Great, thank you as always. Thanks for making this so easy, all the folks that are working on, you know, behind the scenes. We have Javier on here, the CEO of Spruce Biosciences, probably one of the most fun people I get to hang out with in my coverage list. We do a good job of teasing each other and having a good time, but at the same time, Javier's done, I think, a really good job of moving Spruce forward, moving Studies 203- 204 forward, both of which should reach out read out this year. So with that, Javier, maybe you can give us about a three-to-five- minute, yeah, you know, overview of the company, and we can launch into our fireside chat.
Yeah, absolutely. Thanks, Hartaj. Thank you for having me and having Spruce today. So, yeah, Spruce was founded in 2016. It's a company dedicated to endocrinology and addressing the need of CAH patients and CAH families. We, our lead asset is tildacerfont, which is being, it's a CRF1 selective antagonist, been investigated for the treatment of classic CAH in adults and as well as pediatric patients. We're very excited about the stage of the company. We're very excited about having completed the enrollment of our potentially registrational studies 203 and 204. And actually exceeded enrollment targets. So, you know, having two well-powered studies that hopefully will give us very definitive insights as to the efficacy and the safety of the compound. In parallel, we're also, we've also completed and exceeded a target enrollment for our pediatric study.
It's a phase II study in the works conducted in children. And, yeah, super, super, thrilled about what's next for Spruce. We have a number of catalysts in 2024, and happy to tell you about them.
Great, Javier. So, you know, honestly, maybe we can do it like this. So we get a lot of questions from clients about Spruce, and it's starting to heat up, you know, as we get closer and closer to this, you know, the readout. You've already, you know, this looks like it could be a market, assuming if both drugs get approved of, you know, what's called a duopoly, right? So you'd have Neurocrine with their drug. Maybe you could just kind of frame for us very broadly, you know, the Neurocrine readout, not Neurocrine's data. And then how is Spruce positioned with 203 and 204, you know, relative to the readout that Neurocrine's already had, just broadly speaking, and then we can kind of dive into it.
Yeah, I think that, you know, I mean, I've been in the rare disease space for a very long time—and. And I've seen that, you know, usually, seemingly close markets or difficult to enter markets with no real, strong center of care, become incredible opportunities. And I think having more than one company, you know, in a space is actually a very good thing for patients, because it brings patient choice. You know, there are many distinctions and differences between tildacerfont and the other CRF1 receptor antagonist. Tilda was initially developed by Eli Lilly, and, seemingly, designed as a second generation molecule with very unique features, which include, you know, PK characteristics, as well as, potency and receptor binding.
You know, both companies, I think, us and Neurocrine have been very diligently addressing this unmet need and designing studies that are very thoughtful, and hopefully will, you know, bring more choice to patients with this disease. I think that the advent of 203, which primarily measures the effect of tildacerfont on A4, and 204, which addresses the effects of tildacerfont on GC reductions, are gonna be the 2 pillars for CAH and adult potential approval. 203 was designed in a very unique way, as it was 204. Where, in 203, we enrolled patients with pretty high levels of A4, which A4 stands for androstenedione, which is the biomarker that most people use for.
Disease management and high levels of A4 reflect high levels of hyperandrogenemia. So being able to meaningfully reduce A4 is the target of that study. And also, through that reduction in A4, being able to show improvements in androgen-related comorbidities, which should be prevalent in this patient population at baseline, given the levels that we actually disclosed a few weeks ago for around 1,150 nanograms per deciliter. On the 204 side, it's a study that looks at GC reduction again. GC use in that study is higher than in 203. 203 average use of hydrocortisone equivalence is around 27, and in 204 is around 35- 36. So yeah, the higher the steroid, the greater the comorbidities at baseline, and hopefully, as we reduce steroids, we'll be able to show improvements in how patients feel and function.
In that context.
Yep. No, this is fantastic. And then, you know, Javier, we've had some clients, and again, this is not a, you know, Spruce versus Neurocrine thing. You know, we do think that, you know, with the time of the market, two companies being in there. You know, it's gonna be significant for both companies. You know, the possibilities, and I bet you these patients also somewhat underdiagnosed, etc. I guess, you know, with the Neurocrine data out there. Both in terms of, you know, they've presented data on adult and pediatrics. Both in terms of, you know, the reduction in A4, I believe GC also. What are your thoughts? You know, as to what would be the bogey? What would be a win? You know, for Tilda first on 203, and then later in the year on 204.
I mean, a win for patients, Hartaj, will be, We'll be having both drugs approved, right? So, you know, strong efficacy and safety on both ends.
Right.
I think that will provide patient choice. At this stage, there is a, you know, I think I would think the major difference is on administration, right? Tildacerfont is a once a day drug.
Mm-hmm.
