Got the clock running, so we'll jump right in. Good morning, everybody, I think, still. Thanks for joining us for day two of the Citizens JMP Life Sciences Conference. Pleased to have Spruce Biosciences joining us and CEO Javier Szwarcberg to tell us a little bit about their programs and what they're working on. This is a story we've been following for a while, and I think this is actually a really interesting time to talk about everything that's going on with tildacerfont and your program in congenital adrenal hyperplasia. So Javier, thanks for joining us. Thank you. Real pleasure to be here. So this is an area of drug development I think that's getting a lot more interest. In the past, call it a year, it's really heated up. Can you tell us a little bit about Congenital Adrenal Hyperplasia and then your approach with tildacerfont, how you think you could give an option to patients? Yeah. It's a disease that has not seen a lot of research, a lot of advancement, a lot of science coming its way for quite a while. Advent of steroids in the early 1970s, 1980s. The therapy hasn't been modified, and folks had been just accepting the standard of care. I think with the advent of the CRF1 receptor antagonist, which tildacerfont is one of, other therapies have also entered research. And that certainly gives patients that just came back from a patient advocacy group a week or two ago, and there's been you kind of sense a lot more interest, a lot more the community is more revitalized by the amount of research that is and hope. So I think the field is going to continue to change, and I think that's only for the benefit of patients. How do CRF1 receptor antagonists work? They actually bind to the receptor that sits in the pituitary, and by doing that, diminish the amount of hormones pituitary hormones, a hormone called ACTH, adrenocorticotropic hormone that's usually really high in the context of CAH, where the adrenal gland cannot make enough cortisol to sustain life. So cortisol is down, ACTH is typically very high, and puts pressure on the adrenal to make hormone, but the gland can't. So all of the precursors that would have gone into cortisol synthesis are diverted into androgen synthesis. And what patients with CAH experience that are not well managed with externally given corticosteroids is hyperandrogenemia. What are kind of the clinical manifestations of that? Well, high androgens can lead to an array of issues, including depending on the age group, but stunted growth is a very common and a symptom that doctors typically manage for in adjusted steroids to make sure that the kids are within the normal growth curves. Inappropriate maturation in female patients, in girls, it's actually a big deal that needs to be dealt with. The solution, and the only solution that people have had until recently, has been giving patients steroids. You need to give more than the patients actually need to allow the steroids that are given externally to provide a negative feedback on the HPA axis, on the pituitary, and ACTH release and all that. So we've talked about this, I think, in the past, kind of pick your poison. Do you want to have high androgens and have those negative consequences, or do you want to have high steroid use to keep those under control, but then you have Cushingoid-type syndromes? What does that look like for a patient, typically? Do they figure this out, and then do people err on one side or the other? Does that change over time? I think patient needs, frankly, change over time. They do. I think that depending on the age group and what the patient is going through, there will be more or less of a need to be on supraphysiologic doses of steroids. So there will be periods of time when the patient will be more tolerant or tolerate more a state of hyperandrogenemia. There will be times when the adrenals will need to be managed more tightly, and the patient, because of that, will have to receive supraphysiologic doses of steroids. The problem with CAH is that achieving that perfect balance and not that every patient needs to be in that perfect balance. I mean, some deviance from that perfect balance is allowed, but it's really difficult. I can imagine. And I think we jumped over this point, though. But what do we know about the prevalence of CAH? It's actually not a super uncommon, rare disease. It's about 30,000 patients in the U.S., 50,000 patients in Europe. Not that every patient needs to be super tightly managed. The care that patients seek is usually I mean, they've lived with this disease their whole lives. So they're born with CAH. They know they have it. They know they need to take steroids. And by the time they reach adulthood and they become independent, they're probably getting care every, I would say, on the most aggressive side, every three months. On the more normal side, every six months to a year. Which is still fairly frequent. Then you're identified at birth through newborn screening? Yeah. So a nice setup for drug development where you identify patients at birth. We have known biology, and now we have some targeted mechanisms that could help patients. So can you talk a little bit about the data you generated for tildacerfont? And I guess let's focus on the CAHmelia-203 trial that read out