Okay, I guess we're live.
Yeah, I think we're ready to go. Welcome, everyone. I'm Josh Schimmer from the Cantor Fitzgerald Equity Research Team. Very pleased to introduce from Crinetics, we have Scott Struthers, Founder and Chief Executive Officer, Gayathri Diwakar, did I get that right?
Right.
From the investor relations team. So thanks so much for joining. Maybe first, quick snapshot of the company, and what we have to look forward to over the next 12-18 months.
Yeah. Thanks, Josh. Always great to chat with you, and for those who don't know us too well, we're a San Diego-based company doing work in endocrinology and endocrine-related diseases, and maybe some of the things that I think are a little different is that our whole pipeline's been built internally by our discovery team, and there's really nobody else out there that's got such a concentrated focus on endocrinology. We start in the area of acromegaly, which is an orphan, fairly specialized pituitary disease, but our pipeline goes all the way down to things for Graves' disease, Graves' eye disease, and in discovery, we're working hard on oral small molecules for obesity and diabetes.
We're scheduled to submit our first NDA this fall, and very eager to make the transition from a, what I think is a very strong R&D company into, hopefully, a world's premier, fully integrated endocrine company.
Excellent. So then maybe leading with paltusotine for acromegaly to very positive clinical trials, and okay, but subpar standard of care with the somatostatin analog. So as you're thinking about, you know, your foray into the commercial market, I think one thing that has been apparent and that you've also emphasized is your connectivity to the endocrine community. So maybe you can talk a little bit, you know, especially given how vast the endocrine community can be, talk a little bit about that network that you have and how you can leverage that most effectively.
Yeah, so the endocrine community, I don't know that it's vast. It's you know, if you go to an Endocrine Society meeting, which is every year in the early summer, it's maybe seven, eight thousand people. And you know, I've been part of it since I was an 18-year-old undergrad, where I started working on somatostatin and spent my graduate work working on the pituitary, so I've been part of that community my whole professional life. And I just got back from a great meeting in Seville, where all the top leaders in acromegaly, there's about 40, 50 people there, get together to review the latest literature, their latest experiences, and write the consensus guidelines. And it's three days of you know, pure talking acromegaly and eating tapas and Aperol spritzes in the streets of Seville.
That community is, you know, looking for ways to improve the care of pituitary patients, and not just improve the care in their centers of excellence, but to improve the care for everybody out there in the community, and that's why they write these guidelines to try and teach what the best level of care is. I think part of our approach to this is maybe a little different. We're not just there throwing money as a sponsor, we're there as part of the community, trying to help solve these problems to improve care for patients. That goes from, of course, developing the next level of a drug that I think we have. You know, I think paltusotine, the data just shows it's, it's another step above anything else that's available.
But it's also about helping propagate knowledge about how to properly treat acromegaly. It's about teaching patients what they deserve in their care. It's about improving access to these medicines. So we're taking a very holistic, collaborative approach to taking care of patients as a partner to the HCPs and KOLs, not just somebody selling drugs into a market.
So for that pituitary brain trust, you know, that you are a part of, as we think about the shortcomings of the injectable somatostatin analogs, so I think for most of us, the perception is they're fine, but they're IM injections, and so wouldn't it be better to have a pill? Is it, you know, where would you go beyond that? You know, to what extent is the enthusiasm for paltusotine driven by that versus other differentiating parameters?
I think that's the easiest and perhaps a superficial way of looking at it, that yeah, it's a terrible injection, and more than half the time they're not even given properly, so that's easy. But the other problems are that it doesn't last all month long, and so patients have a lot of breakthrough symptoms that often go unrecognized 'cause they don't know there should be another option. The other one that has resonated with the community is, if you start on these monthly depots with a new patient, you start at a low dose. It takes three months before you can tell whether that dose is working, so you go to the next dose, so now you're at six months, and you may need to go up one more dose level.
So you could spend half a year or the better part of a year trying to get the dosage right, and our phase three showed that in two to four weeks, you're there. And it's not just about a speed then, it's about, can you use it differently? So if you've got a new patient coming in and you schedule a surgery for them three months out, well, you're probably not going to put them on the depots 'cause you won't even know if it's working by then. But you could use paltusotine right then and there and give them some symptomatic relief while they're waiting for their surgery. So I think that's kind of eye-opening, you know, and it's just one piece, right?
