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

Ladies and gentlemen, thank you for standing by, and welcome to the Crinetics Pharmaceuticals ACROBAT EDGE Phase II Interim Results and Corporate Update Conference Call. [Operator Instructions] I would now like to hand the conference over to your speaker, Robert Uhl. Please go ahead.

Thank you, operator. Good morning, everyone, and welcome to Crinetics Pharmaceuticals conference call to provide interim results from the ACROBAT EDGE Phase II clinical trial of once-daily oral paltusotine for the treatment of acromegaly. The company will also provide a corporate update. Before we begin, I'd like to let you know that on this call, the Crinetics team will reference data that are presented on a set of slides that you can access from the Investor Calendar events page of the Crinetics website. The interim data from the ACROBAT EDGE trial is also contained in the news release from yesterday afternoon. Joining me on the call from Crinetics are Scott Struthers, Founder and Chief Executive Officer; and Alan Krasner, Chief Medical Officer. Additional members of the Crinetics management team will be available during the question-and-answer portion of the call. Before I turn the call over to Scott, I would like to note that all of the information discussed on the call today is covered under the safe harbor provisions of the Private Securities Litigation Reform Act. I caution listeners that during this call, management will be making forward-looking statements. Actual results could differ materially from those stated or implied by forward-looking 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 yesterday's news release and Crinetics' SEC filings, including its annual report on Form 10-K. I would also like to point out that the content of this conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, April 7, 2020. Crinetics undertakes 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 turn the call over to Scott Struthers, Founder and CEO of Crinetics.

Thank you, Robert. Good morning, everyone. Thank you for joining our teleconference to discuss this important clinical milestone for Crinetics, especially those of you on the West Coast at 5:00 a.m. San Diego time. I will make some high level remarks concerning the interim findings from the ongoing Phase II ACROBAT EDGE trial and update you on other recent developments. Then you'll hear from Alan, who will go through the results of the trial in more detail. We will then be available to take your questions. Results from the EDGE trial we are sharing with you today have been accepted for a late-breaking presentation at the Endocrine Society annual meeting that was scheduled to occur last week. Unfortunately, like many other meetings that had been -- it had to be canceled. However, we felt it was important to share these emerging results with the community. So we're doing so today. Paltusotine is a once-daily oral nonpeptide somatostatin receptor type 2 agonist, designed by our scientists for the treatment of acromegaly and neuroendocrine tumors. We hope paltusotine will offer an at-home once-daily oral treatment that allows patients to avoid disrupting their lives by traveling to physicians' offices for painful depot injections. The first patients entered the EDGE trial roughly a year ago. In this open-label study, we evaluated IGF-I levels of patients before and after switching them to once-daily oral paltusotine from their commercially available depot therapy. Looking at data from the initial patients to complete the study, we are excited to see that the oral nonpeptide maintained reduced IGF-I levels even after the patient's prior peptide depot therapy had worn off. Showing that patients were able to switch to the once-daily oral paltusotine without loss of IGF control, is an important milestone for the paltusotine development program and for Crinetics. Recruitment in the EDGE is now complete, and we expect to report top line data in the fourth quarter of this year. We also hope to present the complete data set at an appropriate medical meeting as soon as feasible thereafter. In addition, we've discontinued the new enrollment in the EVOLVE Phase II trial, which began at the same time as the EDGE trial. We believe that what we have learned from EDGE firmly supports moving paltusotine forward into Phase III development. Rather than waiting for EVOLVE to compete enrollment in the current environment, stopping enrollment now enables data from those patients already enrolled in the study to be available for regulatory interactions on the same time line as the data from EDGE. With data from both studies, we will request an end of Phase II meeting with the FDA and seek the agency's input on our detailed Phase III development plans. Sending -- pending a positive outcome of these discussions with the agency, we are planning on beginning Phase III development acromegaly in the first half of 2021. The positive data from EDGE and acromegaly gives us additional confidence to proceed with paltusotine for the treatment of neuroendocrine tumors as well. CRN1941 is our second oral nonpeptide sst2 biased agonist. We initiated a Phase I trial in healthy volunteers in May of 2019 to examine its safety, tolerability and PK/PD. However, it did not represent an improvement over paltusotine, and we have decided to discontinue its development to focus on paltusotine as a treatment for both NET and acromegaly. We believe that the acceleration and increased efficiency offered by focusing on a single molecule presents the best path forward for the sst2 franchise. In light of cost savings we expect to realize from these decisions and other adjustments to our 2020 operating plan, we have extended our cash runway guidance to take us into 2022. As a reminder, we had cash and cash equivalents of approximately $118 million at the end of 2019. Our other 2 development-stage programs are making good progress. Manufacturing and first in-human-enabling activities are going -- ongoing for both the oral nonpeptide ACTH antagonist for the treatment of Cushing's disease in congenital adrenal hyperplasia and the oral nonpeptide sst5 agonist for hyperinsulinism. All goes as planned, we are targeting the start of a Phase I clinical trials later this year and possibly into early 2021. And we anticipate PK/PD human proof-of-concept data from both molecules in the first half of 2021. With that, I'd like to turn the call over to Alan to provide additional discussion of the results we have seen in the EDGE trial.

