Welcome back, everybody, to the 2024 RBC Global Healthcare Conference. My name is Greg Renza, one of the biotechnology research analysts here at RBC, and we're pleased to be joined with Spruce Biosciences. Joining us from the company is the CEO, Javier Szwarcberg. Javier, it's good to see you, and welcome, welcome back to the conference. Likewise. Thank you, Greg. Thank you for having me here. Yeah. So, certainly, you know, an important year for Spruce, a great deal going on. Maybe for those who aren't familiar with the Spruce story, just highlight the company's mission, the history of with tildacerfont, and really your objectives with CAH. Yeah. So, I mean, our mission is to actually bring drugs to patients suffering from rare endocrine diseases. Frankly, we have a lot of expertise in-house to deal with a number of rare diseases in general. You know, tildacerfont, which is our lead asset, was in-licensed from Eli Lilly in 2016. It was an asset that was initially thought to be developed in major depression and shifted into CAH. It's a CRF1 receptor antagonist, blocks the CRF1 receptor at the level of the pituitary, and you know, it's a proven mechanism to actually address CAH. CAH is a congenital disease, autosomal recessive, part of newborn screening, and kids are given corticosteroids from the get-go, from the moment they're born, to overcome an adrenal deficiency of making corticosteroids. Great, great. So when we think about CAH as your initial focus, just walk us through a bit on the diagnosis, sort of the numbers. It does typify a rare disease of great interest. You touched on this, but just thinking further about, you know, how the de-risk mechanism was, is, and what was sort of the area of rationale for you. Yeah, I mean, so CAH, it's a fairly common rare disease. There's about 20,000-30,000 patients in the U.S., about 50,000 in Europe. You know, as I said, most patients need to be treated. The paradigm of care involves corticosteroids, and they need to be given at supraphysiological doses to overcome the hyperadrenalism that they live with, to provide that negative feedback in the HPA axis and lower levels of CRF and ACTH. You need to overdose with steroids, and that comes with a heavy burden. I mean, patients suffer from comorbidities associated with chronic corticosteroid therapy, as well as comorbidities associated with hyperandrogenemia. So it is that balance that's difficult to reach, and, you know, with the advent of this new class of agents that are going to modulate effectively, hopefully, the HPA axis, you'll be able to, to address that, yin-yang issue of, you know, I give too much steroids, my patient is gonna have comorbidities associated with them. I give too little, and the patient ends up being chronically hyperandrogenic, and also, has issues, when, you know, young, young children suffer from both of those things, and, and that's where, frankly, tight disease management really, really matters. Great, great. Javier, just talk to us a bit about CAHmelia, the CAHmelia programs, 203 and 204. But certainly with some of the data that you've shared on 203, the poorly controlled adult patients. Just talk a bit about the key takeaways there and how you're applying them. Yeah. So we've, w e have a program, our CAHmelia studies, 203 and 204, that encompass the totality of the patient population, right? We thought about segmenting the patient population into two. The patients that were not well-controlled, that are not taking high doses of steroids or as high doses of steroids as in 204, would enroll into 203, and patients that are taking adequate doses of steroids that result in proper reduction in androgen production would enroll into 204. Those patients are taking supraphysiological doses of steroids, and the goal of treatment for each of the studies was different. 203 was about controlling hyperandrogenemia, and 204 was about being able to cut down the use of corticosteroids. So we unveiled results from the 203 study back in March, on March 8, and the results were not positive. I mean, for a number of reasons, but we, you know, it is clear that patients with CAH that are enrolled in the 203 study required higher doses and greater exposures of tildacerfont to be able to suppress the disease. We learned that the 203 patients that we enrolled in the trial tended to be less compliant than in the 204 study, for example, with about 50% of patients having about, you know, 80% compliance. And that's a big deal because if folks aren't really taking enough drug, they're not gonna, you know, benefit from, from, from the drug, right? But even amongst the folks that actually were compliant, and this is data that we released on Monday as part of our earnings release, the effect size wasn't what we wanted. So probably 200 milligrams for this patient population once a day isn't sufficient. So as we venture into the 204 study, we also conducted a sub-analysis of the 203 data set that looked at the breakdown of corticosteroids, right? And learned that patients that are taking more steroids tended to be more amenable to 200 milligrams of tildacerfont in the 203 study and had a better effect in A4 reduction. Now, those two things, the greater compliance leading to better effect size and the higher GC used in 203 leading to greater effect size, we believe both translate into the effect size that we hope to see in 204. The 204 patient population is very different, as I said, than the 203. They tend to have more controlled disease. It's probably a lower bar. When, if you think of an asthma patient that needs to be maintained, it's a very different bar than an asthma patient that needs to be acutely treated, acutely controlled under a period of an exacerbation. And that's how I view, you know, the HPA axis in a 203 type of patient. Yeah. So, we're certainly hoping for a positive study in 204. We also have a study called 205. 