Welcome, everyone. Thanks for joining us for day one of the Evercore ISI Healthcare Conference down in Miami. I'm Gavin Clark-Gartner, one of the senior biotech analysts here, and really happy to be here with Scott Struthers, who is the founder and CEO of Crinetics Pharmaceuticals, and Gayathri Diwakar, who is on the IR side. Thank you both for joining us. Scott, why don't you just start off with an overview of the company where things stand today?
Thanks for having us, Gavin. It's good to be back in the Miami area. Thank you to all of you who got up early for what must be one of the first firesides this morning. I appreciate your interest. So Crinetics is now a registrational stage company focused in the area of endocrinology, and we've actually been operating for a little while. Our whole pipeline is built from things that we created in our in-house discovery group. Our lead program for acromegaly submitted its NDA last September, and we expect a decision then next September. Behind that, it's got another indication in carcinoid syndrome. Behind that, a molecule for treating disorders of the stress hormone axis, like congenital adrenal hyperplasia and Cushing's disease. That's just starting later stage studies.
And then behind that, we have four more molecules that have recently entered development, so you'll start to see new first-in-human data from those over the next 12- 18 months. Also in the areas of endocrinology, but now starting to take some of the tools of endocrinology and apply it to neuroendocrine tumors. And then after that, we continue to invest in new discovery programs. We're based in San Diego. We're well-capitalized and eager to build a global premier endocrinology company.
Awesome. All right, so let's dive right into the programs, and I'm going to switch up the order slightly from what you mentioned. Start off at atumelnant, over on the CAH and Cushing's side. What was the rationale to move the next data update to early 2025? What should we expect from that update?
Okay, so atumelnant is the first-ever antagonist of a hormone called ACTH. ACTH is at the center of the stress pathway when our ancestors were getting chased by lions on the savanna. ACTH goes through the roof and helps you survive, but there's a variety of ways that goes wrong in modern life, which creates disorders of stress, whether it's Cushing's disease or congenital adrenal hyperplasia, or a couple of them, and we're now in phase, just wrapping up a phase I program for congenital adrenal hyperplasia, or CAH, and much to some chagrin, we changed our guidance on the data release from end of the year to early next year, and it was done for a very pragmatic reason, which is I wanted Gavin to enjoy the holidays and not have to write a report on Christmas Eve, just the way the timing was coming out.
So nothing more dramatic than that. We will be reporting data from three cohorts, all out to 12 months or 12 weeks, and I think it gives a good picture of the dose response that is accessible to this molecule.
Yeah, and earlier this year at ENDO, you showed efficacy that was very, very strong. And we've gotten some questions on the safety side, not that there were necessarily issues on CAH, but more about what we should be looking for longer term. So maybe you could just frame the potential events we could be looking for. Is there any type of adrenal risk, even though we're supplementing with glucocorticoid, mineralocorticoid? Should we think about hyperpigmentation? What are we focused on?
Yeah, so what was happening earlier last year. This is an open-label study in CAH, and we also had a parallel open-label study in Cushing's disease. And we started watching the patients come in, and the first two CAH patients got normal hormone levels, which we measure by A4, within the first two weeks, which was the first measurement. It's like, wow, that's stunning. And then the third patient got normal within the first two weeks, and it's like, holy cow, maybe there's something real here. And then the first couple of Cushing's patients, normal within a couple of days, and just on and on to where we felt we really needed to start to disclose this because it was becoming material and all the investigators were talking about it and it was going to come out one way or another.
So we put in an abstract for ENDO that allowed us to talk about the first five or six CAH patients and the first four or five Cushing's patients. And they hadn't all completed, but they'd all had these remarkable responses. And this was primarily at 80 mg, which was the first dose group that we started. So now in CAH, we've finished cohorts of 40 mg, 80 mg, 120 mg. We believe there's 11 or 12 patients in the 40 and 80 mg cohorts and 60 at 120. They're all out now for 12 weeks, so it's a much more complete picture. And I won't expect 100% responses when you start to get the numbers up. You know, something's got to go wrong.
But then Gavin's asking now from a safety point of view, and it's really been very well tolerated from a drug point of view, nothing major to think about. But what we do see in Cushing's is that every patient went from excessive glucocorticoid levels to low glucocorticoid levels, and so they needed some of those glucocorticoids to be replaced. And in the CAH patients, they already don't make glucocorticoids because of a genetic defect in their adrenal, so they're already taking supplemental glucocorticoids, so there's not really a risk in that population of too low. And so other than that, it's been very well tolerated. And then there's the comment Gavin makes about hyperpigmentation. You know, when you ask endocrinologists, okay, what might possibly happen in this situation? And they start struggling for an answer.
The thing that they can grasp out there in the distance is in some odd cases of hyperproduction of POMC products, which is a precursor to ACTH, you can get some melanocortins that cause skin pigmentation. We've been asked about that from a theoretical point of view. We've not seen it. We've not heard of that being seen in other mechanisms that result in high ACTH levels. It's a theoretical risk that we think is minor.
