Welcome to the Morgan Stanley Global Healthcare Conference. I'm Jeff Hung, one of the biotech analysts. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. For this session, we have Crinetics with CFO Marc Wilson and CCO James Hassard. Welcome, Marc and James.
Thanks, Jeff.
Thanks for having us.
So for those who may not be as familiar with Crinetics, can you just provide a brief introduction?
Sure. So, Crinetics actually just celebrated our 15-year anniversary. Company was started by four founders who had been working together for some time prior to Crinetics, and endocrine pathways. And, that's really where the focus has been on discovering, developing, and hopefully soon commercializing small molecules targeting G- protein coupled receptors. And certainly in the last, you know, five, six years, the pipeline has matured beyond paltusotine, our lead product in development for acromegaly and carcinoid syndrome. We now have a second clinical product candidate, atumelnant, which is currently in development for congenital adrenal hyperplasia and ACTH-dependent Cushing's disease.
And then we've got a whole slew of early R&D programs, some of which should be maturing into the clinic here in the next 12 to 18 months. The idea is to really build an endocrine franchise, and there's a lot of unmet need, and this team has figured out how to intervene in a lot of the endocrine pathways, and looking forward to sharing more about the company here today.
Great. Well, let's start with paltusotine. Can you just talk about acromegaly, how patients are currently treated, and the potential benefits of paltusotine?
Sure. Jim, you want-
Yeah, so acromegaly is a disease, a pituitary disease. There are about 27,000 prevalent patients with the disease in the United States. First line of treatment is surgery, but oftentimes surgery is not effective, and so patients then move on to pharmacotherapy. About 10,000 patients are prevalently treated with pharmacotherapy in the United States. 70% of the time, that is what's called an injectable somatostatin receptor ligand. And the other 30% of the time, there are other therapies like cabergoline, SOMAVERT, et cetera. But for those patients that are on injections, they are, you know. We talk to the patients, and there are some downsides.
It's all that's available to physicians and the patients, but it, the injection is usually an 18 or 19 gauge needle, so it is painful. In turn, it is oftentimes patients experience tolerability issues within the first couple of days after the injection, and then, thirdly, oftentimes the depot injection that's intended to be given monthly, the effect of the depot can oftentimes wear off towards the end of the month, so patients have a return of their symptoms or breakthrough symptoms that they experience. The experience that we've had with paltusotine and the benefits of the drug are, first of all, you know, it's an oral medication, so no injection, and that's a real preference from the perspective of the patient.
But secondly, what we have also found is that, again, in the two clinical studies that we've run, there is a rapid and durable effect of paltusotine. So patients, oftentimes see a response within two to four weeks versus three to six months on the injections. The other important piece and important benefit is we're actually seeing fewer of those breakthrough symptoms with paltusotine as a daily, oral medication, and we're seeing less variability in terms of the effect, and less, you know, less issues with tolerability as well. So benefits across the board, especially compared to the injections.
Now, you report a positive phase III results from both your PATHFNDR-1 and -2 studies. Can you just remind us what you saw?
Sure. Yeah, I'll take that one. So the PATHFNDR program was designed to address all acromegaly patients, so those who were on injectable standard of care, switching those patients to paltusotine, as well as to untreated patients, whether they be naive, untreated for some period of time, for a variety of reasons, or willing to wash out. So the switching study was a PATHFNDR-1 study and followed patients for nine months. It was a placebo-controlled study, and at the end of that nine-month period, we saw an 83% response rate in IGF-1, meaning the IGF-1 levels were at or below one times the upper limit of normal, compared to a 4% response rate on placebo. Hit the primary endpoint and all secondary endpoints in the PATHFNDR-1 study.
And we followed that up about six months later with results from the PATHFNDR-2 study. Again, we enrolled untreated patients in PATHFNDR-2, treated them. It was randomized one to one versus placebo, treated them for six months, and at the end of that randomized treatment period, we saw a 56% response rate. Again, same endpoint achieved versus a 5% response rate on placebo. So both studies hit the primary endpoint and all secondary endpoints, which you know was a great accomplishment for the drug and for the company.
Definitely. So the NDA submission is on track for this year. What remains outstanding for the submission? And I guess besides assembling the application, are there any other gating factors on things that still need to be collected?
