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

Great. Good afternoon, everyone. My name is Jess Fye. I'm a biotech analyst at JPMorgan, and we're continuing the 40th JPMorgan Healthcare Conference today with Crinetics. I'm joined by the company's CEO, Scott Struthers, who's going to give a presentation on the business, and then we're going to follow that up with some Q&A. [Operator Instructions] So with that, let me pass it over to Scott.

Thanks, Jess. Thanks for the invite, and thanks for the opportunity to talk to you and the team and all our investors out there in the virtual world. I'll be flipping through slides and giving slide numbers, which the group can follow along on their own. And first, just start by referring people to our safe harbor statements since I will be making forward-looking statements. But if the audience will go to Slide 3, I just wanted to start by saying we had a remarkable year last year as a company. It really was the culmination of a lot of our strategy over the last several years and very much transformative. We started the year with a molecule that had completed Phase II. And we're looking forward to starting Phase Is on 2 more internally discovered molecules. We ended the year with paltusotine in registrational trials for acromegaly. We're beginning to expand into carcinoid syndrome. We showed clinical proof of concept for 4777, our candidate for hyperinsulinism. We also showed clinical proof of concept for 4894 our ACTH antagonist for diseases of ACTH excess like Cushing's disease and congenital adrenal hyperplasia. Discovery kept rolling and we have new molecules that are entering preclinical development now. In fact, we had so much in discovery that we created a whole new company called Radionetics Oncology to use this technology for targeted radiotherapies for solid tumors and Crinetics' parent remains a major owner of that company. And then we also did a couple of financings and added another $260 million-plus onto our balance sheet, giving us a very strong position. And on Slide 4, we outlined the strategy that got us there, which we've been following since day 1. Our overall goal is to discover, develop and commercialize endocrine drugs. And I should note that everything we've built so far in the pipeline, we've built from scratch in-house. But obviously, there's a number of unmet needs in endocrinology. The biology is often fairly well established. It's not a brand-new field. There just hasn't been enough efforts on drug discovery in the area. But the true nature -- the true differentiator of endocrinology is that these endocrine systems are highly conserved between all mammals. And so we are developing molecules that we can look at in preclinical studies that give us endocrine endpoints we can use as biomarkers for registration, that we can use as pharmacodynamic markers in healthy volunteer studies. And this provides early derisking of molecules and tells us in a Phase I setting, what we have to work with. It also means, because we're working in the rare endocrine space, we can do relatively small registrational studies. And then a new bullet on this slide, for those of you who have followed us. We're also now beginning to expand into additional indications as we get our molecules further along in development. And this follows the general strategy on Phase 1, which is measure hormones in animal studies to derisk in a preclinical setting, measure hormones in healthy volunteers to understand PK/PD and then measure hormones again in Phase II and III in registrational studies. Often, the endpoints end together with some clinical benefits and patient-reported outcomes. This has led to the pipeline that's shown in Slide 6. All of these have been developed internally and the patent portfolio, which you can read about on our more extensive corporate deck, goes out into the 2020s. But while these are rare indications, these are not ultrarare indications, and together, add up to a significant population of patients that we hope to be able to help, which could or should translate into multibillion-dollar markets. And this doesn't include the Radionetics, which I'll talk about in other settings. But Radionetics is targeting a large number of different solid tumors, using these same non-peptide drugs as targeting agents. So let me kind of walk through the pipeline from first to earliest. And I'll start with paltusotine on Slide 8. And just a reminder, for those who are new to the story, somatostatin is a peptide hormone originally discovered based on its ability to inhibit growth hormone secretion. Growth hormone, in turn, stimulates this production of IGF-1 by the liver. And if you have a tumor in the pituitary that results in excess growth hormone, you end up with excess IGF-1 in a disease called acromegaly. And somatostatin agonists are effective at blocking that growth hormone secretion and treating acromegaly. Somatostatins also regulates the activity of the enteroendocrine cells that can give rise to neuroendocrine tumors. These arise mostly in the gut, sometimes in the lung and pancreas and in some cases, secrete excess hormones like serotonin, which can lead to carcinoid syndrome, which is a very debilitating aspect for many of the neuroendocrine tumor patients. But many of them