who experienced a rise of IGF-1 to 1.3x the upper limit of normal or higher plus an exacerbation of acromegaly symptoms. Therefore, IGF-1 increases in these participants may not reflect the eventual magnitude of the increase, had we not asked the investigators to intervene early to ensure subject safety. Slide 13 shows individual subject to IGF-1 values at baseline and at the end of treatment. Firstly, one can see visually the distinct difference between the paltusotine treatment and placebo treatment arm with respect to IGF-1 control. The two rescues in the paltusotine arm and the 17 rescues in the placebo arm are depicted in red. You will note that only one patient on paltusotine made protocol-defined IGF-1 criteria for rescue with pretrial injection therapy. The other patient in the paltusotine group had rescue therapy because of adverse events of mild intensity, corresponding with an IGF-1 level of 1.1x the upper limit of normal. The investigator in this case, did not consider the mild adverse events related to study drug. All 17 participants who were rescued in the placebo arm achieved protocol IGF-1 criteria for rescue that is at least 1.3x the upper limit of normal. For the participants indicated in red, IGF-1 values measured just prior to the rescue were used for the analysis of mean values in the previous slide. The next secondary endpoint was based on symptom control as measured by the acromegaly symptoms diary or ASD score. The ASD was developed in accordance with regulatory patient reported outcome guidance and evaluated symptoms of headache, joint pain, sweating, fatigue, leg weakness, swelling and numbness or tingling. Participants reported their symptom severity on an electronic device on a daily basis, both prior to and during study treatment. Participants assigned each symptom score based on a 0 to 10-point scale ranging from no symptoms to the worst symptom with a total maximum score of 70. Slide 15 shows that participants in the paltusotine group maintained control of symptoms demonstrating a 0.6 point decrease from baseline in total ASD score. This was significantly superior to the placebo group, which showed a 4.6 point increase from baseline. Similar to the change in IGF-1 analysis, the fact that participants who meet protocol criteria for rescue receive early intervention may limit our ability to measure the extent of symptom worsening in the absence of that intervention. Despite this, a statistically significant difference was demonstrated with a p-value of 0.02. If we look at individual components of the ASD, paltusotine treatment resulted in favorable trends across all symptoms evaluated and in the case of joint pain and numbness and tingling, were statistically different from placebo. Naturally, we are very interested in evaluating acromegaly symptoms using this tool in PATHFNDR-2 in which uncontrolled patients at baseline are currently under study. Growth hormone less than 1 nanogram per ml is a stringent therapeutic target recommended by the Endocrine Society consensus guidelines. Growth hormone is a useful supportive secondary endpoint. However, it was not used as an entry criterion in PATHFNDR-1. Therefore, in order to assess paltusotine's ability to maintain baseline control this secondary endpoint prespecified evaluating growth hormone maintenance and those who entered the study with growth hormone less than 1 nanograms per ml, which turned out to be 23 participants in the paltusotine group and 18 in the placebo group. In the paltusotine group, 87% maintained growth hormone less than 1 nanogram per ml compared to 28% in the placebo group. This difference was also highly statistically significant with a p-value of 0.0003. In Slide 18, we see a safety summary. Paltusotine is generally well tolerated, and the frequency of participants with at least one treatment-emergent adverse event was comparable in the paltusotine and placebo groups. No severe or serious adverse events were observed on paltusotine. The most commonly observed treatment emergent adverse events are shown on Slide 19. These include symptoms commonly associated with acromegaly such as arthralgia, headache, peripheral swelling and fatigue. GI events such as diarrhea, abdominal pain and nausea, are commonly associated with SRL therapy. And as would be expected, these GI AEs were transient in duration, and none resulted in treatment discontinuation. The paltusotine group showed a notably lower frequency of AEs determined by the investigators to be related to acromegaly, 30% on paltusotine compared to 86% in the placebo group. The physician's AE assessments were, therefore, consistent with the patient's acromegaly symptom diary self-reports that acromegaly symptoms were better controlled on paltusotine. To summarize the safety findings, paltusotine was well tolerated with no severe or serious adverse events. The most frequently occurring adverse events are commonly associated with either acromegaly or SRL therapy. In addition, no safety signals were observed in vital signs, ECGs or laboratory values. Pituitary tumor size was monitored by MRI during the study, and no clinically significant changes were observed. Overall, the safety profile observed in this study is comparable to the larger paltusotine clinical program safety database to date. With that, I will hand it back over to Scott to review next steps for the paltusotine program.