Yeah, so no real major gating factors. It's a large undertaking to compile and submit an NDA. We're talking about over 4,000 documents go into the NDA package. We have held very productive pre-NDA meetings across clinical, non-clinical and CMC, and you know, that submission should be right around the corner here. We've guided to doing that submission by the end of 2024, and we're on track for that.
Can you just talk about your launch strategy? You know, what activities are underway, and how are you progressing towards those?
Yeah. So first of all, again, we've got a great product, and we're pleased to bring a great product in paltusotine to the marketplace within the U.S. and globally. The launch strategy really focuses, though, on three really core pillars. First of all, extending our relationship that we have with endocrinologists, empowering patients, and thirdly, with the payer audience, is really to ensure market access and optimal access for patients within the United States. So on the physician front, we've been going through the exercise of targeting, finding out who is the predominant treaters, segmenting those physicians as well. We've started a disease state campaign for endocrinologists within the community. On the patient front, we have had a long history of patient engagement through advocacy.
We've had a strong relationship with the acromegaly community, and we're looking to extend that relationship on an ongoing basis with patients. And next year we'll do a lot of disease state type of activity with patients alike. And then thirdly, we've actually already started to build out our market access team. So we have already had engagement with payers through advisory boards, et cetera. And again, we've had strong feedback from the payers on the front of the value proposition that paltusotine brings to the marketplace. Additionally, we've done lots of market research, lots of advisory boards with physicians, with patients alike, and we've already started to build out many of our patient services that will really be that wraparound to the paltusotine product.
Great. And how large of a sales force do you need to reach the 200 healthcare practitioners that are responsible for the majority of prescriptions? And, you know, are there aspects of the commercial launch activities that you might gate until potential approval?
Sure. So the way that the market is kind of currently constructed, I talked about targeting and about segmenting. There are 45 pituitary treatment centers across the United States, and the core 200 physicians that are initiating somewhere between 70% and 80% of all initial patients are located at those pituitary treatment centers. There are an additional 1,800 to maybe 2,200 patients that are outside of those pituitary treatment centers in the community, and we will also plan to have reach and frequency with them as well.
In order to cover off that, say, 2,000- 2,400 total endocrinologists and the 10,000 prevalent patients that exist within the United States, we've done the sizing exercise already, and we estimate that we'll need about 25 - 30 sales territories or salespeople out in the field. And then additionally, will be all those support services and additional services and support that the sales team will need in terms of payer coverage, et cetera. But again, a very cost-effective way to enter, you know, the marketplace for Crinetics as our first real launch. In terms of gating, you know, we're planning. We've built out market access, as I mentioned, we've built out market research, we've built out the marketing function.
The next function will be sales, but we look to approach that in a measured way and in a determined way. So as we have ongoing discussions with the FDA and we get some positive signals, then we'll begin to build out that team, and be ready for launch, be ready for approval.
Great. Let's shift to the second indication, carcinoid syndrome. Can you just talk a little bit about carcinoid syndrome? And then, you know, earlier this year, you announced the positive phase II results. So can you just remind us what you saw there?
Yeah. So, carcinoid syndrome is a subset of patients who have neuroendocrine tumors. They have symptomatic tumors, which predominantly result in a couple of key symptoms: flushing and excess bowel movements. So we enrolled a phase II study. We reported out top line results earlier this year, where we saw pretty dramatic improvements in the sense that the number of flushing episodes, as well as patients with excess bowel movements were reduced greater than 60%. We saw a similar effect in flushing severity as well as bowel movement urgency. So, we're paltusotine is operating the same way you would expect a somatostatin receptor type two ligand to operate, and we're thrilled with the outcome there.
We're now on the path to engage with regulators and align on a phase III design.
Now, you'll be starting the phase III this year after meeting with the FDA. Just where are you in your conversations with the agency, and, you know, has that meeting been scheduled? And what do you think the main aspects that would need to get sign-off from the FDA?
Yeah. So the meeting's on the books with the FDA, and that'll be held here in the near future. You know, what's left to align on? There's not a ton of precedent here, like there is with acromegaly, where there's clear guidance from the FDA on drug development for acromegaly. But, what we know are, you know, the key symptoms are flushing and excess bowel movements. So we see those as very important parts to and likely endpoints in a phase III design. So, from the standpoint of, you know, what do we think the study is gonna look like? Likely, you know, one pivotal phase III study, placebo-controlled, at least three months in treatment duration.