also have what are called nonfunctional tumors that don't have associated secretory syndrome. But in general, there's a fairly large population of patients who also benefit from somatostatin agonists that are on the market. And to date, those have been really important new drugs, but they have significant limitations. The main players are Sandostatin by Novartis and Somatuline by Ipsen. And the primary limitation is simply the route of administration, and this is illustrated on Slide 9. And they're both fairly burdensome injections, need to be administered by a health care provider. Sandostatin, for example, is a 2 ml intramuscular injection that requires reconstitution. Yet in total, these agents are selling on the order of $3 billion. And we think that a once-a-day oral like paltusotine would provide important reduction in the burden of care for many of these patients. In our Phase II study last year, we studied the ability of paltusotine to maintain control in patients who are on standard of care, and that's illustrated on Slide 10. So if you focus on the left side of the graph with IGF-1 or insulin-like growth factor, the gray symbols are patients during the baseline period when they're on the standard of care, which is either Depot Sandostatin or Somatuline. They then switch to once-a-day oral paltusotine. Then, over the course of 12 weeks, measuring then the IGF levels at the end of that treatment period. And you can see that the IGF levels at the end of -- on paltusotine are the same as the IGF levels on standard of care, indicating that we can switch these patients from the injectables to the once-a-day oral and not risk control of their disease. This was very exciting for us and gave us confidence to move forward into a Phase III setting for acromegaly, and that's described on Slide 11. We have 2 studies now underway, PATHFNDR-1 and 2. The first PATHFNDR-1 is similar to the Phase II program, where we're switching from standard of care with 52 patients over 9 months and looking at the maintenance of response compared to placebo. So we just need to be at placebo in that study. PATHFNDR 2 is intended to help us reach out to the remaining population of acromegaly patients who are untreated for one reason or another, either newly diagnosed and naive to treatment or have given up on the standard of care and the burden being too much or were willing to wash out of prior therapies, making them functionally naive to start the study. This is 76 patients with the treatment duration of 6 months and, again, a primary endpoint of responders versus placebo. But the data in acromegaly also gave us confidence to begin to move into additional indications, the first of which being carcinoid syndrome. And so this extends to the strategy on Slide 12. So instead now of measuring hormone levels and -- well, following the previous sequence, we've measured hormone levels in Phase I and Phase II and III studies. But now we're expanding into carcinoid syndrome, where rather than measuring just hormone levels, we're measuring functional effects like diarrhea and flushing. Although we're also measuring some biomarkers, but there are those -- in this indication, it's not the primary endpoint. So that study is getting up and going now. We're doing IRB submissions, activating sites around the country and in other countries. And the overall design of the study is outlined on Slide 13. It's more of an exploratory study, comparing 40 and 80 milligrams of paltusotine versus baseline and each other. And this is looking at patients who have symptomatic carcinoid syndrome with excess bowel movements and some of them having excess flushing episodes. It's a relatively short treatment period because we know from the history of somatostatin analogs that patients see relief from these symptoms really in the first day of treatment. But we need some time to be able to measure a statistically meaningful number of episodes. And so during the first month of treatment, they start at either 40 or 80 and are able to dose adjust up 1 unit, including up to 120 if necessary. So these are doses that are higher than being done in our acromegaly program because we have some evidence from the literature of the peptide hormones -- the other peptide agents, that higher doses are sometimes needed in neuroendocrine tumor patients than are needed in acromegaly patients. But after that first month of dose adjustment, then there's a steady dosing for the next month in which we compare the dose levels, followed by an open-label extension to allow patients to continue on the drug and allow us to understand long-term safety and durability of response. As I mentioned, we're getting this study up and going, and we expect top line data in 2023. Next in the pipeline is another somatostatin small molecule oral agonist, 4777. And this is outlined on Slide 15. The difference with this and paltusotine is it's a different chemical structure but it's got selectivity for a different somatostatin receptor, the SST5 receptor. And the initial indication is for the treatment of hyperinsulinism or congenital hyperinsulinism. And this is a disorder that's very severe in kids, where they're born with mutations in the insulin secretory pathway that cause them to secrete insulin in conditions where blood