Maybe we can talk a little bit about commercial strategy, how you expect that to evolve heading into the launch, observing, you know, a couple of things. One, you know, you do have these highly specialized centers of excellence, but then what we find is lots of onesies, twosies out in the broader endocrine community, practices that are primarily obesity and diabetes, and then I've got a couple of acromegaly. So how do you kind of reach those? And, you know, yesterday, you also announced a departure of your Chief Commercial Officer. So maybe you-
Yeah
... can add a little bit of context to that and, you know, what your timelines might be for bringing in someone new.
Yeah. So, yeah, we'd announced yesterday that Jim Hassard, our Chief Commercial Officer, is leaving. He's been a great colleague and has laid a solid foundation and built a great group under him. And nothing's changed in terms of our broad strategy or timelines. We're still on track for submitting the NDA this year, and by this year, I don't mean December 31st. But and the broad strategy of collaborating with the community is still the same. But if anything, I think we're even more ambitious in our aspirations, given the quality of the data and the fact that paltusotine just seems to be the next level of care. And then in terms of... Sorry, how are you phrasing the r emind me how you phrased the beginning of the question about how-
About how your commercial strategy may be taking form and evolving over the next year or so into the-
Yeah. So I think the things you'll see is, first, we're trying to really understand where the patients are. As you said, not all of them see the centers of excellence, and they probably should, but they don't. I was shocked to learn at the Seville meeting that the bulk of pituitary surgeries are actually done by surgeons who do one or two pituitary surgeries a year. They can't be very good at it if they do that. So we need to help on several levels. We need to promote patients getting to the centers of excellence, but we also have to help promote the standards of care developed as part of the consensus guidelines out into the community so that patients are receiving appropriate care, whether they're at the center of excellence or out in the community.
And part of that is probably gonna involve also educating the patients so that they know what good looks like and are able to ask for it. And so the things that we're doing now are spending a lot of time talking to physicians to understand their current thinking, what might resonate with them in terms of some of the things that differentiate paltusotine, so we know where to emphasize, figuring out how to get beyond the pituitary centers out into the community, and then, building relationships with the patients and patient groups, which we've been doing for years. But, you know, we're gonna need them to help, ask for what's best for them.
So it sounds like you're starting to focus on what could be thousands of patients with acromegaly who should be treated but may not be treated. What kind of spurred that recognition that there may be a large pool of untreated patients, and what is your strategy to it, to try to identify them?
So this is where we're really trying to dive deep. From a prevalence point of view, there's about 27,000 patients in the U.S. From the claims data, there's about 10,000 on medical therapy. So what's happening to those other 17,000? I doubt they're all surgically cured. I doubt it. And we know that from a couple different ways, one of which is just our own data in the PATHFNDR program. So in PATHFNDR-1, where we're switching patients from standard of care onto paltusotine, we had a criteria that they had to be controlled with an IGF level below one times the upper limit of normal in our central assay, which is a gold standard assay. And we had a 50% plus screen failure rate, largely because the patients who the investigators thought were controlled weren't actually controlled.
I already know there's quite a few patients out there who aren't adequately controlled. I think there's this whole balance between the burden of the disease and the burden of treatment that causes people who are, you know, somewhat controlled to not take therapy because the burden of the treatment outweighs the potential benefit to them. If we lower that burden with a once-a-day oral pill, like we're doing with paltusotine, I hope we can shift more patients onto therapy.
When you talk about control, I assume you're first referring to the IGF-1 levels being elevated, and if that is the case, to what extent is that a clear correlate to actual symptomatology, right? I mean, if patients seem okay despite a high IGF-1 level, is there still a rationale to treat, and may there be a cohort of patients who are just tolerating that fine?
Yeah. So there's a movement in the patient community that is messaging that disease to them is more than just a number on an IGF assay... and yeah, you might take an IGF at the beginning of the month, and it looks normal, but two weeks later, you're starting to sweat all the time, and your face is swelling, and your joints are aching. And so you may think you're controlled from a IGF point of view, but you're clearly not from a symptom point of view. And with a once-a-day oral, I think we have the opportunity to provide more continuous control throughout the month and, you know, over time. And I think that means something to people, right? 'Cause it's a little bit like... You don't feel your IGF level, you feel these symptoms.