Thank you, Scott, and good morning, everyone. I will begin with Slide 3, which shows the design of the EDGE trial. ACROBAT EDGE is an open-label exploratory trial designed to evaluate the safety and efficacy of oral paltusotine in patients whose IGF-I levels are not fully normalized by long-acting octreotide or lanreotide alone. During the screening period of the trial, patients received their last injections of their previous depot treatments prior to switching to once-daily oral paltusotine monotherapy for a 13-week dose titration period followed by a 4-week drug washout period. The primary endpoint is changing IGF-I from baseline to the completion of the 13-week dose titration period. As you can see, this study consists of 5 subgroups of eligible real-world acromegaly patients. However, the bulk of our early enrollment comes from group 1. These patients are under suboptimal biochemical control despite taking stable doses of long-acting octreotide or lanreotide monotherapy. This profile represents roughly 2/3 of the patients with acromegaly in real-world practice. On Slide 4, you can see that as of the data cutoff date of February 23, 32 patients had been dosed with paltusotine. Group 1 represented 13 of the first 17 patients to complete participation in the trial. The remaining 15 patients, who had not yet completed the protocol, contributed to the interim safety analysis in this data cut and continued in the trial. We have since completed recruitment in this trial with 30 patients entering groups 1 and 2. In Slide 5, you can see in the graph on the left that the IGF-I levels at baseline and after 13 weeks of treatment with paltusotine were stable. During the washout period, IGF-I increased significantly and rapidly. This result suggests that paltusotine washed out within a 2-week period, which is consistent with the 2-day half-life previously seen in healthy volunteers. It also documents washout of lingering IGF-I suppression from remnants of pretrial long-acting injections over the period of approximately 19 weeks since last injection. The graph on the right shows results for serum growth hormone levels and as would be expected, mirror those of IGF-I, providing support for the IGF-I findings. Slide 6 shows a statistical analysis of what I have just described for you from the graphs on Slide 4. The IGF-I and growth hormone levels, 13 weeks after switching to paltusotine, are not statistically different from baseline to peptide -- from baseline on peptide depot therapy, and the levels of both rise significantly after paltusotine is withdrawn. On Slide 7, you can see on the left, the change from baseline for IGF-I concentrations for individual patients at the end of treatment with paltusotine and after withdrawal of paltusotine. You can see from the individual patient data that more than 90% of patients completing 13 weeks of paltusotine treatment maintain IGF-I levels, which then rise significantly 2 weeks after withdrawal of paltusotine. Growth hormone by protocol was only measured 4 weeks after paltusotine withdrawal, but again, provide supportive evidence of the patterns seen with IGF-I. Slide 8 summarizes the safety data that is based on all 32 patients who received paltusotine as of the data cutoff. We saw no discontinuations due to adverse events and no safety signals. Overall, adverse events observed in EDGE are consistent with somatostatin agonist therapy in a population of acromegaly patients. This continues to indicate that paltusotine appears safe and well tolerated, which is consistent with our prior findings in more than 100 healthy volunteers. We are extremely pleased with the interim results from the EDGE trial, and believe that the final safety and efficacy data from this study will support moving forward to advance paltusotine into Phase III development in the first half of 2021. We look forward to sharing the complete data set from this trial in the fourth quarter of this year. I will now turn the call back to Scott.

