Crinetics Pharmaceuticals, Inc. Q4 FY2020 Earnings Call

Greetings. Welcome to the Crinetics Pharmaceuticals, Inc. 2021 Clinical Strategy and 2020 Financial Results Conference Call. I will now turn the conference over to your host, Corey Davis. You may begin.

Thanks, Alex, and thank you all for participating in today's conference call. Before we start, I'd like to point out there is a slide deck that is going to accompany today's presentation. The deck can be viewed using the webcast link provided on the Investor page of the Crinetics website. Also posted on this web page is a news release issued earlier today, announcing Crinetics' 2021 clinical plans and fourth quarter and full year 2020 financial results.

Thanks, Corey, and thanks to all of you listening this afternoon. I'm joined today by Dr. Alan Krasner, our Chief Medical Officer, and Marc Wilson, our Chief Financial Officer. Although we're reporting our 2020 fourth quarter and year-end financial results, the primary purpose of hosting today's call is to provide some additional color on our development strategy and our clinical programs for what we believe will continue to be an exciting year for Crinetics. Now before we get into what we have in store for the balance of the year, I'd like to first touch on some of the recent accomplishments that have set us up for success. Last October, we reported positive Phase II data in acromegaly patients demonstrating that once-daily oral paltusotine allowed patients to maintain their IGF-1 levels when switching from the current standard of care, which are injected octreotide and lanreotide depot therapies. This represented a significant accomplishment as IGF-1 is the biomarker used by physicians to manage acromegaly patients around the world. Once we became comfortable that patients could effectively and seamlessly switch from injectable to our once-a-day oral pill, we approached the FDA and other regulators in order to design a robust Phase III program to support our goal to obtain a broad label and position paltusotine as a differentiated product with a competitive advantage. Following these data and a recent productive meeting with the FDA, we are now advancing paltusotine into a Phase III program. Alan will walk you through that design in a moment.

Thank you, Scott, and good afternoon, everyone. I'd like to start by describing the design of the PATHFNDR-1 study on Slide 5. It was designed based on feedback from the FDA and other regulators and mirrors the design of other recently approved products for acromegaly in the U.S. As Scott mentioned, PATHFNDR-1 will enroll patients who are biochemically controlled on octreotide or lanreotide depot monotherapy. Target enrollment for this study is 52 patients. These patients will remain on their injected depot monotherapy through a 1- to 3-month screening period, during which time we will establish baseline values for parameters such as IGF-1, growth hormone, and total acromegaly symptoms diary score. After completing the screening period, patients will be randomized to receive once-daily oral doses of paltusotine or placebo. IGF-1 assessments will be conducted each month throughout the study's 9-month treatment period. Patients randomized to paltusotine will start at a 40-milligram per day dose. If during months 2 to 6, a patient's IGF-1 level rises above 0.9x the upper limit of normal, that patient's dose will be increased to 60 milligrams as some patients may need a higher dose. Alternatively, the dose can be decreased in 20-milligram decrements if necessary for tolerability reasons. Patients will then be maintained on the dose that was established during the first 6 months of the treatment period. An average of the 3 IGF-1 assessments measured at weeks 32, 34, and 36 will serve to determine IGF-1 responder status.

Thanks, Alan, and good afternoon, everyone. I'm pleased to report that in 2020, Crinetics was able to maintain a strong financial position while making significant advancements in its clinical and drug discovery programs. Our unrestricted cash, cash equivalents and investments improved to $170.9 million at the end of 2020 compared to $118.4 million at the end of 2019. Based on our current expectations, our financial runway extends into 2023, through the anticipated top line data readouts from the paltusotine PATHFNDR studies. As of February 28, 2021, the company had roughly 33 million common shares outstanding. Total operating expenses for the fourth quarter and full year 2020 were approximately $21.8 million and $75 million, respectively. This represented an increase over total operating expenses for the same periods in 2019, which were $15.5 million and $55 million, respectively. Research and development expenses for the fourth quarter and full year 2020 were $16.8 million and $57 million, respectively, compared to $12.1 million and $41.5 million for the same periods in 2019. Increases in R&D spend were primarily attributable to clinical development and manufacturing activities for paltusotine as well as progress in the company's preclinical programs. General and administrative expenses also increased for the fourth quarter and full year 2020, growing from $3.4 million and $13.5 million in 2019 to $5 million and $18 million for the same periods in 2020. These increases were primarily due to personnel costs to support the company's growth. Finally, net loss for the fourth quarter of 2020 was $21.6 million compared to a net loss of $14.5 million for the same period in 2019. For the full year 2020, the company's net loss was $73.8 million compared to a net loss of $50.4 million for the full year 2019. And with that, I'll hand it back to Scott.

