As well. But at the moment, we're dedicated to advanced science in disease states for which there's a real patient on Medicaid. And that includes, to date, congenital adrenal hyperplasia, PCOS, which stands for polycystic ovary syndrome, and also working in a subset of patients with major depressive disorders, all using our asset, which is called tildacerfont.
Great.
Spruce.
Great. I guess we'll just jump right into it. I guess, could you just walk through Spruce and, I guess, the history of Tildacerfont? I guess, what drew you into focusing on tildacerfont for CAH?
Yeah. So we licensed tildacerfont from Eli Lilly back in 2014. The company got officially formed in 2016 and IPO'd in October of 2020. CAH, obviously, a disease state that was discovered many decades ago. And it wasn't until the advent of steroids in the 1950s, 1960s that kind of transformed the disease and allowed patients to have a semi-normal life expectancy. But in return, the disease was polluted by chronic super high doses of steroids that patients were taking in order to suppress the adrenal function, to suppress the hyperandrogenism that was happening. So I view that as being a very large unmet need. When I came into the company about three years ago, the trials were under-recruited, and there was a very large clinical development opportunity with a compound.
Since then, we've been able to recruit all of the programs, have had one study readout in the early part of this year, in March of this year, unfortunately, not the way we had wanted to, and have two more data readouts coming up in December. Those two studies are, frankly, very different than the failed study or than the negative study. I don't want to use the word failed because you can always learn from prior experience, and we've actually learned a ton from the 203 study. But the study did not achieve its primary endpoint, but the two studies that we have lined up are very different in design, studied a very different patient population, actually studying very different doses, which we can get into as we advance the chat.
Great. I guess, let's just get right into it then.
Sure.
204, I guess, in December, you'll be presenting data from both the 204 and 205 studies. Can you just walk through those two studies and what data we'll see?
Yeah. Correct. So the 204 study is the second adult study that we're conducting. We unveiled the first adult study, this second adult study, the 204, which we call the second study out of the CAHmelia program, is an adult study of patients with normal or near normal A4s. For patients with CAH to have a normal or near normal A4, they must be treated with elevated doses of steroids. So the key objective of the study is to demonstrate that we can reduce steroid usage among CAH-treated patients. That study has been running for a while now. All patients have completed 24 weeks of treatment, and the overwhelming majority of them are on the extension program. So we plan to unveil data from the initial 24 weeks, which are blinded, as well as data from the extension part of the study.
Now, let me pivot to the 205 study, which is going to be part, you see, we don't see them as individual studies, but rather as part of a program. So our intent is to display or present, at the time of 204, data from 205 as well. The 205 study was initially conceived as an open-label trial where we tested 50 milligrams and 200 milligrams weight-adjusted among children aged 2 to 10 and adolescents aged 11 to 17. From those initial three cohorts, we expanded the program to treat patients with doses up to 400 b.i.d. So we are doubling and quadrupling the dose used in 203 and in 204 in this 205 study with the hopes that we'll be able to hopefully achieve a larger effect size and possibly pivot towards a larger treatment, a larger dose. Right?
We've also this expansion cohorts of 205, which are cohorts 4 through 9, are testing 200, as I said, and 400 b.i.d. So it's twice daily and with the intent to, frankly, make sure that we're covering the patients throughout the day, which is not dissimilar to what Neurocrine has done. I mean, the current regimen is 100 milligrams of crinecerfont twice daily.
Great. So I guess let's start with 204 first. I mean, just what would you consider a good data set here, particularly in this patient population?
Yeah. The primary is the absolute reduction in steroids used from baseline through week 24. And what Neurocrine has shown has been a change from baseline of about five milligrams per day. So that is the bar that we had set up for the program from the get-go. And so in my mind, that's about to beat. When you look at their data, they call the program the CAHtalyst Study, which was published very recently. They achieved that degree of steroid reduction. But frankly, they lost androgenic control. In the overwhelming majority of patients, where most patients treated returned to baseline, when you look at the mean change from baseline, most patients returned to baseline by the end of the initial 24 weeks of treatment. They haven't presented extension data.
But based on those data, frankly, their approach in many ways violates the primary purpose of GC reduction in patients with CAH. I mean, you reduce the steroids ideally while the patient maintains A4 control. And that's what the 204 study will show. Right? So if we can show the same degree of steroid reduction while maintaining androgenic control, I think that'll be a big win.
Great. So I guess, just given some differences in how the two studies between you and Neurocrine are designed, can you help contextualize how or help guide folks to how someone should look at maybe your data set versus Neurocrine's? Are they directly comparable? I guess, what other kind of data can we see from you guys that'll kind of help build confidence in tildacerfont?