Thank you, Alan. We are pleased that the interim results from EDGE provide strong clinical rationale for once-daily or paltusotine in these difficult-to-treat acromegaly patients. We've learned what we needed to know about the efficacy of paltusotine and believe these results support the advancement of its development into registrational Phase III study. I would like to thank all the investigators, site staff, Crinetics staff and especially patients around the world who have made these exciting results possible and who continue to work hard to complete the ACROBAT Phase II program. With that, I'd like to turn the call back over to the operator, so that we can address your questions. Operator?

[Operator Instructions] And our first question comes from the line of Charles Duncan.

Congratulations on these nice interim results. I had a couple of questions for you. First of all, with regard to the EDGE, call it the sample that you took a look at so far, would you anticipate that the results you've seen in terms of the clinical profile to have predictive value for the results you could see from groups 3 through 5? I mean slightly different kind of setup in terms of what those patients have been exposed to. So I'm just wondering what you think about these first -- or this first group of patients.

Well, let me say a word or 2, and then I'll hand it over to Alan. So this clearly demonstrates the mechanism in play, which is the somatostatin type 2 receptor, is being activated, lowering growth hormone and lowering IGF-I, exactly as one would expect from a somatostatin agonist. And that layer of suppression seems to favorably compared to the peptide depots that the patients were on before. Now in the other groups, we're comparing against a number of other mechanism of actions, patients who have add-on dopamine agonists, who have pasireotide, which is a mixed pan somatostatin agonist or the once-a-daily growth hormone antagonist. So we don't necessarily be -- expect to replace IGF-I control in each of those cases. But the opportunity is to simplify the patient's life and allow them to replace with a once-a-day oral, something that can do a good job of keeping their IGF under control. Now we don't expect that to work for everybody in those cases because those are second and third-line treatments that have a number of liabilities. But we wanted to explore that. So we begin to see the broader group of acromegaly patients where we might be using this drug. Alan, do you want to elaborate on that in any way? Did you have any follow-up there?

I would just add, Scott, I mean, I agree with that completely. It's also not surprising to me that group 1 represents the bulk of the patients because I think these are the most prevalent patients in clinical practice, those that are on somatostatin agonist monotherapy who run a high IGF-I levels. And it is difficult to predict what the other groups will do because, as Scott mentioned, there's all kinds of different mechanisms in play. Certainly, for the most common group, we do have this data.

Two other quick questions. You mentioned the EVOLVE patient population or that recruitment being stopped and that makes sense to us given the COVID-19. I guess, I'm wondering if you've heard from prescribers and/or patient advocacy that they are challenged with the frequent -- having to frequently go in and be administered their current therapy. And does COVID-19 highlight the challenges of the current paradigm?

This is Scott. I think, yes, COVID and frequent office visits do present a problem for many patients to being encouraged not to go to physicians' offices. But in acromegaly case, you really don't have a choice of just going off drug, you need to receive that drug. Now in fairness, in a trial setting like ours, you still need to have very frequent contact with the study site in order to get lab tests and to receive your drug. So they're not really benefiting from that lack of contact today. But certainly, one could imagine something in the future where you don't need to see your physician more than once every 3 or 6 months, and that would certainly be an improvement on many levels, irrespective of COVID. But you might want to say a little bit about what's going on, Alan, in terms of managing through this part of the crisis.