Thanks, Marc. Before we open the line for questions, I'd like to take a moment to recognize all our employees, investigators, site staff and patients around the world. Thanks to their talent and dedication amid the pandemic, we have gone from a company that had a single clinical-stage asset to one with an active pipeline of 3 clinical programs, with more on the way from discovery. As you can see on the table on this slide, this progress has left us poised to achieve a steady cadence of milestones over the coming months. By the end of the year, we expect to have initiated both Phase III PATHFNDR studies as well as the Phase II trial evaluating paltusotine in patients with NETs complicated by carcinoid syndrome. We also expect to have established proof of concept for our 4894 and 4777 programs, as our Phase I trials will assess the ability of these candidates to modulate the relative peptide hormone receptors in healthy volunteers. This should be highly predictive of efficacy in patients. This early stage derisking strategy has been validated by our paltusotine program, which was the driving force behind our IPO a few years ago and was executed at the time when paltusotine had completed its first Phase I healthy volunteer study. Collectively, we expect the execution of our clinical milestones to solidify our position as a leader in the field of endocrinology. We look forward to the year ahead and remain committed to working to improve the lives of our patients. With that, I'd like to thank everyone for joining our call today. We'll now open the call to questions, and I'll ask the operator to moderate them.

Our first question is from Charles Duncan with Cantor Fitzgerald.

Congrats, Scott and team, to a good year of progress. I really like the slides, they're very well organized, so definitely appreciate all the detail. First question, though, is timelines to data, data in '23. I mean, very well-organized program for PATHFNDR in Phase III. And I guess I'm wondering what do you anticipate to be the biggest rate-limiting step? Will it be enrollment or identification of the best patients for this trial, appropriate patients for the trial? What is really governing that '23 timeline?

Thanks, Chaz. I appreciate the question. Maybe I'll take that one. And Alan, jump in if you think I'm missing anything. But patient enrollment is always a challenge in rare disease studies, but we've learned a lot from our Phase II program. And we've implemented a range of things to enhance enrollment, not the least of which is letting patients and their investigators know that this drug can switch patients who are on standard of care to paltusotine without loss of IGF-1 control. So that's huge. The other thing is that we'll be using centers all around the world to conduct this study. Probably with these studies, approximately 100 different centers in multiple different countries. So it's always a challenge. We're going to be working hard on site activations and patient recruitment through multiple mechanisms, but we're pretty confident in that forecast for 2023. Alan, did you want to add anything?

No, I agree with that very much, Scott. I also want to remind everyone that these studies have open-label extension periods, both of them. And that always helps with recruitment, particularly in the rare disease state, particularly in studies which are placebo-controlled. All patients who are eligible and complete the trials would have an opportunity to potentially enroll in the open-label extension.

Okay, and then if I may, a follow-up. It seems like statistical significance relative to placebo, certainly in PATHFNDR-1, is a relatively low bar. But I guess I'm wondering beyond statistical significance, what kind of response rate would you like to see in terms of clinically significant results out of that PATHFNDR study?

Alan, do you want to take that?

Sure. Well, so the endpoint is designed to be inherently clinically significant. And this is the preferred endpoint from the FDA and regulatory community, namely the percentage of patients with normal IGF-1. So showing an increased responder rate that is significant in patients who normalize their IGF-1 is inherently clinically significant, and we know that is the preferred approach from the regulators.

Okay. Maybe I'll just add to that, that we've shown in Phase II that paltusotine can achieve levels of IGF-1 that are equivalent or on par with those obtained with the current standard of care. So in PATHFNDR-1 where we're starting with patients already on injectable who are controlled, we would expect very high levels of responders, so 70%-plus. In naive patients or patients not on therapy, that might be substantially lower as it's been shown for the peptides. So we'd expect those to be down around 1/3, as we previously discussed for patients who are new to somatostatin analog therapy.

That's helpful, Scott. Last question, moving on to the earlier pipeline, 4894 and 4777. Using the stimulation test in human volunteers, I get that endocrinology or endocrine systems are fairly well, I guess, conserved. I'm wondering could you anticipate using a stimulation test when you move into patients to identify patients who may be responders and perhaps use that as an enrichment marker?

Alan, do you want to...

I think that's possible, Chaz. I mean that's something that we would evaluate after having seen Phase I healthy volunteer data. It certainly is intriguing to think of it as a companion sort of diagnostic. The only thing I would say, though, is sort of we know that the ultimate markers that need to be controlled in these disease states. And in addition to showing the kinds of stimulation results where we hope to show in Phase I, we'll need to show, for example, in Cushing's disease, that the overall cortisol output is reduced. Usually, this is measured using urine free cortisol collections. So we'll be looking at a large host of markers, including cortisol output and stimulation type results.