a few, I guess, months or so ago now. And you just had some new analyses you guys put out yesterday. So hot off the press, tell us about that trial, what you learned, and then the new data you guys gave us yesterday. Yeah. So we put together a program, and we've discussed this in the past, that comprised two studies in adult patients. We designed a 203 study, which is the study we read out in March, to enroll patients that were not well controlled with the hopes that tildacerfont at the dose that we used in 203 would control the adrenals in those patients and bring the A4 values down and closer to the normal range. Then designed a 204 study to frankly, it's a polar opposite. These are patients that are well controlled, that are properly treated with enough corticosteroids. Their adrenals are under control, and the intent there is to see whether we can wean patients off steroids down to a physiologic dose of steroid or close to a physiologic dose of steroids while achieving, while maintaining the level of control that the patients came with at the beginning on the adrenal side. We designed them in such a way based on our initial one of the first phase II studies that we conducted, a 202 study. The difference between 203 and 204 relative to 202 is that 202 used a higher dose of 400 q.d. Based on prior evidence that we've seen in the past, in other studies, we didn't really see a dose response with tildacerfont at lower doses or higher doses. We thought we were on kind of the upper part of the exposure response curve. To our surprise, when we unveiled the 203 study, we didn't see the efficacy we expected. A number of factors have actually come to light since we unveiled the 203 study results. We realized, frankly, early on that the compliance rates in the 203 study were actually much lower than the 204 study and, frankly, suboptimal for any type of study, measured both by pill count and patient reported. So if you don't have compliance, you're not going to have high exposures in a difficult-to-treat patient population, already difficult to treat even if they would have taken the full dose of 200 consistently. That, frankly, exposed this study, and I think was the major factor driving the efficacy that we saw or the lack of efficacy that we saw. We then, since we unveiled the primary data, we've looked at a number of post-hoc analyses and, frankly, to try to learn off 203 and see what can we apply as we move the program forward, but also to gain conviction about 204, to determine whether do we need to make any changes to 204, what's the likelihood now that we've unveiled 203 relative to 204. And it's clear that patients that were more compliant to therapy appear to respond better to therapy. And that's one of the new analyses that we've released. And also, folks that are taking more steroids, meaning having a disease that's more controlled, tend to have a better response on A4 reduction. So perhaps the bar is lower in 204 patients than it is in 203 patients. I mean, some of the A4s of 203 patients were in the thousands. So their glands were hyper-refractory and, frankly, difficult to control with the dose we used of tildacerfont. So where I'm going with this is I think that the 204 study has a very meaningful opportunity here to unveil positive data. We're also studying. We know that for the 203 patient population, 200 milligrams of tildacerfont once daily given at night isn't enough. So the 205 study, which was set up as primarily a pediatric study, we added two cohorts in that study to treat adult patients prior to dosing children at 200 b.i.d. and 400 b.i.d. And those adult cohorts are going to be, in my mind, quite informative. When is that data coming? In Q3. It's going to come, we're going to unveil the 205 adult and younger patients cohorts concurrently with 204. Interesting. So in patients or healthy volunteers? What are we going to learn from those? No, these are patients. Patients. So enough time to see A4 reductions at what are the doses again? So it's 200 b.i.d. So it's twice the amount we're given we've used in 203 and 204 given in the morning and at night and 400 b.i.d. OK. Monday morning quarterbacking, the compliance coming in, do you see that in real time? Is this a CRO issue where they knew that patients weren't taking the drug and not where patients are just saying, "the heck with it. I don't care. I'm not taking the drug? Yeah. I mean, we're treating the same studies, obviously the same, or have treated the same study. The study is the same. And as part of study conduct, you monitor compliance. I mean, that's an element of that's an important element that's being watched by the data monitoring committee. These are blinded trials. So there was a data monitoring there is a data monitoring committee in place for both studies. And we realized that the compliance rates for 203 patients were actually much lower than 204. While the studies even before we unblinded the data, we put a lot of measures in place to actually ensure that people start taking more drug. I mean, and those are pretty standard measures. And I think we've gone above and beyond to ensure that folks in 203 take more drug, but we just weren't successful. That's partly related to the lifestyle and the choices patients