Thank you, Alan. At Crinetics, we're committed to addressing unmet needs and delivering value to the entire acromegaly community from patients to healthcare practitioners for the healthcare systems as well. In addition to a convenient once-daily tablet, we also intend to provide at-home delivery and comprehensive support services for patients. For healthcare practitioners, we plan to provide extensive support services that we believe will reduce adoption hurdles. Finally, we expect to add value to the healthcare system as the at-home option may reduce the cost for patients, physicians and payers by reducing the number of [ offices. ] Today's exceptional results bring us one step closer to these goals. Slide 22 summarizes the market opportunity in acromegaly and carcinoid syndrome, our second indication for paltusotine. Paltusotine represents a multibillion dollar opportunity. The somatostatin analog market is well established based on current injectable for the treatment of both, acromegaly and carcinoid syndrome. In acromegaly, there are approximately 27,000 people living with the disease, 11,000 of whom are currently considered addressable. About 10,000 of those are now on endocrine pharmacotherapy. In carcinoid syndrome, the opportunity is even larger with approximately 33,000 patients in the U.S., all of whom we view as addressable. With both of these patient populations, we have the opportunity to help many people focus on living their lives rather than navigating the challenges of injectable therapies. We are in an exciting time of paltusotine's development. In the fourth quarter of this year, we anticipate preliminary results from the Phase II study of paltusotine in people with carcinoid syndrome, with a Phase III study in people with carcinoid syndrome planned to begin in 2024. Importantly, we expect to report results from PATHFNDR-2 acromegaly Phase III study in the first quarter of 2024. If positive, this will demonstrate the ability of paltusotine to help an additional segment of the population, those patients previously untreated or recently diagnosed with acromegaly. Finally, our open-label extension studies in people with acromegaly are ongoing, and we look forward to continuing -- look forward to continued follow-up of these participants, some of whom have been treated for nearly 4 years. We are delighted with these compelling results that were presented today. The resounding success of PATHFNDR-1 is an important advancement in the development of potential new treatment with people living with acromegaly. We plan to file the NDA in 2024, and if approved, we believe that paltusotine has the potential to shift the acromegaly treatment paradigm and provide a much-needed oral therapy that can provide reliable, consistent and durable control to people living with the disease. Thank you all for being here this morning, and we will now be happy to take your questions.

[Operator Instructions] The first question today is from the line of Yasmeen Rahimi with Piper Sandler.

Congratulations for the outstanding data. Two quick questions. The first one is you guys have done a phenomenal job on managing the placebo and PATHFNDR-1 through your really-thorough site selection. I guess the question that a lot of investors have is what is the likelihood that, that type of strategy of lowering placebo also holds through for PATHFNDR-2? And then have you had a chance to look at the duration of diagnosis with acromegaly in various subgroups to kind of point us to the direction like of a patient that had acromegaly, maybe for 5 years versus 10 years, was their response uniform? Would love to get some color on both of the questions, and I'll dive back into the queue.

Thanks, Yas. Maybe I'll take the first part and hand the second part to Alan. But I think at Crinetics, we try really hard to make sure we make high-quality drug candidates. And that was reflected in the responder rate IGF control and symptom control in the study. We also strive for high-quality clinical trials, and I think that is reflected in the placebo rate that you see here. This placebo is in part that the quality of the study is because we spend our entire company's life focused on endocrinology and many of us for decades with -- in the field with these same investigators and sites and friends around the world. And this is actually the placebo rate that we would expect based on prior literature and off-site the work of Alessandra Casagrande, who did one of the largest studies on acromegaly remission rates which showed that after a period of time like this, 9 months approximately, you should see a 5% to 7% remission rate in an acromegaly population. And that's exactly what we saw in this study. And by the way, Alessandra is the -- now the lead medical director on the program, and she reviews every single patient going into the study and can tell us the history of each one. And I think there's a lot to run in a clinical trial and entry, who comes into studies, that's not adequately captured in clinicaltrials.gov, and it's the hard work of high-quality investigators and people on staff like Alessandra to make all the difference in the quality of the study. And Alan, do you want to comment on the second part of the question around...