Okay.

Thanks, Chaz. I would like to add to Alan's comment. I don't believe we will need to enrich patients in either congenital adrenal hyperplasia or Cushing's disease. In both conditions, patients respond to ACTH at the adrenal level, so blocking ACTH should effectively reduce adrenal steroid levels for any patient with these diseases. Therefore, I don't think we need to be concerned about enrichment. Our focus should be on administering this drug to patients at the appropriate doses determined during this Phase I study.

Our next question is from Tyler Van Buren with Piper Sandler.

Thank you for the updates. I have a few questions on different topics. It seems that PATHFNDR-1 is aligning with expectations, although there may be some variations compared to other trials. The dose titration up to 60 mg should help in effectively managing a significant number of patients. However, I wanted to ask about PATHFNDR-2. Why didn't your closest competitor conduct a similar trial for approval or labeling? Do you think it was because they were uncertain about achieving the same level of control as standard care, or was it potentially more challenging to recruit these patients? Additionally, is there anything about the study that might make patient enrollment easier, such as the shorter 12-week duration?

Thank you, Tyler. Let me address that. The main purpose of PATHFNDR-2 is to ensure that the label does not require patients to have tried or responded to injectable therapies before they can use paltusotine. This is why we focus on treatment-naive or untreated patients. Why should we subject a patient to unnecessary injectable therapy when they could start on paltusotine right after their diagnosis and when they're ready for medical treatment? This was the rationale behind PATHFNDR-2. As for PATHFNDR-3, -4, and -5, I believe -2 is sufficient for the time being. We've already demonstrated in Phase II that patients on medical therapy who had not reached normal levels could maintain their IGF levels comparable to the standard of care. I see that as already achieved. However, as part of our commercial strategy in a couple of years, we might conduct additional Phase IV studies to further refine the label and offer guidance on using it in combination with other therapies. I'm excited about the long-term prospects for this molecule since we have patent protection until the 2040s. We will invest in ensuring we create the best possible label and provide the best guidance to both physicians and patients for this molecule.

Our next question is from Joseph Schwartz with SVB Leerink.

I'm Joori calling in for Joe. I would like to know more about the duration of your PATHFNDR-2 trial. Can you explain where the two-week timeframe originated? Additionally, do you believe that duration is sufficient to evaluate the efficacy of paltusotine in patients who are new to treatment?

Joori, thank you. Alan, why don't you answer that question?

Yes. I just want to clarify the trial duration for PATHFNDR-2, the treatment duration is three months. And yes, it's adequate time for paltusotine to reach a steady state and for the IGF-1 response to paltusotine to reach a steady state. This is evidenced from both our Phase I and Phase II data to date. These are patients who are untreated and start out with high IGF-1 levels. It's a placebo-controlled trial. So it's appropriate to limit the duration to that, which is necessary to show the treatment effect. Three months is very reasonable for that purpose.

Okay. Great. Thanks for clarifying that.

Yes. And as a reminder, they will all also be eligible for an open-label extension to provide additional data on long-term durability of response and safety. This applies to all our Phase II and Phase III studies.

Okay. And then I was just wondering if you could just help set expectations with your new formulation that can be dosed twice as high. How are you thinking about this translating to efficacy in your Phase III? Are you expecting it could be higher? Or like what percentage of your patients do you think you're going to have to get to the higher dose to get meaningful efficacy?

Yes, so in our Phase II program, we showed that 40 milligrams should be adequate for the majority of patients. But we added 60 milligrams just for those patients, which we expect to be a smaller proportion, that may need a little higher exposure levels or weren't getting the full exposure they needed out of 40 for one reason or another. So again, the goal is to provide adequate coverage for all the patients in the study.

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

I know that after the Phase II data, there was some discussion about potentially increasing the dose to 80 milligrams. I'm curious about why you decided on 60 milligrams in the end. Also, I noticed that in PATHFNDR-1 you are measuring the primary endpoint at three time points, whereas in PATHFNDR-2 it appears there are only two endpoints. I'm interested in why you are using these two different benchmarks.

Thanks, Doug. Alan, do you want to answer that?

Sure. On the latter question, so the PATHFNDR-2 study is a shorter treatment period, shorter periods of the final dose stabilization period. So we're sort of more limited in terms of our time frame there. And generally, 2 or 3 to constitute an average IGF-1 is adequate in this kind of setting. And I'm sorry, what was your first question, Doug?

In terms of dosing, I recall discussions about potentially testing higher doses following the initial studies. It seems you might have considered an 80 milligram dose, but it appears you're not pursuing that option. I'm interested in understanding the reasoning behind your decision to go in this direction.