And so in the end, we're trying to make people feel better and live longer. If the IGF is high for a long period of time, you're gonna have damage. Kinda like hypertension, you'll have long-term damage, but you may not feel it because of the IGF, but you will feel these symptoms.
Where do you expect the greatest inertia in shifting this market will likely be?
You know, I think, we're gonna have to find that out. So you could argue that if you're well-controlled on an injectable, why rock the boat? And that may be the view of a physician, but you ask the patient who's going in every month, trying to, you know, drive across town, find parking, and then can't sit for a couple days, they may have a different perspective on it's working, right? So I think activating the patients, educating the physicians about what the patients really feel, empowering the patients so that they're willing to tell their doc that they have these symptoms coming through, you know, each month. I think we need to work across the stakeholder spectrum to help improve the standard of care and to help improve the expectations of standard of care.
Yeah, the data for paltusotine and carcinoid syndrome has also been quite exceptional. I know you're planning on initiating a phase three trial. Maybe you can give us some of the... your latest thinking on that design. And I know some are starting to wonder if a placebo-controlled trial really is feasible, given the current standard of care for these patients. So what is your confidence in that design, including a placebo control?
Yeah. So our thinking is that it needs to be placebo-controlled, but similar to our acromegaly studies, you'll have criteria for rescue so that patients don't get too sick on placebo. But it's the clearest, quickest way to show meaningful efficacy, and it's also something that it doesn't need to be too long. You know, we showed in phase two, in the order of a few months, that you can have very clear signals on efficacy. And apart from that, the study designs will include measuring both bowel movements and flushing, both frequency and severity, and impacts on patients' lives. But we need to finalize our statistical treatments and endpoints and conversations with the FDA, which is coming up this fall.
But it's gonna be a combination of resolving all the symptoms, which are flushing and bowel movement-related.
At peak, do you expect acromegaly or carcinoid to have more paltusotine patients, or is it too early to say?
There's more patients with carcinoid syndrome than there is currently medically treated with acromegaly. But right now, the people on therapy with carcinoid syndrome versus the people on therapy with acromegaly are about the same, and so it's gonna be a bit of a horse race, right? So can we expand the use of medical therapy in both indications? So I don't know the answer yet.
Maybe we can turn to atumelnant. Some again, very impressive data from the ACTH inhibitor for CAH and Cushing's. Maybe you can give a quick snapshot of how you see that product fitting into the treatment armamentarium for both those conditions.
Yeah, so atumelnant, you know, you have to say it three times before you can get to stumble through it. Atumelnant is... it's one of the more remarkable things that we've ever done, and at least that I've seen in my career. You know, we've known about ACTH and Cushing's disease since Harvey Cushing had his first patient back in 1910, and it's been obvious to many of us that the right way to treat these diseases of ACTH excess is to develop an ACTH antagonist. But nobody's been able to do it, and we expected it to be, you know, very efficacious, but the data we saw blew us away.
So in Cushing's disease, our investigator, Lynnette, at the NIH, Lynnette Nieman, is one of the top Cushing's docs in the world, and when patients can't get controlled locally, they go for two weeks for an inpatient visit with her to try and get their disease under control. They've already failed out in top medical centers. And so these patients come to her, and the first or the second day after they start getting atumelnant, they're normal, and she's never seen anything like it. I've never heard of anything like it. And so that was, that was remarkable. And then in the CAH patients, you know, the CAH patients were measuring adrenal androgens, like A4 or androstenedione. And the first time point, which was two weeks after they started on atumelnant-...
They're all coming down to normal levels, and they may start at some of them started in the thousands. They're coming down into, you know, under a hundred or so. It's just remarkable data.
Do you, for both CAH and Cushing's, do you expect these will also be placebo-controlled trials, or would either need an active comparator?
Yeah. You know, the endocrine division and the FDA particularly likes placebo-controlled trials, and I think we need to, you know, first prove efficacy and utility. And an active comparator in an area where, like CAH, you know, what would the comparator be? There's no other approved drug yet other than glucocorticoid replacement, so there is no active comparator.
That could change by the end of the year.
I'd love to do that head-to-head, but-
Yeah, but I mean-
But I don't-
Why, why, why not? I mean, I think the data certainly would suggest that would be a very plausible trial for you to run.