sugar is low, pushing their blood sugar even lower and causing risk of hypoglycemic events that can cause neurodevelopmental disorders and even death. It's a very burdensome disease. The treatment options are poor. We outlined some of those on Slide 16. But the bottom line is while sometimes surgery can take out a focal disease in the pancreas, the options are often only full pancreatectomy or infused glucose or diazoxide, which is ineffective in about half the patients and has black box warnings for pulmonary hypertension and other things. There are some other agents in development but nothing else looking at the inhibition of insulin. So 777 really is unique in going after the root core of that disease. Plus it's a once-a-day oral and I bet if we did a survey of kids and asked them whether they have some -- rather have a great flavored oral solution or something delivered by a needle, I think we know which direction they'd choose. So we showed last summer in the single ascending dose arm of 4777 that both, first, it was safe and well tolerated up to 120 milligrams. But perhaps more importantly, we showed that we could suppress insulin secretion in a variety of different stimulated conditions, some of which pharmacologically mimic the mutation in kids with the disease. And that gave us a great deal of confidence moving forward into the multiple ascending dose arm, which is described on Slide 18 and is currently underway. So this is a 10-day treatment period. Of course, we're looking at 10 days' worth of safety and effects on pharmacokinetics over time and what are steady state levels of the drug. But we're also looking at the effects on biology, repeating the maneuver that we did in the Phase I setting, in the single ascending dose setting, where we use a sulfonylurea, which stimulates brief hyperinsulinism through mechanisms that very much mimic the genetic mutation in about half the kids. And then we look at the ability of 777 to reduce that hyperinsulinism. We're doing that using a tool from diabetes research, which is called a glucose clamp study, where we mimic the condition of kids with hyperinsulinism being on a glucose support and the ability of the drug to withdraw that glucose support. Of course, we're also measuring other things each day, the obvious safety parameters, but also fasting plasma glucose, insulin, et cetera. And the main goal of this study then is to give us the go-ahead for Phase II, help us bracket the dosing and give us the final PK/PD information we need to scale dosing to the pediatric population as well as examine the effect of biology over the course of 10 days and ensure that we don't have some loss of responsiveness with time, which we haven't seen in a preclinical setting, but you do want to do that in a human setting. So we're excited to see the results of that. We're gearing up, if that's successful, to just launch the Phase II program for that later this year and expect to hear more and more updates to that in the first quarter. 4894 is our other internally discovered program also in Phase I. It also is a first-in-class nonpeptide oral small molecule, in this case, as an antagonist of the hormone ACTH or adrenal corticotropic hormone. And the role of ACTH is outlined on Slide 20. It's the center of the stress pathway. It integrates all the various stress detection systems in the body, integrate at the secretion of ACTH. That then acts at the adrenal gland to control the secretion of cortisol. Next to a single receptor, the melanocortin type 2 receptor who is a professional ACTH receptor doesn't do anything else and it's right there in the adrenal and nowhere else. So it's really as a single choke point for what's called the hypothalamic-pituitary-adrenal axis. And it's something that people have looked for, for many years. In fact, we first knew about Cushing's disease, which is one of these applications in 1910. And there's 60,000-plus papers in PubMed about ACTH. But this is the only antagonist program that we know of and the only one that has entered the clinic. So the initial indications for this are Cushing's disease, which is very much like acromegaly. It's caused by a benign adenoma of the pituitary gland, but in this case, cells that secrete ACTH. And as you can imagine, this over activates the adrenal gland, results in high levels of cortisol. The other indication that we're looking at is congenital adrenal hyperplasia. This is a little bit different in that it's a disease of too little cortisol because the enzymes that make cortisol have been mutated and nonfunctional. And that results in a loss of negative feedback to the pituitary. So there's way too much ACTH in this case. And the ACTH stimulates reduction of precursors to cortisol by the adrenal. Most of those are androgenic and have a variety of negative effects, both in men and women. So Slide 21 shows the place of the ACTH antagonist in this treatment. In this pathway, it's the only way to directly act at all of the functional aspects of the adrenal gland. Each of the other agents have a variety of limitations, whether they're pituitary directed or steroidogenic inhibitors or glucocorticoid receptor action blockers like mifepristone or RU-486. So this is something that the endocrine community is really excited to get