Yes, so this is all based on dose response and exposure response modeling work that's been done and shared with the FDA. And we really believe that as Scott mentioned, 40 milligrams should cover the vast majority of patients and only a small number of outlier patients with the increased exposure. And 60 milligrams should cover that degree of exposure needed in that setting according to the modeling.

Okay. And then just one final question, just typically when you have an untreated patient going on to an injectable therapy, typically how long does it take for them to reach biochemical control?

Generally, long-acting injections are administered once a month. To evaluate the full effect, it's common to wait until after three injections or about three months in a clinical setting. However, with paltusotine, which is absorbed more quickly and taken daily, the time to reach steady-state effect and pharmacokinetics would be significantly shorter.

And presumably, along those lines, just given your ability to dose titrate much quicker should give you a much longer window than what you typically see with an injectable?

A much longer window to assess...

I would say this is not exactly what one would traditionally mean by dose titration. We are starting at a dose that we expect will be effective for most patients, and then we offer a higher dose for those who may need a bit more. It’s not really dose titration; we aim to use the right dose initially, and we have a backup option in case it isn’t sufficient.

And Scott, why was the decision to start with 40 and not potentially, sort of, just given how quickly you can pivot, start with 20 and then move to 40?

There's really no reason for patients to experience a lack of control. So we begin directly with a dose of 40. However, in the PATHFNDR-2 study, there is a brief period where patients start with 20 milligrams before moving to 40. This is because patients who are new to somatostatin analogs often experience some gastrointestinal side effects during the first week or two of treatment. We wanted to provide a gentler introduction to the medication.

Our final question is from Daniel Wolle with JPMorgan.

This is Daniel for Jessica Fye. First, starting maybe with PATHFNDR-1. Is there a washout period after the screening period right before the 9-month treatment period is initiated?

Hi, Daniel. You want to answer that, Alan?

No, no, these are patients in PATHFNDR-1 who are on octreotide or lanreotide. And we screen them, and we find that they have a normal IGF-1. And then they randomize to paltusotine versus placebo at the time they're due for their next injection. So no, there's no washout involved in PATHFNDR-1 initially. But this is a 9-month study. And during that period, their preexisting injections will washout as the paltusotine is taking over control of IGF-1.

Got it. Okay. And then regarding the rescue criteria definition, is it dependent on the two consecutive IGF-1 greater than equal to 1.3x upper limit of normal and exacerbation of symptoms? Or is it just failure on the 2 consecutive IGF-1 scores?

It's based on both IGF-1 and symptoms. And this is a precedented criterion used previously for the most recent acromegaly drug approval. So we do know this is a successful way to manage patients safely through these kinds of placebo-controlled trials.

Okay. And then for PATHFNDR-2, given that these patients are not well controlled, does it make sense to go against placebo? Why not an active agent in the control arm to create a stronger efficacy profile for paltusotine?

We expect that these untreated patients will achieve control once they begin treatment with paltusotine. The reason for using a placebo-controlled design is that such studies offer simpler designs, which assist regulators in better assessing the safety of the drug. Regulators, particularly the FDA, tend to be more comfortable with placebo-controlled trial designs. Furthermore, this type of trial for this patient population is established as a Phase III trial for another approved acromegaly product. Therefore, we believe this approach is the most scientifically rigorous, which will provide us with clear answers in a reasonable timeframe, and it is also the most acceptable to regulators.

But I'd also add, Daniel, that we've got a great deal of baseline control data already with the ACROBAT EDGE study. And we'll be having in PATHFNDR-1 baseline control data to compare with paltusotine as well. So there'll be plenty of active control comparison, just not a head-to-head in these current studies.

Got it. Okay. And the last one, what’s the rationale for PATHFNDR? Sorry, that has been answered. But the other question is, given the shorter duration of the treatment period for PATHFNDR-2, how come data is still being released in 2023 along with PATHFNDR-1, which has a longer treatment period?

Well, studies are always controlled by a mix of recruitment rates and treatment periods. We did pretty extensive feasibility on both studies at sites around the world. So that's why we started PATHFNDR-1 first. The treatment period is a little bit longer. And in PATHFNDR-2, it's a little shorter. So that's why we expect them to finish at about the same time.

Thank you. We have reached the end of the question-and-answer session, and I will now turn the call over to Scott Struthers for closing comments.

Thank you, everyone. I just want to thank you one more time for joining us on the call. And we look forward to continuing the advancement of our clinical and discovery programs. We'll keep everyone updated along the way as best as we can. And have a safe spring. Thank you.

This concludes today's conference, and you may disconnect your lines at this time. Thank you for your participation, and have a great day.