make. You can't force someone to take a drug. They were very honest and open about what they did. Unfortunately, the amount they took wasn't sufficient to result in adequate exposures and an effect size. Yeah. It's tough to get an answer when no drug works if you don't take it. It's tough. In the subset of patients who were compliant, can you talk a little bit more in detail about the effects you saw and how much confidence does that give you? Yeah. I mean. Or is it still too low of a dose, even in the patients that were compliant? Yeah. That's where I was going to go. I mean, I don't want to just hang our hat fully on compliance. I think that the dose we used for the 203 study was actually lower than what the patients needed. Even amongst the patients that were fully compliant, the effect size wasn't what we were hoping to see, definitely higher than the patients that were less compliant. And I mean, also reflected by ACTH. ACTH is kind of a more direct marker of drug effects. For your mechanism. For the MOA. The effect size on ACTH was quite profound throughout the study. We reported the open label effect size of a 45% reduction from baseline. But there were reductions from baseline throughout the blinded period and throughout the extension phase. Just the most profound effect was a 45% during the open label period. So, then, what I think you circled around this. Why should investors have confidence that 204 would work when 203 failed? It's the same dose, but your expectation would be that you don't have to have as tight a control because they're already under control. So it's more of a maintenance-type paradigm than an induction. Is that the right way to think about it, or how would you? Yeah. No, no, no. That's one important element. Another important element is that people in 204 are actually taking more drug. They're being more compliant with therapy. And I think, to your point, I think that maintaining disease control is usually easier than controlling. I mean, you have many examples in disease management, like in asthma. I mean, treating an acute crisis is much more difficult than actually providing control, providing a therapy that's going to lead to sustained control. The dose of inhaled corticosteroids, for example, are much lower. In the 204 trial, different goal. So you're also looking at something slightly. You're looking at can you reduce your steroid dose? Can you talk a little bit about the steroid dose they're coming in at, where they need to go? What do you want to see? And then there's also differences in the trial design between you and Neurocrine, who's got a CRF1 receptor antagonist as well, in terms of how you're allowing patients to drop their steroid dose. So can you walk through kind of that design protocol? Yeah. So patients in 204 are coming in taking more steroids than patients in 203. The average in 203 was around 27. The average in 204 is around 35 at baseline, 35, 37 at baseline. And we have, frankly, a more natural, more standard of care-driven approach to glucocorticoid reductions in the 204 study, whereby patients that have achieved or came in with an A4 that was within the upper limit of normal, they are allowed to actually titrate the steroids down. If they have not reached that threshold or their A4 is higher than the upper limit of normal, they're not allowed to go down, unlike Neurocrine's program, where there's a period of forced titration where patients go down, in essence, regardless of the A4 value. And then, at some point, the steroids are allowed to be titrated up or down, depending on where the A4 value was. I think we'll learn more about Neurocrine. They have announced that it will be presented at ENDO, some of their data. In early June. Right, coming up in June. So I think people are going to make the comparison between the two programs. In 204, you guys have a higher steroid baseline dose. You don't have the forced titration, and you might be at a suboptimal dose that you're testing. How does that interplay with expectations for what you want to see and what people should expect? I mean, I think that the steroid dose in 204, we believe it's optimal for the patient population that we're studying in 204. Frankly, the study results will speak for themselves, and we'll just have to wait until that data unblinding. But the fact that we've not achieved the efficacy we were hoping for in 203, in my mind, does not mean that the odds are meaningfully reduced for 204. I think that I would have loved to see 203 positive data and then a meaningful read-through into what we'll see in 204, but that wasn't the case. Now, relative to Neurocrine, I think that a framework where for the 203-like patients, we embark in a b.i.d. regimen. And once patients are controlled, they can probably go down to a q.d. regimen, assuming 204 is positive, could be a potential differentiator. I think we need to learn more about the long-term safety of each of the molecules and assess whether there are other points of differentiation through clinical measures, which we're collecting and they're collecting and hopefully will be unveiling at some point after the 204 data. Back in March, when we saw 203, we also saw preliminary pediatric data. Can you talk about that study? You mentioned you're