Yes. Certainly for clinical trial patients, the situation does make it difficult for the visits that are prescribed in the protocol to occur. For this reason, we've issued protocol amendments -- emergency protocol amendments, which can be immediately implemented to give the patients from the sites more flexibility on which of these visits need to be conducted in person. And we think this is already having -- this is already helping the conduct of the trials quite a bit. I've also been very impressed with our clinical research sites in our studies. They've been really working hard to maintain the trial to ensure the safety of the research patients and also follow the protocols as closely as possible. In some cases, they really have to go to extended efforts to make these things happen and work with the patients to find the ways to meet with them and do the appropriate follow-up. And I just want to commend all of our ACROBAT research sites and the research patients who are really pulling together.

That's helpful, Scott and Alan. Appreciate the color. Last question is for Mark. And I know that this is probably not one that you can answer specifically. But given the cash guidance into 2022, I guess, I'm wondering if you've contemplated a range of Phase III trial sizing and designs that I imagine you'll talk about specifics in the future. But does that cash into 2022 include starting up the full range of Phase IIIs that you'd expect out of -- for paltusotine.

Yes. Thanks, Chaz. This is Mark. You're right. It does contemplate spend on preparation for Phase III and conduct of a range of Phase III studies. So we still need to hold conversations with regulators to finalize those designs for the pivotal program and the number of patients that will need to participate. But at this point in time, we don't have all those details settled, and we'll wait for the end of Phase II meeting to provide further guidance.

Congrats on the data.

Thanks, Chaz.

And our next question comes from the line of Yasmeen Rahimi.

Team, congrats on the data. A number of questions for you. Let's get started on the first one, which is can you give us a little bit of color on the titration? Like what dose did you end up to the extent that you could disclose it at this point? And then the second question for you is, can you give us a little bit more detail how rescue is defined? And the slide deck has said rescue is just significant worsening, but was there any biochemical measurements that were included? And then I have a follow-up.

Go ahead, Alan.

Okay. So the doses in this trial are actually blinded to the sites. So we have not analyzed and we're not disclosing the dose information. In terms of -- I'm sorry, Yasmeen the second part was regarding...

Rescue.

Rescue.

Yes, the second part -- yes, Rescue, what was the definition -- biochemical definition for rescue.

Yes. The primary part of the definition is in this slide. It's an unacceptable worsening of symptoms of acromegaly in this study. Also, the -- of course, the investigator has to agree that there's no further benefit for the patient to continue in the study. There wasn't a biochemical component to this definition. And again, no patients in the study met that definition to require rescue.

And then another question we had was I know it's challenging to look at this data because the study wasn't designed. But can one look at any measurements to assess whether breakthrough symptoms were improved at this time point? And then given that the study is fully enrolled, are you able to tell us how many patients are in group 3 through group 5?

So in the study, we are measuring and collecting symptom information. That data has not been analyzed in this interim analysis. But certainly, when the final data report is out, that will be included. And the patients -- so you can see as of the time of this data cut, there were only 4 patients in the original 17 that were not included -- that were not in group 1. At that time, there was 1 patient in group 2; 2 patients in group 4; 1 patient in group 5; 0 patients in group 3.

Congrats again.

Thank you. By the way, I just wanted to add, I think that sort of overall distribution where group 1 is the most prevalent, again, reflects what is likely seen in clinical practice. A lot of the combination regimens that we're exploring with groups 2 through 5 are less commonly used.

And now that we've completed enrollment, there'll be more than 30 in group 1 and another 10 or 12 in groups 3 through 5.

And our next question comes from Tyler Van Buren.

Congratulations on a positive update. I just have a few. So the first one is, I guess, understanding the difference in the patient populations between EDGE and EVOLVE in terms of biochemically uncontrolled and biochemically controlled. Can you just, I guess, describe a little bit further your confidence in these patients behaving similarly when given treatment? And your confidence behind moving straight into later-stage studies? And then the second question is what data should we expect to see in Q4? How many -- approximately how many patients and what information on efficacy and safety overall should we receive? And then I just have a quick follow-up on that.