I think their patients had larger A4 levels. I think the average was around 620. Ours is more towards the normal range, probably around 220, which I think makes the data sets perhaps a little different. Another element to consider is the algorithm they've used to titrate steroids. They used a forced titration, which in many ways maximized the GC reduction but compromised or put androgenic control at risk. Frankly, I wouldn't say it's an apples-to-apples comparison, but it's the best comparison one could do.
I think that in addition to the initial 24-week data, we will have data on the extension part of the study, which I think will be very relevant to assess whether patients that are switching from placebo to active treatment are experiencing benefit, which will be I mean, we don't have all patients through the second 24 weeks of the study, but we will have a decent chunk. And we'll be able to report data along those lines. Right? I think those two data points are probably going to be most informative off 204.
Great. I guess, as we're kind of thinking about the study, I guess, in light of 203, are all these patients fairly compliant? I guess, anything to note about this patient population?
Compliance rate is much better. I mean, the same data analysis that we've looked at as it relates to compliance when we unveiled 203 holds now that we're discussing 204. Right? Compliance rates are very different. 204 patients are much more compliant. I mean, we really haven't had any type of study conduct situation or issues in the 204 study.
Great. So I guess, can you help contextualize, I guess, 204 results with what you guys are evaluating in 205? I guess, you're exploring some higher doses. What do you hope to see from 205? How do you plan to share the combined data set?
So the 205 study is, frankly, quite different than 204. It's open-label. Studies doses of 200 b.i.d. and 400 b.i.d. relative to 200 q.d. in 204. Treats patients for four weeks. And that's the data that we'll be reporting. At the completion of four weeks, patients are allowed to titrate the steroids, but not before that. Right? So it's primarily a study where we will be checking the effect size achieved on A4 change. The threshold defined by Neurocrine on that study is about 50%, I would say. When you look at the data from the phase 2 study and the initial data in the four weeks of Catalyst, they achieve roughly a 50% change from baseline. So that's our target. That's our aim. And we will be presenting data from 205 in the context of A4 change, as well as a few other hormones, but in conjunction with 204.
Is that 50% a placebo-adjusted rate? Or I know there's something a little bit high with Neurocrine's placebo.
The placebo-adjusted rate was, frankly, a little lower in the I mean, when you look at the Neurocrine data, the placebo patients actually have anything worse than a little bit. And their treatment effect was slightly lower than that. So the data that I'm reporting is placebo-adjusted. But we didn't have placebo. We don't have placebo on the 205 study.
Yeah. That's fair. OK. And then, I guess, when you're thinking about these two studies together, I guess, what's the next steps? Assuming everything goes well, how are you guys planning on proceeding to a future trial?
Yeah. So we hope to be able to guide, frankly, on what are we going to do. Right? I think it's going to be important for patients, physicians, to understand what is going to be our next step, what are going to be our next steps. And for that, we felt quite compelled that we needed both data from 204 and 205. And hence, frankly, our re-guidance from Q3 to actually Q4 of this year. So following the data unveiling, if the decision is to advance the program forward, we will get ready and gear up for another phase two meeting with the FDA and present to them a very fleshed-out phase three study to hopefully confirm the benefit or the favorable benefit risk ratio for tildacerfont. I think that based on the data that we know today, there is still a very large opportunity remaining in the market.
The CRF1 receptor antagonist mechanism certainly works and target engages and has through 24 weeks durable efficacy. There are other competitors in the market, and we can talk about how they are positioned and what are they trying to achieve if there's interest on your end, but I think our key intent is to address what's in the more near future for us, which is alignment with the FDA through an end-of-phase two meeting and then hopefully initiation of a phase three program that will confirm the benefit of the drug.
Got it. And what does that kind of phase three look like? I guess, any kind of should we be thinking about a Neurocrine trial design as comparison here? Or is it a good analog?
I think that's probably a good start. So at the end of the day, the drugs can be compared head-to-head. But frankly, we will try to bring in learnings from our current program and bring in pitfalls. I mean, I think although their trial was positive and the jury is still out there on this concept of androgenic control while achieving or loss of androgenic control while achieving GC reduction, they have a PDUFA date that's for both the pediatric and adult NDAs by the end of the year, the very end of the year. And we'll see what their label looks like and try to design something sensible.
What's been some of the physician feedback to maybe the Neurocrine data and elements where they'd like to see differences in trial design or see improvement?
I think that what we've been hearing is that the study accomplished what it was designed to accomplish, that the study was designed kind of in two buckets. Right? One bucket was to show A4 reduction, and the other bucket was to show GC reduction. And it accomplished those two. I feel that the approach perhaps could have been a little bit more physiologic and more patient-centric to actually show what patients care about, which is reducing their steroids while achieving androgenic control. This doesn't mean that they will not show what I'm articulating in the context of an extension part of their program. So we just need to, frankly, await. And I'm not sure when will they present the extension data. But I wouldn't be surprised if it's end of.