Yes, around duration of disease, right, yes? Okay. No, I'm not aware of evidence from previous literature that duration of disease has a direct contributory impact here. We stratified the study based on the most important parameters that have been shown to affect outcome, and that would be primarily baseline IGF-1 values. We continue to investigate this database, and we'll continue to do so as we get our next Phase III trial in. But yes, these patients, in general, have very long-standing disease. The imbalance that we noted on duration of disease, I do not believe is -- impacts these results. This has been seen in previous studies as well with no defined impact there from that.

And Yas, I realized I didn't directly answer your question about PATHFNDR-2. And I just want to note that very many of the sites in PATHFNDR-2 are the same sites in PATHFNDR-1, the same staff here at Crinetics. And we'll be working with the same sites in all our programs going forward. So yes, I would expect this quality of the study to be in PATHFNDR-2 in the carcinoid syndrome, Phase II coming out, in our Cushing's disease trials or CAH trials and all the trials that come in the future.

Our next question is from the line of Charles Duncan with Cantor Fitzgerald.

Congratulations, Scott, to you and the team, very robust results and very nicely reported and obviously conducted trials, so I appreciate that. So Scott, a couple of quick questions in terms of what happened in the trial. In terms of the percentage of patients that were up-titrated to 60 mg, can you give us some more color on that? And then I know very small numbers, but in terms of GI safety observations, do you have any color that you can provide on the timing severity and cadence of the GI safety observations over the course of 36 weeks?

Great. Thank you. Alan, can you take that?

Sure. Well, on the second point, Chaz, most of these events were occurring early on as is typical for SRL side effects. They ranged in duration from 1 to 50 days. They -- in other words, they were all transient and self-resolving. Nobody stopped the drug because of these. This is all very typical of SRL related effects. With regard to the doses, the -- by the end of the trial, half the patients on paltusotine ended up on the 40-milligram dose and half ended up on the 60-milligram dose. Recall that in the trial that the protocol required up-titration to 60 milligrams if IGF-1 was greater than 0.9x the upper limit of normal. This is a little bit more aggressive on up-titration paradigm that I think would occur in clinical practice. This was to ensure clear responses in patients. It is not clear to me at this time that the increase to 60 was necessary. We don't -- we are in the midst of evaluating whether there was incremental benefit to the increase. So I would say the jury is still out on ultimately whether that 60-milligram dose will be needed in the acromegaly patient population. I'd like -- I would recommend that we reserve that judgment until we have our PATHFNDR-2 data. Remember, these are the patients who start out with elevated IGF-1, because they are either naive to therapy or not currently on pharmacologic therapy. I think that will be the real test of the dose range.

Okay. That's helpful. And perhaps my next question is better answered after PATHFNDR-2. But I'm just going to ask you to speculate, if you would. And just going back like 5 years ago, when we conducted diligence on paltusotine in terms of being a biased agonist. Do you think that it may have differential activity that goes beyond just some really important compliance advantages that could drive persistent therapy to actually having different activity relative to the peptides and therefore, having activity that translates into efficacy over time?

Yes. Thanks, Chaz. Always nice talking to a fellow pharmacologist. Yes, it's important, I think, to remember as we work on making drugs, we look at so many different dimensions of both, the pharmacology and the pharmaceutical characteristics, and signaling and biostagonism and other aspects of receptor regulation are core to every one of our discovery programs, not just the SST2. But in the case of SST2, actually, that led to paltusotine, of course. The original hypothesis was based on work from Agnes Schonbrunn and Jean Claude Reubi, which showed that octreotide was a potent inducer of receptor internalization and desensitization, particularly in patients with neuroendocrine tumors such as the ones that cause carcinoid syndrome, and they have some fabulous publications there. And the way we started that project was an NIH grant to look at the underlying effectiveness of -- or the underlying biostagonism. However, we haven't directly tested that as part of the program, and it's difficult to disentangle those mechanisms and how they contribute to the actual performance of a drug in a clinical trial setting. But it comes back to this notion of putting all the craftsmanship we can into a molecule and then seeing how it plays out. And I think it played out quite nicely, of course. In PATHFNDR-1, the role of biostagonism, I don't know, but certainly, the consistency of dosing and PK exposure I think were quite important. I'd be very curious to see how that plays out in the carcinoid syndrome trial in particular, and we'll be keeping an eye out for that.

Our next question is from the line of Cory Jubinville with LifeSci Capital.