Part of the reason is that you run these trials globally, and, you know, even if crinecerfont gets approved this fall, which I expect it would-
Yeah
... that's only the U.S.
Okay. Right. Fair.
I have a very, very quick question. So the endocrine standard is not testing up to do it against standard of care, meaning that if, when you're designing the trial in the United States, the FDA mandated the other drugs already approved. Like, it's not... They're mandating it not or there are guidelines or whatever it is that they use?
Yeah.
There any that you use then?
No, there's, it's not like some of the oncology drugs where it's standard of care versus a new agent. It's, you know, you need to demonstrate efficacy one way or another, and the simplest way is typically placebo-controlled.
Yeah.
It's definitive, too, right?
Do you have some early thoughts in terms of what the phase III trial designs might look like?
In CAH?
CAH and Cushing's.
Yeah, so I'll take Cushing's first 'cause it's. There's quite a bit of precedent, but the goal is to normalize 24-hour urinary cortisol, and so far, in every patient on 80 milligrams, we've done that in our phase II trial. In CAH, it's a little more uncharted territory. The FDA has apparently guided that glucocorticoid reduction is a clinically meaningful endpoint 'cause the toxicities associated with high levels of glucocorticoid replacement. But the adrenal androgens have a lot of problems of their own, and so we need to have a conversation with them. But what I suspect atumelnant can do is normalize A4 levels and allow you to get to normal levels of glucocorticoids. You shouldn't have to compromise and choose one or the other. You just bring people to normal.
And how you translate that into a statistical endpoint is something that we need to discuss.
Do you anticipate one or two trials for each indication?
I anticipate one at this point.
Okay. I guess Cushing's has some common features to acromegaly in the sense that there is a standard of care. Probably a lot of patients are on that, and so you kind of had PATHFNDR -1 and PATHFNDR- 2 designed to evaluate transition patients from prior therapy as well as new patients. Do you think you would combine those two into a single Cushing's trial, or how would-
Yeah.
How would you kind of navigate that?
Yeah, I think so. I mean, one of the great parts about Cushing's and acromegaly is it's exactly the same pituitary docs at the same pituitary centers. So, you know, whenever I'm talking to one of our friends about acromegaly, they're also always asking me about progress on Cushing's, so there's a lot of synergy there. The advantage of Cushing's is that from the currently available agents, there's not these long-acting depots. It's all daily orals, and that means you can do washouts and switching much more easily than you could in acromegaly, where you've got to worry about the carryover effects from these long-acting depots. So I do think you can combine all comers into a single trial.
Okay. What kind of lag might you expect from between starting phase III for CAH versus the Cushing's program? 'Cause it's a little bit behind.
Yeah. It's... That's mainly historical more than anything else, but we're working now to talk to the FDA, finalize protocols, get the phase III started for CAH, probably early next year, and we're a little bit behind that on Cushing's, so sometime next year, I want to start the Cushing's study, but we're just not quite at the same place yet.
Because you've been wonderfully efficient with your answers, we have six minutes to talk about other pipeline programs, and you know I'm a big fan of-
you know, 'cause we could probably spend the rest of the day talking about those.
Absolutely, but maybe we can talk about the hyperparathyroidism program, some of the unmet need there.
Yeah. So just to be clear, so we're talking about too much parathyroid hormone or PTH, and there's a lot of awareness lately about too little PTH and hypoparathyroidism, but both are problems. You know, if you have too little, you have hypocalcemia. If you have too much, you have hypercalcemia. And too much PTH also causes severe bone damage, kidney problems, other things. And so, in PTH, there's several conditions that cause too much PTH activity. The simplest are benign adenomas of the parathyroid glands. There's four of them in the thyroid, and those cause hypercalcemia, bone turnover problems, other things, bone pain, for example. But then there is what's called hypercalcemia of malignancy, where many late-stage cancer patients start making a PTH-like peptide that causes hypercalcemia of malignancy, and they need something better as well.
And then there's a whole group of different, what are called secondary and tertiary hyperparathyroidism associated with kidney disease. And our approach is to start in the primary hyperpara, which is kind of the most straightforward, clean population, move into hypercalcemia of malignancies, then move into the secondary and tertiaries, you know, as we gain experience with the drug.
I think.