their hands on, and we're eager to bring it to them as soon as possible. In the Phase I SAD setting, we showed, again, single doses that were well tolerated up to 80 milligrams. We saw good pharmacokinetics and drug-like properties. And more importantly, we saw that it blocked the actions of ACTH, consistent with the mechanism of action, and allowed us to see dose-dependent suppression of cortisol production, giving us pharmacologic proof of concept. So now we're in the MAD portion of that Phase I study just like 777, and this is outlined now on Slide 23. But again, it's a 10-day protocol, measuring a variety of things each day. But one of the key things we're measuring is the stimulation of cortisol production by an ACTH challenge, both at screening and after we've achieved steady state at day 10. So the idea is that 4894 can prevent excess cortisol production or at least reduce it. And again, we're using this to -- as a gate to Phase II to help us bracket our dosing to understand safety over a multi-dose setting and to understand any effects of multiple doses on the biology of these pathways. So we're excited to see this data. And it comes out again in the first quarter. And also, we expect, if that's positive, to be starting the patient studies, Phase II later in this year. But Discovery Group hasn't slowed down. And we did last year announced the next program we anticipate to enter into development. And those are antagonists of the hormone -- parathyroid hormone. This is illustrated -- some of the indications for this are illustrated on Slide 25. The parathyroid hormone has a variety of actions in the body to control calcium metabolism that acts at the bone, the kidney, the intestine. And in cases where you have too much parathyroid hormone, you have imbalances in calcium and effects on bone and effects on kidney. And so an antagonist is a logical way to help mitigate this excess PTH. Perhaps the most obvious indication is primary hyperparathyroidism. This is very much like the pituitary diseases I told you about earlier. It's caused by a benign adenoma, in this case, in the parathyroid gland that secretes too much parathyroid hormone. It's actually fairly high incidents with more than 100,000 cases a year in the U.S. Many of those are treated surgically. And a good surgeon can often remove the diseased gland. But there's also quite a few patients who don't successfully undergo surgery or unable to for a variety of reasons, leaving a treatable population similar to what we see for acromegaly. But beyond that, there's other diseases of excess PTH. In many late-stage cancer patients, they start secreting a hormone related to PTH called PTHrP, which activates the same receptors and causes humoral hypercalcemia of malignancy that can be pretty debilitating in that population. And then there's a whole bunch of different indications or subsets of patients in the chronic kidney disease setting where the kidney failure results in lack of vitamin D and an inability to properly regulate PTH secretion. And this is really quite prevalent and a various subsets of these patients may benefit from a PTH antagonist. So you see, again, in this program, the paradigm of animal studies giving us measures of calcium control, going into healthy volunteers, measuring calcium and some other markers, then getting into primary hyperparathyroidism and then expanding the indication into some of these more broad indications. And this program is now at the stage we call candidate selection. We've got several molecules that, as best we can tell, have all drug-like properties and good behavior in animal models. But we're doing some non-GLP toxicology studies to understand the safety margins of each -- or at least, I should say, begin to understand the safety margins of each and select the best candidate and hopefully a backup for first in man enabling studies. Typically, when we identify that candidate, we're able to get it then into a clinical Phase I setting in about a year, given all the work in CMC and toxicology needs to be done. And then we go back into a healthy volunteer setting and look for clinical proof of concept like we did for the 3 programs I told you about before this. So if I put all that together, you see what happened last year. This year, we're expecting quite a bit of moving the ball forward as well. The MAD data for both studies coming out in the first quarter, the paltusotine carcinoid syndrome study, getting the first patient dosed in the near future. I think getting clarity and getting a start on those Phase II programs for 777 and 4894 will be really important for many of us. and of course, making sure we have that next part of the pipeline moving forward. Because after all, the goal for the company really is to build a sustainable pipeline, continue to invest in discovery but take those all the way to patients that need them around the world. This sets up for a big year in '23 with the readout of the PATHFNDR studies, the readout of the carcinoid syndrome study, getting that Phase I proof-of-concept data from the PTH antagonist and, of course, watching the progression of the other pipeline programs moving forward as well. So with that, I'll stop and thank the audience and turn it back to Jessica for the Q&A session. Thank you.