Congrats all around the team, look incredible to say the least and certainly exceeded our expectations. Two from us. To start, what degree can you attribute today's outcomes? And the shift in formulation from the [indiscernible] in Phase II to the spray dried dispersion tablets in Phase III. And in your view, what implications does this formulation shift have towards the upcoming PATHFNDR-2 readout and as well as development in carcinoid syndrome?

Yes. Thanks, Cory. I appreciate that. Cory, we've had a number of questions about this "new formulation", but it's actually several years old now, and we've done all the work with the PATHFNDR program with that. And all the patients in the open-label extension are also on that formulation as well. And I think it's just a routine aspect of small molecule drug development that as you move forward in development, you work to continuously improve the formulation until you land on a final tablet type that we then use for the registrational studies. And by the way, we're using registrational batches and all the CMC parts of this have been worked out to a great detail by our Crackerjack CMC team. So it's the same thing in PATHFNDR-2, the same formulation, same tablets that we use in PATHFNDR-1, same tablets that we're using in carcinoid syndrome. And it's, again, part of, I should say, when we optimize everything we can about the molecule, every single atom in the molecule, but also everything we can about the process, the salt form, the polymorphs, the formulation, the tablet coating, the embossing on the tablets, all those things that make an easy-to-use final product that patient just takes every morning.

Excellent. And I guess also, how are you thinking about patients to the label via the acromegaly symptom diary score, another FDA loves to focus on feel and function? And in addition to that, can you provide us a little bit more context on the ASD profile of patients with PATHFNDR-1 in regard to their baseline scores, and in that case, what do you view as a meaningful magnitude of change overall, and also within some of these key components of ASD, whether it be headache or arthralgia, et cetera?

Alan, ASD has been your baby, maybe you can answer that question.

Yes, the acromegaly symptom diary was kind of developed from scratch following FDA guidance on how to develop patient-reported outcome tools for use in clinical trials. We've started using it in our Phase II Acrobat trials and published the results of its psychometric performance within the last year. What kind of one of the main goals of the development work for new tool is to kind of predict what the meaningful -- what the minimal meaningful change in score would be. Based on the Phase II data, we would estimate that to be between 4 and 6 points on the scale. Remember, the total maximal severity score is 70. We are looking at different patient populations in our Phase III program. This patient population, the PATHFNDR-1 population is the best controlled over long periods of time of all the acromegaly patients in practice. And as you would expect there, their symptom burden is the least or would be expected to be the lowest of the acromegaly patient population. But even still, even in this population, the scores are not 0. The mean baselines are in the 10 to 12 range, and even these degrees of change that we see are quite -- I believe, to be meaningful in this patient population. The changes -- the tool is clearly very precise or I would say the variability around these data are less than you might expect from a survey type tool. And we were able to show even in this kind of narrow range of fairly well-controlled low symptomatic patients, a statistical difference when patients come off their medication, which I think speaks a lot for the utility of this kind of tool and its precision. PATHFNDR-2 though, that patient population is probably the real way to assess the impact on symptoms, because these are patients who are naive or not on therapy and therefore, start out with high IGF-1 levels. We don't have data from PATHFNDR-2 yet, but I expect their symptom scores, their symptom burden would be greater than we see in this PATHFNDR-1 patient population. And I suspect differences with treatment would also be even more noticeable. I do hope that it will help us and potentially someday, these kind of data might appear in the label. That, of course, is a review issue for the FDA. But we certainly have been developing this patient-reported outcome tool in accordance with their expectations for documenting its validity. So stay tuned on this, and we'll have more to report when we have our PATHFNDR-2 data.

Fantastic. And one follow-up, if I will, on ASD in PATHFNDR-2. Given the greater severity of baseline scores in that population theoretically, do you feel that 4 to 6-point difference would also be a meaningful change there?

I believe so. In theory, that showed a play regardless of patient population, I would have to remind you though that those numbers are published in our -- based on our Phase II data, we are going to be updating our psychometric analysis of the ASD with this rich new source of Phase III data as that data becomes available. All of that would be included in our NDA application and all the associated psychometric analyses. So that least meaningful change may be updated. But still, since -- and part of the reason we emphasized in our presentation, the difference in adverse events related to acromegaly symptoms is because -- remember, the adverse events are reported by the physicians, the ASD is a patient-reported outcome where there's no filter between the patient and the database. And they correspond these trends to correspond very nicely. So therefore, I believe these differences in symptom burden are real even in this well-controlled patient population.

Our next questions are from the line of Joseph Schwartz with Leerink Partners.