You want to take that, Alan?

Sure. Yes. So as Scott mentioned earlier, I think we have confidence in the mechanism here and that the compound is being absorbed and hitting its target, the sst2 receptor. We have completed a study recently that showed a 70% of bioavailability of the compound. And this study as long -- as well as data from healthy volunteers shows growth hormone in IGF-I control very much consistent with what has been seen. So I really think that based on this, the drug has efficacy, and that should apply to any patient with acromegaly regardless of their baseline IGF-I. So in other words, the controlled patient population that you referred to, that just means their IGF-I happens to start out less than 1x the upper limit of normal. This particular patient population starts out a little bit higher than that, about 1.3. But I really think efficacy applies to both populations. And in fact, in theory, would apply to any patient with acromegaly. In terms of data readouts, as we discussed earlier, at the end of the year, we should have final data from both ACROBAT, EVOLVE and EDGE to share and go over with the FDA end of Phase II meeting. We do have, as Scott announced earlier, 30 patients enrolled in groups 1 and 2 in EDGE. And we also have in the remaining groups about 10 more patients or so for a total of about 40 from EDGE. And in EVOLVE we have 12 enrolled patients. So that gives you an idea of the patient numbers.

Okay. That's helpful. And then the decision to move forward with paltusotine, and that makes a lot of sense. Can you just describe the clinical pathway forward there a little bit more, in particular, when might we see efficacy data, I guess, the early signal of efficacy data in NET patients?

Yes. So there's 2 indications with in-site NETs. And the peptides somatostatins were originally approved for the treatment of carcinoid syndrome, which is a symptomatic part of NETs that occurs in about 20% of the patients. They experience severe diarrhea & flushing and somatostatins are very efficacious very rapidly. So that would be the initial indication we would go into to get some experience in a relatively easy clinical trial setting. And then the second indication would be to look at the antitumor effects of the drug themselves -- itself, which would be longer development. And we'd lead with the carcinoid syndrome study. We're still trying to figure out how to leave -- interleave this into our overall development plans. We have the materials where we could start something like that right away, but this does not seem the time to start a new clinical trial. And so to take advantage of that gap that we may have, this is something that would likely start in 2021, when we have the to-be-marketed formulation available and things have settled down. So we're still working on the direct plan of when we'd start that.

Okay. That's very helpful. And just one final question for a point of clarification based on questions I'm getting from clients. Is this data with the oral solution? Or is it with the capsule?

This is with the capsule. First generation solid capsule. We're working now on a second-generation capsule that we will -- hope will be the final to-be-marketed form.

So our next question comes from Joseph Schwartz.

Great. Congratulations. I was encouraged that IGF and growth hormone levels after 13 weeks were in line with what patients had achieved on the injections. I was just wondering if you had any color you can share about any time points before the end of that treatment period. Did you notice how IGF or growth hormone levels behaved then? Is it possible to describe the shape of patient biomarker curves before 13 weeks?

Yes. I think we should save that for when the full data is available, but you can imagine that you're doing a dose titration, you've got drugs coming off. The depot is coming off, the new drugs coming on. So if there is some variability as it settled down into the right dose level.

Right. Okay. And then sort of related to that is how, qualitatively, could you share any thoughts about how the uptitration scheme worked out in your view? Do you think there's any reason to tweak that in any way for the next study?

Well, we don't really know how it worked because we're blinded to the titration events at this point. I can say that the frequency of titrations presented some logistical challenges and required frequent blood sampling in order to support once-monthly titrations. So in a Phase III study, we'd spread that out, you have more time, and it would be much less of a burden on the patient. And we're going to be looking at all angles in the Phase III to make this trial as easy as possible for the patient and the sites too.