Great. Thanks, Scott, for that presentation. [Operator Instructions] Maybe I can start with paltusotine. You described your Phase II data in acromegaly. I guess, is there anything specific you would call out about the profile that gives you confidence in the success of the ongoing Phase IIIs?

Let me also introduce Alan Krasner, our Chief Medical Officer; and Mark Wilson, who are here in the room with me. And let me ask Alan to answer that for you.

Yes. Just -- Scott described our Phase II clinical trial results in acromegaly patients, which show that paltusotine has IGF-1 suppressive properties, very similar to the approved first-line injections. That was -- those apparent Phase II studies were core studies and about 13 weeks in treatment duration. But that was the original impetus. Since those studies have read out, we have reported data from our long-term safety extension study. It's called Acrobat Advance, which basically show a long-term maintenance of IGF-1 control, very similar to each patient's baseline level. This goes out -- these data go out 51 weeks, up to 51 weeks in duration. So it basically gives me further confidence that paltusotine has about the same degree of efficacy in acromegaly patients as do these injections.

Got it. And you talked about the designs of the PATHFNDR trials. But can you also describe the powering assumptions for each of those studies? Why is the PATHFNDR-2 study in the treatment-naive patients smaller than of PATHFNDR-1, switching from standard of care?

Right. Sure. Absolutely. So PATHFNDR-1 is a trial in which patients who are biochemically controlled on one of the injections are switched to paltusotine, this time, for a 9-month period. It's a placebo randomized controlled trial. In that setting, based on the Phase II data we saw, we would expect that a large number of the patients who are switched from injection to paltusotine will maintain their biochemical control. And in both of our trials, by the way, the primary endpoint is percent responders, responder being defined by normal IGF-1 levels. So we are anticipating around -- we were, for sample size calculation purposes, we're estimating around a 70% response rate in those patients who switched to paltusotine. And those who switched to placebo, we're estimating more like a 20% response rate. This is based on the experience in the recently completed OPTIMAL trial Chiasma ran which led to the most recent acromegaly approval. So the sample size calculation in that study is 52 patients would give us 90% power to show a difference. Again, as Scott said, all we need to do is beat the placebo arm between active and placebo. The other trial, PATHFNDR-2, this sample size is actually a bit higher. PATHFNDR-2 are patients who start out with high IGF-1 levels because they're not currently being treated or naive. And in this case, we're using -- they're being randomized to either paltusotine versus placebo. And in this case, we are estimating a responder rate that's lower than PATHFNDR-1. And that is very consistent with clinical experience with octreotide or lanreotide. Most patients treated with either of those drugs. Only the minority of them actually achieve a normal IGF-1 with monotherapy. So our estimated responder rate in that trial is lower. And for that reason, the sample size is a bit higher. That 76 patients should give us 90% power. Is that helpful?

Yes, thanks. How many patients do you expect might need to titrate up to the 60-milligram dose in Phase III, given it kind of seems like the 40-milligram dose should generally be adequate? And how will physicians make that decision?

So, absolutely. Our dose response and exposure response analysis predicts that 40 milligrams should be adequate for most patients with acromegaly. However, you're right to say that in our Phase III trials, we do have an opportunity to uptitrate to 60 milligrams in the event that certain individuals might need more. The decision to do that is based very simply on IGF-1 control. If their IGF-1 is not at target using the 40-milligram dose, then the investigators can increase to 60 milligrams a day. We have this because there's always outlier patients who might need higher doses. And we have to remember that acromegaly itself can result in alterations in body composition that might affect the amount of drug that's necessary to achieve the therapeutic exposure that we're looking for.

And when do you expect to reach full enrollment in the trials? Is that something you'll announce? And similarly, when could we see data? And which study would you expect to read out first?

Well, we've guided '23 for the data readouts and we've tried to be a little vague on exactly when for obvious reasons and largely because we're not exactly sure which would read out when. So I'd welcome all our viewers to join our internal pool as to which study finishes first. The second study is a little larger but shorter, and it starts a little bit behind the first study. So it's kind of a horse race. We're not sure which, when. I do think we'll announce as we finish enrollment in each of the studies. And then it starts the clock ticking, and you'll know more about the time line.

Got it. And what's the size of the commercial opportunity in acromegaly? I think one of your slides flashed up the revenue for the injectable products, but I think that includes NETs in some instances. So what about the acromegaly market in particular?

Yes. One of the things we're doing this year and I hope will be useful to investors is to really talk more about the market opportunities for all our programs. So our best guess at the moment for acromegaly -- and it's more than a guess. I mean, we've been digging pretty hard. But these numbers aren't directly available, so it's still inferred. But if you take the sales of the existing somatostatin for acromegaly and you add in somavert which sells a couple of hundred million, it's a growth hormone antagonist, then you add up to around $1 billion in sales of the existing agents. So overall, a $3 billion market. And then that leaves the remaining $2 billion as neuroendocrine tumors plus some off-label uses for some smaller indications. But actually, there's a piece of that, that doesn't make sense because you may have noticed in our early slides, there's way more than twice as many patients with neuroendocrine tumors as with acromegaly. And even just carcinoid syndrome alone is probably 3x the treatable population of the acromegaly indication. And so our hypothesis that we're trying to dig into -- and I should say that the treatment guidelines recommend somatostatin analogs for most of the different types of patients with neuroendocrine tumors, whether they're functional or with carcinoid syndrome. So our hypothesis is there must be a significant number of patients who, for one reason or another, are not getting or refusing care based on the burden of care. And the question we're asking ourselves is, can we unlock that market with a much more lower burden of care with a once-a-day oral.