Congrats to everyone at Crinetics on the great execution here. So first question is, it's impressive that 91% of the patients chose to enroll in the OLE, I was wondering if you can talk a bit about what the screen failure rate for the randomized portion of PATHFNDR-1 look like and how representative of the overall acromegaly population, the PATHFNDR-1 sample is.

Alan?

The screen failure rate, I can get you shortly. However, it was lower than we experienced in our comparable Phase II study because of very careful prescreening and patient selection procedures in this study. I think in general, the reason screen failure rates in this population can be high and were high in our Phase II experience is because this patient population is well controlled, is selected based on the degree of biochemical control. And we need them to be biochemically controlled for enrollment in our studies based on a modern-day clinical assay for IGF-1 that's known to be well validated and up-to-date with respect to reference ranges. I would say overall, though, that in practice, patients who are exquisitely well controlled on lanreotide or octreotide monotherapy represent the minority of patients in clinical practice. The reason we need this patient population for this kind of study is because of the primary endpoint of maintenance of control in the normal range. This is why we wanted to supplement PATHFNDR-1 with PATHFNDR-2. PATHFNDR-2 represents more of the kind of real-world patients who are either newly diagnosed or off treatment. And we -- in that study, evaluate the ability of paltusotine in a treatment mode. This study, PATHFNDR-1, is about the maintenance of treatment indication as outlined in the FDA guidance on acromegaly development. PATHFNDR-2 is the treatment indication. And that would be, I think, a real test for the drug as well as in kind of the pristine environment of not having background medication on board. Both are very relevant for clinical practice. Patients who need to switch, patients who need to start a new medication, we would like to -- we are studying both populations, so that we can hopefully launch with a broad labeled indication.

That's very helpful. Second question is, is there any evidence from PATHFNDR-1 that paltusotine is able to shrink patients' tumors? Have you measured this in this trial, or do you have any plans to evaluate that going forward? And how important would this potential feature of a pharmacologic treatment for acromegaly be?

Alan?

Well, we do follow MRI scans in all of our long-term treatment trials. And in this study, we see stability of pituitary tumors. This is what would be expected in this patient population. And also, very importantly, in our long-term Phase II extension cohort in which patients now -- a number of patients have been treated for over 3 years of [ paltucity ]. Again, we see long-term stability of the remnant pituitary tumor size. Shrinkage of tumors is more often seen in the kind of preoperative kind of setting with acromegaly. Generally, what one sees in the kind of maintenance population of patients is long-term stability on the SRLs. And I think paltusotine is showing that same sort of long-term profile.

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

Congrats on the data. Just to start, in terms of the dosing, obviously, as you noted, it sounds like about half of the patients ended up on the 60 milligram. I think you said that just given in clinical practice, you would expect more patients to probably stay at the 40-milligram just because you had very sort of tight rules in terms of up-titration, but I'm just curious, did you see any signs? Or are you going to look at the database to see if there's any incremental value from a symptom standpoint of potentially driving IGF-1 down a little bit more?

Thanks, Doug. Yes, we still have a lot of detailed analysis to do that didn't make its way into the top line. So we'll look at that. We'll look at adjustments of dose and the effect on symptoms and IGF, but we'll also look at that as we go into PATHFNDR-2 and get a comprehensive picture of how much value the extra dose at 60 provides to the individual patients, but it's a little too early to say at this point.

And I'm just curious, is it too early? Was there any incremental cost from a tolerability standpoint for moving to the 60-milligram? It doesn't look like it, but I'm just curious if you did that.

There didn't seem to be.

The next questions are from the line of Jon Wolleben with JMP Securities.

Let me share my congratulations. Two for me, one on the data. Most of the rescues in the placebo arm happened fairly early to midpoint of the trial, and then it seemed like most of those patients rolled over to the open-label extension. So I wonder if you could talk a little bit about IGF response to those patients once they were rescued and then switched over to paltusotine.

Yes, thanks. This is actually very consistent with what we expect based on the literature and our previous Phase II results, which looked at the PK of both, octreotide and lanreotide, and showed that 3 months was fully adequate for washout of prior therapy, but we went longer just to make sure. Yes, there's a rich source of data in patients rolling into the open-label extension, but we're going to save that for a little bit, because we've been digesting a huge amount of data from the primary part of the study now. And I think the open-label extension will provide data on a regular basis for years to come. So stand by for that one.