We would like to enroll a broad set of carcinoid syndrome patients, just like we did in our phase II study, where they would be naive, untreated, but symptomatic, as well as patients who are willing to wash out of injected standard of care. So what those endpoints look like is it flushing? Is it excess bowel movements? Is it a composite? Those are things that we need to align on with the FDA here later this year. But we're looking forward to that interaction, as well as providing the clarity on the study design. But the team back home in San Diego is gearing up to initiate that study by the end of this year.
In terms of the study design, how do you think about the potential for measuring breakthrough symptoms that occur with standard of care SRL, SRLs?
I think, you know, it for the, for the naive patient population that we recruit, not, not necessarily a possibility, but for those patients who are willing to wash out of the injectable standard of care, I think there is an opportunity to measure those breakthrough symptoms during the kinda run-in washout period, and then do a comparison, you know, back to that once the study is done. But that's really our opportunity from a standpoint of comparing that to the injected standard of care.
Mm-hmm. And then, as you think about commercializing paltusotine for acromegaly, can you just talk about the potential physician overlap with carcinoid syndrome and what kind of synergy that you would expect with the two potential launches?
Sure. Yeah, so what is interesting. I talked earlier about the forty-five pituitary treatment centers, and these are predominantly academic centers across the United States, and there is a good overlap with the NCCN cancer treatment centers that exist across the United States. So there it's a matter of maybe seeing the oncologist in one floor and then seeing the endocrinology department on another floor, but they're in the same academic institution. So there is good overlap there. There are more oncologists within the community setting that we will, you know, likely expand the team slightly towards, but already there's a tremendous overlap on that front.
Also, what we can leverage moving forward as we move from acromegaly towards carcinoid syndrome and towards our other, you know, endocrine pipeline products, we're also an ability, w e have the ability to leverage all the support services that we're developing, where we have the opportunity to leverage our specialty pharmacy network to in distribution to serve those patients. So there is beyond just the overlap in terms of the prescribing community, there's a number of capabilities that we also have the opportunity to leverage as we proceed from acromegaly through all the other indications that we have at Crinetics.
Great. Let's move to your second asset, atumelnant. Can you just talk about CAH and why atumelnant represents the next generation of therapies for CAH?
Yeah. So congenital adrenal hyperplasia is essentially a disease of excess ACTH that causes excess excessive adrenal androgens. And those androgens essentially can cause development issues in pediatrics, can cause hirsutism, so there are untoward effects of those androgens. The current treatment for CAH is really glucocorticoids, and the glucocorticoid treatment comes with its own level of side effects that physicians are really not happy with. So there is this between the physician and the patient, there's this trade-off between affecting the androgens and also dealing with the side effects of the glucocorticoids. Today, there is no approved treatment. And really, as we look at atumelnant and bringing that to market, it is really getting to the core.
It is really an ACTH antagonist, so it's getting to the core of the issue, and we really see the opportunity not only to normalize A4 and other androgens, but we also have the opportunity to really decrease the glucocorticoid replacement back to physiologic levels. So again, a win-win for patients and for physicians.
Now, you presented initial results recently at ENDO. Could you just talk about what you saw for the data in CAH and how that's differentiated?
Yeah. So, back in June, at the Endocrine Society meeting, we had the opportunity to present at least an initial cut of data from our ongoing phase II study. The majority of the patients were on our 80 milligram dose. We did share some data from a 40 milligram dose of atumelnant. And what we saw was, you know, rapid and profound, and sustained reduction in the adrenal androgens in A4 and 17-OHP. So, these were on the order of 90%. And Jim talked about, you know, finding a way to normalize A4, and we got these patients to normal levels of A4. So, this was a really exciting presentation of data at ENDO earlier this year.
We look forward to, later this year, presenting a more fulsome cut of the data from all three dosing cohorts, and out to 12 weeks.
Okay, and so for that data update, you know, can you just talk a little bit more about what we should expect to see from that update? You know, how might it be different than what we saw from ENDO?
Yeah. So I think it's gonna be really confirmation of what we saw at ENDO. And but again, out to the full 12- weeks for all patients in each of the three dose cohorts, 40 mg, 80 mg, and 120 mg. So there may be some additional clinical signs and symptoms that we've gathered along the way that could be important to share in that setting. What it allows us to do is then go and speak with regulators on what are the next steps here, and we're gearing up to initiate a pivotal study in CAH in the first half of 2025. But having the full data from all three dose cohorts puts us in a great position to go engage with the agency.