Crinecerfont is a twice a day drug.
Mm-hmm.
The studies aren't identical. You know, I think that. There are meaningful differences at baseline in both 203 and 204 relative to CAHtalyst, which is the acronym that Neurocrine used to define their program. So I think that, you know, as the data unveils as the year goes on, they announced a few days ago, you know, some projections on when they intend to submit the NDA. You know, we have ENDO coming up in June, and I'm sure that's gonna be a meeting where both us and Neurocrine have a presence. I think that we'll be able to learn along the way, you know, what actually happened over time, what are the actual endpoints?
Where clinical endpoints, clinical intermediates, where us and them, so a difference and improvements over time. Understand more about the algorithms that were used to titrate glucocorticoids and be able to compare if one does the efficacy be between the two studies. I think that, frankly, the market is very large. I think the market definitely can bear more than one or two compounds. And I think that, you know, having two companies doing market shaping, initially non-branded and then branded, and doing disease education, and engaging with payers and having engagement with regulators. It's only going to be good and frankly grow the market, and it's. I don't see it as an us and them. I see it as an us, you know, with them.
Yep. No, Javier, that sounds, I mean, that's great. I mean, it's like, you know, in a two-person market with really no good standard of care. Steroids not having a great reputation, glucocorticoids, you know, that's I think that's a great attitude. You know, one question I would have is that, you know, just in terms of what Neurocrine has publicly disclosed. You know, it looks like the A4 levels, you know, were decreased placebo-adjusted by about 2/3. The GC reduction was by about 50% placebo-adjusted. You know, is that what you'd like kind of like to see Tilda hit too, and then being once a day? Does that add an advantage to Tilda if it kind of hits around that, ± around that a little bit.
Yeah, roughly. I mean, I think the data, the Neurocrine data was very strong. I think that if we end up achieving those numbers, you know, it will be a good win. It will then be, frankly, on the physician and on the patient to choose which of the two therapies they'll like to go under. I feel that, you know, there is a. Our studies, as I mentioned earlier, were designed to enrich for patients with high levels of androgens in 203 and high levels of steroids in 204. And I think that's gonna give us possibly a more abnormal baseline characteristics, right, in the context of comorbidities associated with high androgens and high steroids. And because of that, and assuming comparable efficacy.
You know, we may have an opportunity to show benefit in those secondary measures if we could during the if they're sensitive to change during the period of time we're watching them. So, you know, I think that. Frankly, the separation of the two drugs initially will be based on what's currently available, A4 and steroids, but ultimately and over time we'll have to relate to improvements in secondary endpoints.
Yep.
Yeah.
Yep. No, no, that's fantastic. And then, you know, got a couple of specific questions. You know, in terms of just the upcoming adult study readout in the 203 study, you know, I believe that readouts in the first quarter of this year. Patients who achieve A4 control are allowed to start GC reduction. What can we expect to see here, and how many weeks into the GC.
We'll be unveiling in March. We've actually got it to March. In March we'll have results from 2 studies, 203 and 205.
Right.
The 203 is the study, the first unveiling of the. The first adult study, 205 is our phase II study in children. The 203 study will unveil topline data and topline data only, which is data through week 12. During the initial 12 weeks of a trial, steroids are not allowed to be titrated. So, it is only at week 24, Hartaj , when patients are allowed to titrate steroids in the context of the 203 study.
Right.
That data won't be available. Now, in the context of 205, we have a four-week period where steroids aren't to be titrated, and between week four and week 12, steroids are allowed to be adjusted. The primary endpoint of 205 is a safety study. It's a dose response study, obviously, but it's a primary, really, endpoint to safety, and our key efficacy endpoint is the proportion of patients that reduce steroids or reduced A4. So we'll be reporting on that endpoint, as well.
Is 205, randomized placebo control, Javier.
It's randomized, but it's not placebo control.
Got it.
It's an open label trial.
Yep, understood. Okay. And then, you know, another question is, what's considered a physiologic dose of corticosteroids? You know. What would be considered a meaningful reduction in GC dose.
I mean, a physiologic dose, it's anywhere between, I would say, 11 mg/m² to 13-14 mg/m².
Mm-hmm.
That typically translates into a steroid dose of, you know, anywhere between 15 and low 20s depending on the body surface area of each of the patients. You know. The question around a meaningful reduction. I mean, one would argue that. You know what you want to see is patients actually reducing steroids down to physiologic levels, right? So that would that is probably the best clinical measure. You know, if somebody starts with a steroid level, and it depends how much they're using. But if a steroid level around 40. And they can go down to 25, that'll probably be a very meaningful effect. So I think that, you know, as we unveil our primary into A4. As we learn more about.