Got it, and then just to provide some context here, I guess, how large is the CAH market? Is there room for more than one player?
Oh, definitely. I mean, I think that the first entrant is going to have to do fairly serious disease education and market shaping. But I think that over time, patients will realize the benefit of a drug. And I don't, by any means, believe that this drug should be a tiered drug or selected for patients that can tolerate or don't do well on supraphysiologic doses of steroids. Because everyone in any field of medicine will acknowledge that using more than physiologic doses is unwanted due to the very many unknown side effects of steroids. So I think it will eventually be widely adopted. And I do believe that the market opportunity is very large. It's a very large global opportunity, actually, not just in the U.S.
Got it. Can you spend some time to talk about the competitive landscape here? You mentioned the Neurocrine approval around the end of the year. I think we've seen some other mechanisms or early data from other mechanisms this year. How do you think, I guess, the CRF1 antagonist or the product space adopts multiple mechanisms?
Yeah. I think the Crinetics actually reported data on a small molecule that binds to the ACTH receptor at the level of the adrenals. I thought their data was very strong. It was limited in just a few patients. But the amount of A4 change was fairly impressive. There are some off-target effects of that blockade that might lead to other kind of unwanted issues that will only be picked up as therapies given for a longer time and more patients are treated that might relate to, among many, skin hyperpigmentation due to off-target effects of that receptor. And there are other matters as well. But there's potentially a fear that patients may reduce the number of precursors. And if they miss a dose of steroids, go hypoadrenal. And that's a fairly real concern in this patient population who are known to be less compliant than you would think.
Lundbeck is developing a monoclonal against the same target. That's in early phases of development. And there's another company called Harbour BioMed working on a CRF1 receptor antagonist monoclonal antibody, which will work higher up. It will be kind of an analog, a longer-acting, more durable analog of tildacerfont and tildacerfont. So there are a number of options. I mean, frankly, I think this will only expand, in my opinion, expand the market, expand the opportunity, and give patients more choice, which I think is foundational to advance their care. So yeah, that's my point of view on competition.
Great. And then you're also exploring the CRF1 receptor antagonist class in other indications. Can you talk about the opportunity in PCOS, MDD, potentially maybe outside of that? Does the data you've generated with 205 and the dosing work you've done in CAH help with that?
Yeah. That's a good question. I mean, the PCOS opportunity was studied in a study that was not parallel group design, but rather sequential dose escalations. We met the primary in that study. The primary was a reduction in DHEAS, dehydroepiandrosterone sulfate, levels. It was interesting to see that, frankly, to learn after the study completed, that DHEAS was not perceived by many GYN physicians and endocrinologists to be, frankly, a pathogenic androgen, but rather an intermediary area, one that circulates in blood. It's meaningful, can be detected, but doesn't cause disease. And also, the effect size that we saw on DHEAS reduction wasn't to the full extent of one sees when, for example, a PCOS patient gets treated with steroids.
So although we engaged in meaningful and deep discussions around partnerships on PCOS front, we thought that it would be best to first define the dose and possibly define the dose through the 205 study and in CAH before one embarks in a PCOS study with a different dose. So that's kind of where we are with PCOS. On the MDD front, MDD standing for major depressive disorders, we have partnered with a German company called HMNC Brain Health. They are a company that's currently developing a couple of companion diagnostics for major depressive disorders, one trying to tease out which patients will benefit from a vasopressin V1b receptor antagonist. And then the one that we've partnered with them is on a companion diagnostic that will help identify which patients will benefit from a CRF1 receptor antagonist.
So in fact, they will be presenting some of their companion diagnostic framework at a meeting today here in Boston. It's called the CNS Summit. And yeah, I look forward to that poster presentation. But it's one that will actually bring meaningful potential for tildacerfont in addition to CAH. It's a very large patient population. The companion diagnostic excludes about 50%-55% of patients with MDD and would allow to treat 45% of patients if the initial developing framework turns out to be true. So the status of the program is we've made Tilda and label Tilda. The intent is to initiate the program in the first part of 2025. It's going to be probably a European-only study. And then based on the deal, which we've actually communicated externally, we have the rights to license the companion diagnostic and advance the MDD program ourselves.
Great. So I guess in the last minute, it sounds like the December readout will be pretty important. Can you just lay out, I guess, how you're thinking about the next year and also highlight cash and cash runway?
Sure. We finished the quarter with a bit over $60 million in cash, which should give us a cash runway into the end of 2025. We've been very open about and voiceful about our desire to look at other things and potentially partner and license and look at other strategic options, which we've been very active on and hopefully to be able to communicate and engage with the investor community at the right time on those, but at the moment super-focused on tildacerfont for CAH and hopeful that we'll find a path forward for the drug. I think it's a drug that is going to give patients more choice and.