That makes sense. We could spend probably the rest of the time on atumelnant, so let's move over to Paltusotine and cover some more ground. You just laid out your phase III plans. Anything you want to highlight there from the trial design, specifically why flushing was chosen as the primary, any comments around powering, et cetera?
Yeah, so carcinoid syndrome is characterized by two main symptoms. So these neuroendocrine tumors make serotonin and other bioactive peptides that cause diarrhea and flushing. And most patients experience flushing. Many patients experience diarrhea, but it's not always 100% of each at the same time. So you need to think about how do you design a study that treats both of those. And if you require that everybody have both symptoms as an entry criteria, then you start to prune the list. And if you simply do some sort of an endpoint, which is a responder using both as the primary, then that starts to screw up the powering and get complicated. So we came to an agreement with the FDA that our primary endpoint is going to be around flushing, which is the cardinal symptom of carcinoid syndrome.
A carcinoid flush can't be mistaken for much else, not a menopausal hot flush or other things, and then a second key endpoint of diarrhea and/or bowel movement frequency, I should say, to be precise, and then we'll have a stratification so that there's a certain number of patients with that symptom, and then we think that combined, that's enough to seek an indication statement of the treatment of carcinoid syndrome, so having a primary and a key secondary is more a construct of how you think about doing the stats on the endpoints rather than prioritizing one over the other.
Yeah, makes sense. And to be clear, you're testing in carcinoid, not in neuroendocrine tumor, right? So one of the questions we get is, how will providers look to use this commercially since you won't have the PFS benefit on the label? And it's kind of a second question embedded within there is, when you unveiled your NDC platform targeting neuroendocrine tumors, did that inform part of this decision for development in carcinoid?
Yeah, it did. So again, to orient the audience, neuroendocrine tumors are actually reasonably common. And about 20%-30% of those, typically midgut NETs that make it to the liver, cause the secretion of these factors that cause carcinoid syndrome. And the injectable SRLs are known to both relieve the symptoms of carcinoid syndrome and to slow progression of the tumors as measured by PFS. And so the symptomatic relief is fairly obvious. We will, in fact, measure PFS in this study and in the open-label extension of these patients. The problem is there's no real practical way anymore to do a control group as part of the study to have PFS as a controlled endpoint. So we'll have to calibrate those PFS observations against some sort of a synthetic external control group to give practitioners confidence that it's behaving like other SRLs in slowing progression of tumor growth.
But what I've said in a lot of settings is also that the role of SRLs in slowing tumor growth is important, but it used to be the only thing we had. And now there is the whole field of radiotherapies, which I'm sure many of you are aware of, that are having profound effects on survival in patients who start to progress with neuroendocrine tumors. So you have a backup tool. And then if we did figure out some way to invest in a PFS-controlled study, it would be big and expensive. And at the same time, we're developing this new technology called non-peptide drug conjugates, or NDCs, that's a lot like antibody drug conjugates, but using our small molecule platform for targeting in ways that you just can't do with antibodies.
We've just announced that we have a candidate from that program for neuroendocrine tumors and other tumor types that express SST2. Rather than spend our capital on incremental, I'll say, marketing type of data, we're advancing the field with a non-radioactive approach to treat the underlying neuroendocrine tumors, hopefully with a cytoreductive activity.
Yeah, that's great. And for the sake of time, we're actually going to skip over paltusotine and acromegaly today, even though it's on track to be your first approved drug. There's been a lot of discussion in the past. So instead, let's go over to hyperparathyroidism, where there's just been less time and attention because it's been earlier, but now it's progressing nicely. So maybe you could just lay out hyperparathyroidism. What's the current treatment paradigm, the disease, what you're attempting to accomplish with the drug?
Yeah, so hyperparathyroidism. So we could just go on in endocrinology all day long, so I'm sorry we only got 20 minutes here. And so hyperparathyroidism is the next compound after 9682, our NDC, that we expect to get in the clinic. So it's entering IND-enabling studies now. You have four parathyroid glands that are embedded in your thyroid, and they make PTH, or parathyroid hormone. And when they become secreting benign tumors, sometimes one of them or sometimes four of them, they produce too much PTH, which causes hypercalcemia. And that hypercalcemia needs to be managed in a variety of ways. Often you can remove the gland surgically, but there's a lot of patients who can't necessarily have that. There's 200,000 patients with hyperparathyroidism, so it's a very common endocrine disorder, and a lot of those patients just aren't surgical candidates.