There-
even in primary hyperparathyroidism, I don't know if people see an unmet need today because a lot of patients are treated with surgery, and it has a pretty high cure rate. But I think if you're able to change the treatment paradigm and allow people to take a once daily oral pill, which this will be as with all the pipelines in our compound, it might allow patients to use surgery instead. And there's also patients who are not eligible for or decline treatment, so I think it has the opportunity-
Yeah
- to be transformative.
Thanks, thanks for pointing that out because I think it also says something about our philosophy. So we're not trying to make drugs to go get a slice of some market share in an existing market. We're trying to make drugs that are transform the treatment of patients with endocrine diseases, and I think we'll see that in acromegaly, like we're starting to talk about. I think we can see that in hyperparathyroidism. As one of my favorite co-owners of Crinetics likes to say, "If you had an effective mechanism, why would you go gouge out the parathyroid glands, when you could just treat it medically?
There's no risk to leaving adenomas in place?
Um, there's-
If you can control the-
These are not malignant, so it's not like they're metastasizing. And there is significant risk in doing surgeries, especially above the neck. Just, you know, many people have various thyroid surgeries, and my wife had a thyroid benign. It wasn't a parathyroid, but a thyroid one. And they said, "Well, the one thing you gotta worry about is bleeding. So if you start having any breathing issues, you know, call in and let's take care of it." But, you know, the day after the surgery, she started swelling up, couldn't breathe, could barely intubate her. So it was a life-threatening emergency post-op from that. So it always kinda struck me on a very personal level that you shouldn't take surgery slightly.
Hmm. Could one say the same about pituitary adenomas causing acromegaly or Cushing's, that medical therapy may be a suitable alternative to surgical intervention?
So again, if you can get into one of the great centers, like Mass General or something, where somebody does two, three, five pituitary surgeries a week, I'd go there and get it out. They'll do a good job. But if you're out in the community and somebody's done one or two a year, you got to remember, the pituitary gland is surrounded by the carotid arteries and the optic nerve. It's why it's a very difficult surgery through the nose, and if you can wait till you get to a good surgeon, or in many parts of the world, there's just not access to good surgery. I think a good medical therapy is certainly should be an option.
Maybe, coming back into PTH, why is Sensipar not a perfectly good option for primary, secondary, and tertiary?
Sensipar helps a bit with the hypercalcemia, but it really doesn't change the PTH levels, so it doesn't help the bone. There's a few tolerability issues with it. So I think it's similar. There's a bit of a reasoning by analogy that it helps, but you could do a whole lot better if you had the right mechanism.
Do you think you'd need to show a bone outcome benefit in clinical development for approval, or would PTH and calcium levels suffice?
We're discussing that right now. I think a bone outcome would be very powerful data to help show the benefit of a PTH antagonist. But you've got to balance that against the complexity of the bone studies and the size of the bone studies. So that's something to be determined, but in a phase I healthy volunteer study, we'll see very quickly what the pharmacodynamics are, and that'll help guide the future development of the study. And that's true of most of our programs, where in phase I, early, even the SAD data, single ascending dose data, you really know whether you have a drug or not, and then the rest of the development is about refining the labeling.
I think you're anticipating start of the phase I in 2025. Do you expect to have that PK data next year as well, or would that be in 2026?
No, I expect it next year.
Okay. My sense is that the unmet need in the hyper PTH is somewhere in the ballpark, maybe higher even than hypo PTH. Maybe we'll kind of frame the unmet need from that lens.
Yeah, so, so, like, like, Gayathri was mentioning, there's, there's probably 100,000 patients with hyperpara right now, many of whom go on to surgery and can be resolved. But even then, there's a large number who can't, and, and there really isn't much for the hypercalcemia of malignancy, right? That's, that's a much higher unmet need and a much sicker population. So I think that... You know, I don't have head-to-head numbers off the top of my head. Maybe you remember. I'm starting to get, I'm getting drowned in numbers of all our various markets that we're getting into. But, you know, it's certainly a significant opportunity and probably larger than the hyperpara community.
Right. I think we're probably talking for acromegaly, carcinoid syndrome, we're talking in the tens of thousands. I think this will be more than that, but we don't have a specific number quite yet. I think we need to do more market analysis.
Yeah. I think we're out of time. Scott, Gayathri?