Where do you think atumelnant best competes in the CAH market, or, or how do you see it being positioned in the treatment paradigm?
So I think in terms of position, we go back to, you know, this is a unique opportunity to really, again, normalize androgens within patients and really, you know, cut back glucocorticoid levels back to physiologic levels. So this isn't just about lowering A4 or androgens. This is actually about being able to normalize them at those levels. As we get more information, we'll, you know, and more information about competitive products as well, we'll be able to refine our positioning. But the going in position is that this is a unique opportunity to have this win-win in terms of normalizing A4 and normalizing the physiologic levels of glucocorticoids as well.
I know it's still a little early, but what is your latest thinking on the potential design of the phase III and the potential endpoint that you might use? You know, should we expect it to be similar to that that was used in crinecerfont, or are you likely to adjust that endpoint?
I think, you know, it's. It's at the minimum a very good proxy for what we would anticipate our phase III program to look like, and you know, presumably Neurocrine went into that phase III study having discussed this endpoint with, with the FDA, so you know, we'll learn more later this year from, from them, but at the very least, we think that it's gonna be demonstrating a reduction and hopefully normalization of adrenal androgen levels, as well as getting to physiologic levels of glucocorticoids.
Now, the second indication for atumelnant is Cushing's disease. Can you just talk a little bit about Cushing's disease? And, you know, at ENDO, you also presented initial data for that indication. Can you just remind us of what you saw?
Sure. Yeah, so, so like acromegaly, Cushing's disease is actually a disease of the pituitary. So it is a tumor on the pituitary gland, that rather than excessive production of growth hormone, like in acromegaly, this is excessive production of ACTH. And what that leads to is then elevated levels of cortisol, and it's the cortisol then that is then the cause of the disease, and all of the untoward effects of, again, Cushing's disease or excess cortisol. The current treatments that are available include osilodrostat, ketoconazole, some that are on-label, some that are off-label. But all of the current treatments come with their own peculiarities and, you know, unfortunate drawbacks.
And so again, what we see with atumelnant is an opportunity to get to the heart of the matter and to antagonize the ACTH that then will reduce the cortisol and again lead to what we hope to be a better treatment on the marketplace.
Great. Now, you're also expecting to report additional data by year-end. What should we expect to see for Cushing's disease?
Yeah. So, just a reminder, we've been running this study in partnership with the NIH. So what we're seeing, we're recruiting some of the most severe Cushing's patients, and they're being referred to the investigator there. We did share data from a handful of patients back in June, and we've continued to accrue patients in this setting. So we really wanna see sort of confirmatory data from that small handful of patients in ACTH-dependent Cushing's disease. We are looking at additional doses in that setting too. So is there a dose-response relationship? And that should put us in a position to then figure out what are the next steps for this program. As Jim mentioned, there are a number of approved agents out there. They all have their drawbacks and limitations.
You know, we hear it more often than not that endocrinologists are coming to us and saying: "You know, what can you do for my Cushing's patients?" So, it provides us with a unique opportunity with this novel mechanism to deliver, you know, a much-needed therapy for these patients.
Great. Maybe one last question on the early stage programs. You're undergoing candidate selection this year for a number of early stage programs. So which of those programs do you find most interesting?
Yeah, so when we've gotten this question in the past, you know, our boss, Scott, says, you know, he doesn't have a favorite grandchild. I don't have any grandchildren, so I can't give you that answer, but I am pretty excited about the PTH antagonist for primary hyperparathyroidism. This program has been in development at Crinetics for a number of years, and there are about 100,000 patients a year who are diagnosed with hyperparathyroidism. Surgical success rates are high, but there's still a number of patients who either are not eligible for surgery or where surgery is not curative. Roughly 10%-20% have primary hyperparathyroidism and have to go on to pharmacotherapy.
So we wanna make sure that we can bring a novel agent to market here for that indication. But certainly, you know, from our SST3 antagonist for ADPKD, a little bit outside of endocrinology, but an endocrine approach, our TSH antagonist for Graves' disease and thyroid eye disease. And then we've got some programs earlier in development targeting diabetes and obesity, GLP-1 and GIP.
Great, s o l ooks like we'll end there. Thanks so much for your time.
Yeah. Thanks, Jeff.
Thanks, Jeff.