205 is a pediatric study, but we've added a few arms in the 205 study of tildacerfont at 200 BID and 400 BID. In order to enable dosing in children, we included arms in adult patients in the 205 study, which will be dosed first, and hope to bring that data along with the 204 data in Q3, you know, to our Q3 release. I think that's gonna be quite informative, right? Getting the, you know, assessing the efficacy of 200 milligrams in 2 0 4 study, as well as, twice and frankly, four times the dose that we've used in 203 and in 204, to assess whether we have better target engagement with a higher dose and be able to construct a phase III program for adult and peds that's based on the 205 data. Okay, great. Y eah. And with respect to that compliance, and I know you and the team have been relentless about execution and educating patients. It's really a genuine effort for this community and this population. What are some of those pushes and pulls that you continue to learn and have learned about patient compliance and even the degree of persistency and adherence that they can or have the potential to demonstrate? Yeah, that's an important point. I mean, we have, like 203 and 204 sites tend to mostly overlap. Mm-hmm. So we actually attempted to activate both studies at all sites so that sites will have the option to enroll patients into 203 or 204. So we didn't treat patients in 203 any different than patients in 204. The vendor applied the same standards. We applied the same standards. We tried to educate sites on the importance of compliance and taking the medicine with food at every opportunity, in newsletters, investigator meetings, discussions with PI, site monitoring visits. And it is frankly shocking to see that there is such a disparity in the compliance rates between the two studies, right? Yeah. So, I mean, you know, I don't think it's something Spruce did or something Spruce did wrong, but rather the nature of CAH among 203 patients. And they are, you know, they are in the bucket of being 203 or being poorly controlled for a reason. Yeah. One of which could be the poor compliance or inability to tolerate steroids and kind of the, choices they make, right? Yeah. And just talk a little bit about the design of 204, the titration regimen, and what happens if patients come in or near the upper limit of normal. Will they be able to titrate down their steroids immediately? How does that work, and how should we be thinking about the trial design? Yeah, we wanted to frankly mirror clinical practice when we designed a titrating schedule for 204. So patients in clinical practice, typically, you would titrate down a patient steroid dose once the A4 is within the upper limit of normal. And that's the algorithm that we followed in the 204 study. There wasn't any type of forced titration. And I think that's important because the results hopefully will be able to be translated to real world, real life. Most patients are coming into the study with A4 values that are within the upper limit of normal, and they can frankly, readily be eligible for a GC reduction. Mm-hmm. I think that, you know, our titrating schedule in the 204 is different than the schedule that Neurocrine followed, and which is gonna make, you know, somehow, a difficult comparison or a direct comparison between the two programs. But nonetheless, I think that both programs were designed thoughtfully and hopefully will advance the thinking in CAH. Great. And let's just lay out those plans. You mentioned the 204 to 205 data. You're thinking about a path forward for a potential phase III. Just lay out those areas as we look forward, what we should be looking to that are going to, you know, reestablish the new inflection points for Spruce. So upcoming catalysts for the company are the readouts for both 204 and 205 in Q3. Following those readouts, we plan to engage with the FDA and have a you know formal proper end-of-phase 2 meeting and discuss the path forward for tildacerfont in CAH. The 204 data readout in Q3 will be the full data set. We won't have the full data set in 205, but rather a subset of the data set, and I hope to be able to inform on the 200 BID and the 400 BID at that same time. Okay. All right. Great. And just talk a bit, Javier, just about your resources and your allocation of your cash. And so you mentioned that your mission as a rare disease company, you know, how are you thinking about the runway and the deployment? Yeah, we closed the quarter with a little over $81 million in cash. We have enough cash to actually run the company all the way through the end of 2025, which obviously covers the current catalysts that I discussed. It also covers the initiation of a phase II program, if there is to be one, following 204 and 205, and after FDA engagement. So we feel well positioned to be able to run the company. I mean, the board was incredibly supportive of the effort that the current team, the management team