Got it. So that's a good pivot into next. Can you elaborate a little bit more on your clinical development strategy in that setting? And I guess to the extent you think that NETs are undertreated with the injectable products, what do you think the commercial revenue opportunity is for that segment and maybe as well as the slice that is carcinoid syndrome?

Yes. So the kind of simple answer for the strategy is acromegaly, carcinoid syndrome, they're nonfunctional tumors. The nonfunctional tumors are going to take a little longer, bigger study. And the carcinoid syndrome is shorter and more focused. So I see a staging of indications. In terms of the revenue opportunities, this is something, again, we're trying to really look at. The proven cash revenue already is $2 billion. But exactly the makeup of that between carcinoid syndrome and the nonfunctional tumors is a little less clear. But we're beginning to think that quite a few -- maybe the majority of patients in the -- that are being treated with the analogs now have carcinoid syndrome because really, it's a highly motivating disease and the somatostatin agonists are really quite effective. In the nonfunctional tumors, these are really pretty slow growing. And you do know that quite a few patients choose to do a wait-and-see type of approach. And if the tumor starts to progress, then they address it. I hope we might change that equation with a lower burden of care because even in the nonfunctional tumor, somatostatin analogs have been shown to be pretty efficacious in slowing down PFS.

Great. Maybe we can switch gears and talk about 4894. What levels of cortisol reduction do you expect to see in the MAD data?

Maybe you want to take a shot at that, Alan? And then I'll make a comment.

Yes. The MAD is 10 days of dosing. And it's -- we're going to be assessing safety PK. The PK will be at steady state. The pharmacodynamic assessments which show cortisol suppression, I expect to be largely the same. And we will have demonstrated that it is intact over a period of chronic dosing. Remember, we're dealing with healthy volunteers in the Phase I study. But this PK/PD data will be used to construct a dose prediction model for patient studies, which we hope to kick off at the end of the year. Based on the relevance of the ACTH exposure, the disease relevance of the ACTH exposure, we believe that the cortisol suppression is predictive of efficacy in patients because we can estimate how much ACTH these patients are exposed to.

Yes. So maybe I'll add to that. So I agree with Alan that it's predictive, but I would say more qualitatively, not quantitatively. So what we need to do in the patient setting in Cushing's disease is lower 24-hour urinary cortisol levels after a significant period of time, months of dosing. And in CAH, similarly, lower adrenal androgen levels and their requirement for glucocorticoid add-backs after months of dosing. And those are relatively long-term steady state endpoints. And yet in our SAD studies, we've got a lot of fast rates going on. We've got the decline in synthesis rates of cortisol. We give an ACTH challenge, which has a half-life of minutes. And so while I realize the desire is to handicap the late-stage studies relatively quantitatively, I think fundamentally, the Phase I is telling us about pharmacology but not necessarily about quantitatively what we expect in a late-stage setting. And then in the end, a lot of patient -- a lot of folks are asking about like a percent. I think that's not quite the right way to think about it because in the disease, what you care about is not so much a percent lowering but a normalization. So can we get a Cushing's patient back to the normal range of cortisol? And if they start high, the percent of reduction is even higher to get back to normal than someone who's just above normal and comes down. So I think it's more about normalization. And I could say something probably similar in the CAH patients, right? We're trying to get them back to physiologic cortisol replacement and eliminate all the bothersome aspects of the androgens that have most of the squall eye of CAH. A long-winded answer of saying it's hard to make that quantitative translation.

And I hear what you're saying on that. But just to push back on that a little bit, I think if you showed a very low percent change, folks might not be as optimistic about normalization in patients down the line. So is there some kind of minimum change that you would want to see? I think Alan said PD that was the same. And I think maybe he meant the same as what you saw in a single ascending dose?

Yes. You wouldn't want to see a big drop in efficacy over 10 days, right? Now I don't know mechanistically why you'd expect that, but that would not be a good thing. And I must say we probably haven't explored the full dose range as well, right? We're a bit limited in how far we can go in patients. We might be able to go higher -- sorry, in healthy volunteers. We might be able to go a bit higher in patients. But these are all the types of questions we're asking in the MAD studies right now. And it's a traditional MAD. So we're playing with different doses and working our way up.

Okay. Great. Well, look forward to that update soon, and we are out of time. So we've got to leave it there. But thank you for the presentation and the thoughtful Q&A. And thanks, everyone, for listening in.

Thank you, and best wishes to everybody.