Okay. And then can you discuss PATHFNDR-2, the two stratum you guys prespecified and the power assumptions in the trial and how the data yesterday gave you more or less confidence in how you've designed PATHFNDR-2?

Yes, sure. Alan, do you want to take that?

Sure. So I think the PATHFNDR-1 data being unequivocally positive, gives me even greater confidence in PATHFNDR-2. We, in this study are looking at patients with elevated IGF-1 at baseline. And we're looking primarily at the rate at which they achieve a normal IGF-1 using a modern assay. In that setting, I would expect lower overall responder rates than we see in this maintenance population, I think that would be true for any pharmacologic therapy, including the SRLs. That being said, I think we're well powered to show a difference from placebo in this important patient population. The powering is based on -- well, first of all, the study was modeled after lanreotide's registrational trial in which they enrolled a similar group of patients stratified according to whether they're naive or not recently treated versus those who are treated but willing to wash out of their treatment during a screening period in stratum 2. Based on the lanreotide registrational trial, we know that responder rates as defined by normal IGF-1 achieved at endpoint would expect it to be lower in stratum 1. Those are the naive patients versus those who were previously controlled on treatment and washed out. So our power of calculations took into account how many from each of these stratum actually end up being enrolled into our trial. In the case of the lanreotide trial, in their stratum 1 equivalent versus stratum 2, they enrolled about 50% in their stratum 1 versus stratum 2. Now in our case, to my happy surprise, we actually were able to enroll significantly more in stratum 1 than in stratum 2. These are the naive patients. They would have the lower responder rates, but they would also be sort of a more pristine group without background therapy as I mentioned earlier. And this, I think, would really increase the meaningfulness of showing a statistical difference to placebo, having predominant enrollment in stratum 1. So we have prespecified in the study when it was designed to increase the sample size dynamically based on enrollment in stratum 1 versus stratum 2. And given the larger number of stratum 1 patients, we increased the original sample size -- target sample size from 76 patients to 98 patients, and we actually ended up enrolling 112. So we should have plenty of patients to evaluate and show a statistical difference in responder rates from the overall patient population in PATHFNDR-2. We will, of course, also look at the specific relative responder rates in each of the strata, but the power is primarily designed on the overall group of patients in PATHFNDR-2. Is that helpful?

Got it. Yes, super helpful.

Our next question is from the line of Brian Skorney with Baird.

Let me add my congrats on a phenomenal result. A couple from me. I mean I guess just when we think about the PATHFNDR-2 data site when we got it in the first quarter, will we get to see out of the percentage of placebo patients who are rescued where their rate of IGF-1 normalization [ winds ] up? It seems like there's some ability to compare to injectable standard of care, even if it's not in a standard RCT format. I'm just wondering if you're getting ongoing rescue rates from PATHFNDR-2 and can kind of characterize at all what percentage patients may be getting that on placebo. And then my follow-up is just there was this one patient who seems to rebound really quickly and was rescued. I don't know if -- I didn't hear if you addressed it, but this patient actually takes the drug, or are they noncompliant? Just wondering if you have blood concentration levels on this patient's -- patient or have a hypothesis of what's going on there?

Yes. Let me take the first part and hand the second part to Alan. Thanks, Brian. Yes. There's a great deal of information in the rescue arms of both, PATHFNDR-1 and PATHFNDR-2. And so we will be looking at that. And then those rescues then shift on to the open-label extension and received paltusotine, so there's additional information there. So we -- there's a lot of fascinating stuff as we start digging into those and the time courses of individuals, both on symptoms and IGF levels, and really look forward to being able to do that, a little too early now, but hoping to do that soon. And then Alan, do you want to take the second part of that on patient's escape?

Oh yes, absolutely. Yes, you're right that -- well, first of all, by and large, all of the patients who required rescue, including all of the 17 on placebo who required rescue, when they got started on their rescue, the IGF-1 responded in the downward direction as expected. This particular subject in the paltusotine arm who had an escape was an interesting case. This patient came in the normal range with regard to IGF-1, was randomized. And as you saw, IGF-1 went up to the point where the patient met criteria as defined in the protocol for rescue. Patient received the rescue lanreotide injection, the same medication they were using before the trial. And there was not a prompt downward IGF-1 deflection. We are continuing to file this patient. I don't have a ready explanation as to why this particular patient seems to have a sluggish response to SRLs. Patient actually has a history of this. But my -- we will learn more as time goes by. I think this is just the kind of outlier variability you see in human clinical trials. And in general, all the other patients had the expected response to the rescue injections.