Okay. That makes sense. And then lastly, do you necessarily need to only study patients like those who are enrolled in the EDGE study in Phase III? Or would it complicate things to include patients like those who would have been most appropriate for the EVOLVE study as well in Phase III?

Yes. So that'll be a conversation we need to have with regulators. I think a conservative approach is to follow along the Special Protocol Assessment that Chiasma had achieved with the FDA. And that was a study in patients who were fully responding to somatostatin-injected amyloids. It's not the biggest population. It's not necessarily ideal, but that would be the most conservative path.

[Operator Instructions] Our next question comes from Douglas Tsao.

Congrats on the data. Just as a starting point, sort of following up some of the questions in terms of dosing, did you get a sense that the response as you uptitrated was sort of linear? And the reason I'm asking is, obviously, these were patients who were not in biochemical control, you did see some improvement, and they started came in at an average of roughly 1.3. Do you see, if you push the dose a little bit more, there might be an opportunity to actually bring some of these patients actually into the biochemical control or perhaps a little closer to biochemical control?

Do you want to take that one, Alan?

Yes. So again, the dose data has not been analyzed. It is blinded to the sites. But I can't say that what you're suggesting, I wouldn't rule out that possibility. Remember, this is a time-limited study. It's a short Phase II study. And as Scott mentioned earlier, we would anticipate a longer-duration study in Phase III with more spread out visits. I think only a longer study could answer the question you're asking. And certainly, that will be evaluated as part of Phase III.

And do you think you could take the dose up a little bit further from the levels, especially given the safety profile you saw?

Yes. We have a very wide preclinical safety margin. Again, there aren't safety signals emerging in clinical data so far. So I think the answer is there is room to go if we need it, but only the data will tell us what sort of exposures we do need to achieve the targeted IGF-I in growth hormone control.

Great. And just a couple of more follow-ups. Just in terms of GI, the tolerability looks quite strong. Were patients given anything prophylactically to control diarrhea? Or was this just sort of pure -- just simply -- just given a dose with paltusotine?

No. No, there's no prophylactic concomitant medications required in the protocol at all. Certainly, individual investigators can prescribe symptomatic-type medicines as they see fit. But no, there's no systematic prophylaxis in the studies.

And anecdotally, did you hear that, that was taking place? Or does it seem that the tolerability sort of is what it is at face value?

No. I have not heard of such measures being needed or being used regularly by our investigators. Generally, my impression of the GI side effects is they tend to occur early, and they are often sort of transient or at least self-limited with continued dosing. That continues to be my anecdotal impression, but we still need the final data and more patients in our study to really be more definitive on that. But certainly, that is the sort of pattern that's observed with the marketed somatostatin agonist. Generally, you hear about the GI side effects. For example, with the monthly injections or every 6 weeks injections that patients use, we often hear that patients have a sort of an acute bout of GI distress, loose stools, abdominal discomfort for that week or so after the injection. And then as the exposure to the compound comes down on the curve, then their GI side effects tend to wane. In our case, there are GI side effects at sort of an expected frequency, but I get the impression that they are transient as well by and large.

Okay. Great. And then just one final question, Scott. I know you indicated in terms of pursuing NETs, you are going to most likely go into the carcinoid syndrome initially. Do you anticipate eventually going after the tumors just in the context of how meaningful that was for lanreotide's commercial success in NETs?

Yes. It's a logical sequence of development for the drug, and it's a logical use of the drug. Those patients could use it as much as the acromegaly patients, and there's a lot more of them. But it is a bigger trial, and we need to make sure we're ready to take that on. And so it's -- we're going to be very thoughtful about when we do start that study.

And congrats on all the data.

Thanks, Doug.

Thank you. And I'm not showing any further questions at this time. I'd now like to turn the call back to Scott Struthers for any further remarks.

Well, thank you, Alan, and thank you, everybody. We're -- thank you for your participation in our call today. We appreciate your interest and continuing support for Crinetics. And if you have any additional questions, please feel free to contest -- contact us and please stay healthy.

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