adding some adult cohorts, which is interesting. What data will we see in 3Q and expectations there? Yeah. The 205 study, interesting. I mean, there was, in my mind, clear target engagement. I think that there was also an element of variability in the data and lack of consistency across the board on A4 changes. And I think that's reflecting probably variable exposure. I mean, kids have higher metabolic rates, typically. And that metabolic rate usually is attributed to liver CYP expression and gut CYP expression. So I believe that a higher dose in children will probably be very much welcome. And if we can define a dosing regime that will work in children and adults through the 205 study, we can then embark in phase III programs for both the adult and the pediatric indication that will be more encompassing with a dose level that's more suitable. So we're going to have two important readouts third quarter this year. And now, as far as next steps, you're thinking I think you guys have said an end-of-phase II meeting with FDA targeting first quarter of next year, yeah, and then starting two phase III trials in adults and pediatric patients? Yeah. There will be a program in adult and pediatrics, whether it is two separate studies or we make one large study, including both patient populations. Probably we'll do two separate studies. But that's to be determined. I mean, the 204 data will be top-line data based on the 24-week data cut. The pediatric data that we intend to unveil in Q3 will be an interim cut on kind of where we are in that study. And hopefully, it will be informative of the higher doses. But the study is enrolling at the moment. So it's evolving. Yeah. With Neurocrine's drug, crinecerfont, going to FDA review soon and potentially getting the market in the next year or two, what would be a differentiating characteristic for tildacerfont that would make that a more attractive option? Is there a role for two similar drugs, or do you have to be different in some way? In what way could that be? I mean, I think that it's, and I've seen this play out in rare diseases. There will be patients that don't tolerate one drug but tolerate the other. I think patient choice is always important and give prescribers the opportunity to have options. I mean, the q.d./b.i.d. could be a potential differentiator. And we might differentiate on secondary endpoints. We might differentiate on tolerability and safety. I mean, there could be a number of parameters that may actually dictate patient preference in favor of one drug versus the other. And all of those are to be determined as we evolve our program and they unveil data on their program. You guys had also generated some data in PCOS, polycystic ovary syndrome. Is that becoming more interesting, less interesting with congenital adrenal hyperplasia? How are you thinking about other opportunities for tildacerfont? Yeah. The lifecycle management of tildacerfont, given the data that we unveiled in March, is kind of becoming more prominent. And thinking about what options do we have for the compound outside of CAH that we can potentially embark on, I think all of the options certainly revolve around learnings from the 205 study, which are with the higher dose of tildacerfont and whether the treatment paradigm for some disease states may not need to be q.d. We can accommodate a b.i.d. regimen. So whether it's q.d. or b.i.d. is still to be determined. But there are a number of options, one of which is PCOS. When we unveiled the data on PCOS in August of last year, we noted clear target engagement on DHEAS, which is a hormone that's often elevated in patients with PCOS, not very pathogenic, doesn't cause a lot of disease, but is an intermediary hormone that eventually gets converted into stronger androgens inside tissues. I think that if we would be to test a higher dose in patients with PCOS, we might see a higher effect size and maybe an effect size in the androgens that truly matter, which were, in many ways, kind of an afterthought in the context of that trial. So I think the door remains open in PCOS. We'll be, hopefully, unveiling data on the full data set soon, as opposed to just the interim data that we presented in August, but also thinking about other options. OK. So we have a couple of important readouts here on the near-term horizon. A question we always like to end with is, can you remind us of your cash position? You have cash through data. But obviously, with these subsequent development plans you're thinking about, how much money do you think it would take to get tildacerfont through a phase III program? Obviously, dependent on data and what you see. But big picture, what would make sense for a budget for a phase III program? Yeah. We have cash through the end of 2025. That cash, obviously, is enough to get our current data readouts more into a 4, more into a 5, and to initiate the programs that we just discussed, a phase III program in adult and peds, and to get those programs going. OK. So to get them up and running is in the budget? Yeah. Perfect. OK. Well, we're looking forward to seeing the updates. Javier, thanks again for giving us hot off the press data from yesterday. Of course. A real pleasure to be here, John. Thank you so much. Thanks, Javier.