Next question comes from the line of Gavin Clark-Gartner with Evercore ISI.

Let me also add my congratulations on the data. I just wanted to clarify one of the comments you just made on PATHFNDR-2 to make sure I heard it properly. Did you say that the group of washed out patients was previously controlled on somatostatin therapy? And then does this imply that the group untreated for 4-or-greater months was not responses to somatostatin therapy?

Yes, that is correct for stratum 2. These are patients who are controlled on their SRL therapy and then wash out. It wouldn't make sense to take patients who are known to be unresponsive and then to SRLs and then put them in an SRL trial, of course. With regard to the patients who are not currently on pharmacologic treatment. Yes, the same principle applies. But we don't -- what we -- the way we handle that is we say, look, if the patient is known to be unresponsive to SRLs from past experience, again, it wouldn't make sense to put them in this kind of a trial. But we don't have -- we -- there's latitude there. We don't necessarily have strict criteria for defining responsiveness in that case. We'd let the investigator use their judgment. In the case of the truly naive patients, of course, there's no cap on eligibility, IGF-1. And in that case, no one has any experience with medication yet to end. So we take all comers there.

Yes. So maybe just to reiterate for those that are a little newer to the story, stratum 1 has patients who are either naive to therapy or they've been off therapy for a long period of time, and we don't know whether they responded or not. But if we knew that they did not respond, it wouldn't be ethical to bring them into the study. Stratum 2 is very much like the same patient population in PATHFNDR-1, except these patients who couldn't get into PATHFNDR-1 in many cases and though therefore, undertook a washout period until their IGF rose and then are being retreated with paltusotine.

The next question is from the line of Catherine Novack with Jones Research.

Congrats on the fantastic data. Just a couple for me. The first is you maintain that you're seeking a broad label for FDA approval. But I just want to clarify, are these PATHFNDR-1 data is sufficient on their own for approval? And then in the event that you don't achieve the broad label, how do you anticipate supporting patient switching? We've seen time and again the patient preference for an oral medication, but how does this factor into their decision there and their physician's decision to switch to an oral medication?

Got it. Let's let Dana Pizzuti, our Chief Development Officer, answer that. She has submitted and approved more NDAs than most people I know.

Thanks, Scott. Catherine, in terms of the suitability of just filing with PATHFNDR-1, our overall development strategy though, included trying to achieve as broad a label as possible, which would mean not only the maintenance of therapy indication which PATHFNDR-1 supports but also the treatment indication, which a large majority of PATHFNDR-2 would support, right? And we very much consider this as a sort of a package, right? And one of the other considerations is the sort of size of the safety database, and we feel that with the addition of PATHFNDR-2, we significantly supplement the ability of our -- of showing the safety of the compound as well. So we really consider these two trials complementary and self-reinforcing. So in the first instance, we wouldn't really consider filing this without waiting for the second trial.

Yes. And just a follow-up on the supportive switching side of it. I mean, clearly, we could style with just the first NDA -- with the first PATHFNDR-1. But we want to make sure that even patients switching don't have to establish that they were previously controlled on an injected therapy as is the case of the population of PATHFNDR-1. So this broader label is consistent with the most regulatory guidance -- necessary not the label, but our approach to the labeling is consistent with the recent regulatory guidance just this year, about two separate indications. One, the maintenance of acromegaly therapy; and second, the treatment of acromegaly, and that's PATHFNDR 1 and 2.

Got it. And then just last question on the subject of a PATHFNDR-2. Based on historical literature and the lanreotide studies, what do you expect if any, to see a placebo response rate in this patient population? And then is there anything you are concerned about or want to highlight in terms of the patient characteristics or study design of PATHFNDR-2 compared with these pivotal studies that might impact our assessment of them?

Alan, maybe you could talk about that.

Right. And actually, it's targeting back to Yas's question earlier. In PATHFNDR-2, remember, these are patients who start out with high IGF-1 levels. And in some cases, could be fairly markedly high. Therefore, I would expect fairly low placebo response rates. In other words, for example, if you start out with a IGF-1 level of 1.5x the upper limit of normal or higher, getting to the normal range kind of on placebo spontaneously is -- would be very unexpected and unlikely, even taking into account the variability of the assay and the biologic variability. So I would expect fairly low placebo response rates in this study. And again, I believe that active drug will achieve a change from baseline in many of these patients. And hopefully in a sufficient number, achieve normal IGF at the end of the day. We did identify change from baseline in IGF-1 as a key secondary endpoint in that study, because I think that is a very important metric for physicians, particularly in that patient population as well as achieving normality. And I'm sorry, I forgot the second part of your question.