has put in play. I think we have the right individuals in the company today, despite having had to shrink the company a bit and, you know, having gone through an incredibly painful process of letting people go. Sure. It was never easy. But yeah, we feel well positioned to be able to do that. You know, on the same stroke, you know, we're also looking at other things and looking at opportunities and life cycle management. Mm-hmm. Elements of tildacerfont and as well as other things. We remain very optimistic about the future of Spruce in our upcoming data readouts. And when you think about CRF1 antagonism as an MOA to your mention about opportunities, what other areas and what other areas have you explored that, you know, could actually help to realize the value down the line of tildacerfont? Yeah, I mean, the mechanism is really interesting. I think it addresses the biology of CAH, you know, squarely. You know, we've initiated a while back a program in PCOS. We hopefully will be presenting the full data at ENDO, which is a meeting coming up at the beginning of June, and that could open up additional opportunities. But there are also other angles that we could take on tildacerfont that extend outside of the, you know, CAH, which is our primary focus, and potentially PCOS, that we'll communicate at the right time. Okay, great. Great. Just want to pitch to the audience if any questions for Javier? Great. Yeah. Hey, Javier, thanks so much for taking my question. I just wanted to ask, you know, just in reflection of 203 and, you know, dealing with those poorly controlled CAH patients and considering sort of the compliance aspect of taking a drug such as tildacerfont, what's to say that, you know, that may not happen in the future with looking beyond 204 in clinic in, you know, a real-world setting? You know, how can patients be better empowered or emboldened to take a drug such as tildacerfont to ensure that real-world outcomes are more reflective of what you're wanting to see in trials, such as with 204, to kind of keep that opportunity for these poorly controlled CAH patients open? Yeah, that's a great question, and one that's frankly challenging to answer, right? It's, I mean, you would think or the general teaching is that when patients embark in a clinical research, they tend to be, they embark in a clinical experiment, and that clinical experiment reflects a more controlled setting, and doesn't reflect- may not necessarily reflect reality when patients go out in the real world. And I do believe that CAH patients generally are not, frankly, taking their steroids every day, right? They, I mean, the severity of disease varies, depends on how much 21-hydroxylase they have, they have activity on. And if the enzyme is partly active, if they make, you know, 2%-3% enzyme, they will be able to make some cortisol. But also the precursors that build above the blockade, the enzymatic deficiency, have cortisol-like activity. So patients don't actually, you know, they can go through periods where they're not taking or they're not being compliant, and that's not uncommon among kids that go to college. And unfortunately, you know, when they end up not taking their medicines and they go through a stressor event, such as dehydration, or a heat stroke or an alcohol binge, or surgery, or trauma, they actually crash and burn, and it's very difficult to recover those patients from that situation, right? So, you know, when you think about these type of therapies, they, they need - they have a half-life, and they need to be given consistently and on schedule. So, I mean, there are other drugs in development in the context of CAH that are more longer acting, like monoclonal antibodies that are going to be, you know, studied in the context of ACTH blockade. There are small molecules that are acting in different aspects of the HPA axis. There's gene therapy, right? Which is frankly, the ultimate cure, that's also being studied in the context of CAH. So, you know, small molecules give you the flexibility of, generally, inexpensive to make, they tend to have some off-target effects, and you can predictably assess the effect on the target. But, you know, as fields, as rare disease fields evolve, usually, there are more advanced therapeutics that are gonna come into the equation that might address this compliance issue. Thank you. Any other questions for Javier? Can you comment on the intellectual property position on tildacerfont? Sure. So we have a method of use patent currently that will extend the composition of matter, which will expire shortly in 2028. The IND of this drug and others in the same class was filed a long time ago under the framework of major depressive disorders. You know, if we get approval, patent term extensions will extend the patent to 2032. A number of method of use patents that will extend it to 2038 and beyond, if approved. Thank you for asking the question. I do remember when there's a whole bunch of, y eah, well, you can characterize it, the results as failures, but the results were no better than the serotonin reuptake inhibitor. Usually, you know, some of those studies had Lexapro as a comparator, and they were no better than Lexapro, and that resulted in those, the majority of those drugs being shelved. Great. Any other questions? Great. Well, Javier, thank you very much. Yeah. Thank you so much for your question. All right. Take care. Thanks.