But also, I think if we had an effective medical therapy, you might change the notion of surgery as the primary way of approaching it, or at least get it under control and then go into surgery. And we're trying to figure out how this would fit into disrupting the treatment paradigm. But the notion is you want to get the calcium under control. And one of the other things that goes wrong with these patients is severe bone disease. So I actually have a staff member who is. We're starting to get, as we get into more prevalent diseases, starting to have more and more personal connections to the types of diseases we're treating. And she has terrible osteoporosis caused by this. She's had multiple surgeries, trying to get this all fixed and taken care of. Endocrinologist appointment takes six months to get.
The therapies out there are bisphosphonates to help protect the bone and calcimimetics, which can do some for the underlying hypercalcemia, but that's about it. We think there's an opening for something that just fundamentally gets in and blocks the activity of the excess PTH, the very simple idea to a very common disease. In addition to these primary hyperparathyroidism, a lot of late-stage cancer patients start making what's called PTHrP. It's a closely related peptide that does many of the same things and results in what's called hypercalcemia of malignancy. We're looking to apply to that, and we're figuring out the sequence of activities and development. It will all start with a healthy volunteer study where we look at safety, PK, and then pharmacodynamics is measured by effects on calcium and parathyroid hormone.
Yeah, that's great. And maybe just help us kind of frame the market opportunity. You noted the total market size, but maybe give us a little more granularity. Do we know how many patients are ineligible for surgery every year? Or would, second question would be, may opt to not go for surgery? Any analogs to inform that?
Maybe I'll let Gayathri answer with what she remembers on all this. We're just getting into this.
Sure. So of the PTH or hyperparathyroidism patients, about 90% are actually asymptomatic, and so most of them tend to go into watch and wait, but a meaningful percentage do get surgery. And then of the 10% who are symptomatic, a higher percentage of them get surgery, and then the remainder go on medical therapy. So we're still working on exactly what this percentage looks like. And then those patients that get parathyroidectomy, some of those actually still need medical therapy after that. And so there's a couple of places where we can get patients who are on therapy now. And then Scott mentioned also changing the treatment paradigm to divert more patients away from parathyroidectomy into a less invasive medical therapy.
Yeah. All right, so looking forward, when you do start a phase I healthy volunteer study as the first step, is there going to be a challenge component to this one? Or are we going to be looking at just kind of the endogenous biomarkers?
Yeah, I think the endogenous biomarkers may be adequate. There's not a routine PTH challenge. So from a practical point of view, it might be a little tricky to get. But I think we'll learn enough just by looking at endogenous levels.
Yeah, maybe just frame what exactly are those different biomarkers?
Oh, yeah. So if you have PTH, if you give somebody PTH, their calcium goes up. If you block their PTH, their calcium goes down. There's a lot of regulation around calcium, one of which is PTH. So we may see some changes in calcium. It's tightly regulated. But part of that is if calcium starts to go down, your endogenous PTH should start to go up, and you can measure that readily too. So between the two, I think we've got a handle on what's happening to the PTH system in a healthy volunteer. And then, of course, we'll get into the patients where you can look at correcting abnormal levels.
It may be a little early for this question, but have you given any guidance around how quickly you expect these different measures to move and the effect size you're looking to see in a phase I study?
Yeah. Things that happen the same day. So single-dose studies should be adequate to get a signal, but you may want the multiple-dose arms to really understand some of the accumulation of the PK or the accumulation of the biology. The thing that kind of is uncertain in these phase I studies is you've got to pick a starting dose that's well below pharmacology, and then you've got to work your way up through a series of single ascending doses, and then you start into the multiple ascending doses. A lot of the timing depends on how good you are at that first dose selection. If you're low and you've got to step through quite a few doses, it's going to take a while. If you're lucky and you get one that starts to have a signal, you can get some results pretty quickly.
Yeah. All right. Well, we're a couple of minutes over, so maybe I'll just, in many programs, we didn't even touch on, kind of an embarrassment of riches, but maybe you can just frame broadly what we're looking for in 2025 and also what we didn't really get a chance to talk about.
Yeah. So 2025, we'll be expanding our two clinical candidates, our two clinical programs into more indications, later stage of phase IIIs and phase II/IIIs. So you'll see that starting to roll out. But then the 9682 NDC will start first-in-human studies in patients with SST2-expressing tumors. And there's a lot of those, including NETs, but beyond NETs. PTH will start. We have a candidate for Graves' disease and Graves' eye disease. That should start first-in-human studies if the IND-enabling work goes well. What am I missing? We're working very hard to get our obesity programs to a quality of candidate that we're ready to take into the clinic. I know there's a lot going on in that space, but I think there's a lot of half-baked efforts in that space. And so we're trying to make a very well-polished molecule for that.
I'm feeling like I missed a molecule. Did I?
TSH.
Yeah, I got TSH. Getting harder to keep track of this. I need to build myself a cheat sheet. I can't remember the compound numbers of all of them anymore.
We'll expand the session next year.
I appreciate it.
For a longer time period. Well, thank you so much, Scott, Gayathri, for joining us. And thanks, everyone, for listening in. Have a good day.
Thank you.
Thank you.