Just any substantial differences in the study designs that we should be aware of or patient enrollment versus the lanreotide studies.

Well, so patient enrollment, I would say, the patient -- the mix of eligible patients for the study is very similar to the registration of lanreotide study. I would say, in our case, in PATHFNDR-2, we have a 6-month treatment duration, which distinguishes it from the 9 months of PATHFNDR-1, but after the 6-month randomized controlled period in PATHFNDR-2, all these patients once again have an opportunity to participate in a single arm open-label extension, just like we're doing in PATHFNDR-1 and just like we did in Phase II. Otherwise, the basic design of the study is very similar. It's a randomized placebo-controlled trial, double-blinded and so very similar otherwise.

And has many of the same centers as PATHFNDR-1.

Right.

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

Adding my congratulations to the entire organization. Just want to ask with respect to further data and analyses from PATHFNDR-1. Scott, do you expect to provide those ahead of the PATHFNDR-2 to top line readout with the Endocrine Society meeting not until, I believe, next June. Just wondering how you're thinking about your disclosure plan.

Thanks, Leland. Yes. So in between now and then, we've got the Brazilian Endocrine Society meeting, the British Endocrine Society Meeting, a variety of investor forums, the European Endocrine Society meeting and then, of course, Endo. And I think there'll be fresh data at all of these.

Great. And then I just wanted to ask with respect to the global opportunity for paltusotine. If you could maybe let us know your thoughts on applicability of these data and perhaps PATHFNDR-2, with respect to other international potentially large markets in acromegaly.

Yes. Good question. I mean we're doing these studies in 18 different countries around the world, and we're committed to bringing the drug to all the people around the world who need it. And generally, this package should be -- that we're doing now for the U.S. should be good for most countries. Of course, Japan requires a separate set of country-specific study. And we're doing that in collaboration with our partner, SKK. And I should note that typically, China also requires a certain population of Chinese subjects in the study. And PATHFNDR-2 has recruited a significant number of patients in China, which should satisfy that requirement, so that additional studies in China for specific submission there would not be required. So I think we've got every base covered. We just need to decide on how to do that and how we commercialize in these different regions, where we partner and where we go along.

Our final question is from the line of Cory Jubinville with LifeSci.

[indiscernible] follow-up from us. You touched upon this briefly towards the end of your prepared remarks, but would love to hear in greater [indiscernible] that makes your strategy regarding the types of support services you're looking to provide patients and prescribers to garner a greater market capture. I mean we know with injectables, there's a at-home administration service for a subset of patients on commercial coverage and would love to know what might it at home service that you mentioned look like for paltusotine. And also the prior [ auth ] process is probably one of the reasons care is so concentrated at the distant excellence. So we'd love to hear your strategy there.

Well, just talk a couple of broad brushes, but yes, I suppose you can get that injection at home, and we have talk to many patients who do. So you just need to be sure you schedule time when a person shows up on time and you're at home and maybe the kids are at school, so they don't see you, and you're not on vacation. And that's probably better than taking a couple of buses across town for an injection, but it still makes the therapy intruded on your life. I hope we have something just like Amazon showing up and with a specialty primary [indiscernible], ships a 90 days supply to your door and take it with you on vacation as you need. In terms of supporting the physicians, yes, the burden on prior [ auth ] things is really getting out of hand. And if you partner with the right specialty pharmacies, they can provide support and templates and other ways of trying to ease that burden as best we can in a compliant fashion. Both our commercial group is now fleshing out. We have, of course, our Chief Commercial Officer, Jim, who was -- we've talked to in the past, and we also have a Vice President of Market Access, Vice President of Marketing and Vice President of Operations, doing all the analytics. So this whole strategy is being developed and being put in place as we speak, and we'll be talking more about it as we get closer to launch.

Thank you. At this time, I'll hand the call back to management for any closing remarks.

So thank you, everybody. We appreciate your attention and support over the years. And thank you again to all the patients and sites and Crinetics staff that made this study a success. Enjoy the rest of your day and thank you.

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