What other CRF1 receptor antagonists' effect sizes are in the context of a primary. We'll be able to contextualize and put that in context. But what you really want to see is people going down to a lower level, and I think that's gonna have the greatest impact on comorbidities associated with steroids.
Yep. And then.
I would say also, Hartaj, that any steroid reduction is meaningful. I mean, these people, when you talk to folks that actually treat patients with CAH, they'll tell you, I rarely reduce steroids. I mean, I typically maintain or increase during periods of need.
Mm-hmm.
So, to frame a treatment paradigm where steroids can be reduced down to physiologic is currently not within the toolkit of any treating physician. So, frankly, any steroid reduction will have an impact in the long run on how patients feel and function.
Yep. Then, just in terms of that, you know, I think you had mentioned this in the pediatric program, the 205 study. Would we see any steroid reduction there in March, or we'd have to wait for that data.
No, we'll see. We'll have data through week 12, so we'll have some data on A4, and as well as 17-OHP reductions.
Yep. Okay. And that's for the 205 study specifically with pediatrics, A4 and steroid reductions. Okay.
Yep.
Got it. And then, you know, can you just talk a little bit about androgen control? I know we're going here, you know, through specific parts of the CAHmelia studies. How do you define androgen control in the CAHmelia studies in the context of GC reduction?
You know, currently, when you look at the standard of care at the moment, right, and treatment guidelines and how physicians are currently practicing. The framework that most people use is one where. When patients, I mean, the reason why you give super physiologic doses of steroids is, frankly, to control the androgens. So the framework that people use in practice is once you see an A4 that's either within the upper limit of normal, or very close to the upper limit of normal. That's when you start titrating steroids potentially down, right? I mean, you don't need as much or once you see the A4 controlled, you actually keep the patient on that same dose of steroids so long the patient is tolerating and not having side effects.
So we used a very similar framework, in our, in the context of our CAHmelia and CAHptain program. So steroid, you know, androgenic control is defined as having an A4 within the upper limit of normal. For us. I think that's a very sensible way, perhaps conservative way, but sensible way of titrating and adjusting steroids relative to how patients are actually clinically doing. Yeah.
Yep. You know, that's very helpful, Javier. And so just to be clear, when we see the 203 and 205 data in March, at that point you'll have a topline readout, right, and save essentially the meat of what you're gonna be presenting, 203 and 204, 205 for a medical conference, which could be, for example, like an ENDO in June.
That's about right. Yeah.
Yep.
Yeah.
Well, what if you don't mind me asking, do you know what the abstract deadline is for ENDO, or would it be more like a later, like a oral kind of?
It's mid-April.
Okay, it's mid-April. Got it. Okay. Got it. And then maybe, you know, if you can also help frame the 204 study. Javier, just quickly there. I know it's been talked about endlessly, the GC reduction. And then off that. You know, how long would it take you for to have your pre-BLA meeting with the regulators, assuming 204 reads out, you know, positively.
Yeah. So 204, as we've guided, will be available in Q3, and we hope at that time to be in a position to meet with the FDA. We'll probably hold an official end of phase II meeting. And, express at that time, if the data is robust and strong and conducive to a submission, express our desire to submit in and soon after that hold a pre-BLA meeting, pre-NDA meeting, rather. The intent here is, frankly, to have enough clinical safety data to be able to take the regulatory requirement of, you know, that the FDA has, and at the same time allow for the data set to mature so that we can collect secondary endpoints. I think the secondary endpoints are pretty foundational to a benefit risk assessment.
Biomarkers alone may not be sufficient, frankly, and I feel that. You know, if we can allow the data set to mature a bit, collect clinical data, and then go in with a pre-NDA meeting would be probably the wisest approach.
Yep. And is there, Javier? You know, just roughly speaking, as you've been kind of, I'm sure, looking at. You know, CAH, possibly, you know, marketing tildacerfont there. What's the ± around when you think tildacerfont could get approved after the Neurocrine product? I mean, is it within 6 months, within a year, just roughly. Where do you think you'll be assuming the Neurocrine product gets approved on a regular, whatever is their regular schedule.
Yeah, they have guided to submission in Q2 of this year, and depending on that, they've stated that they're not sure whether there'll be an advisory committee attached to it. So I would think that, if they end up getting priority review, their approval might be, you know, in the latter part of 2024, early part of 2025. I think that a submission of tildacerfont could safely be expected in the second half of next year. And whether we get a priority review or a standard review will obviously depend on data.
Yep. Got it. And then, you know, here, I guess, you know, at some point you're probably gonna go ahead and hire a chief commercial officer, or maybe you might already have one. You know, what what do you think? Assuming that you know the Neurocrine product gets approved on the current studies, and with his profile. Where do you think that even with a 6th or maybe nine-month lag, you know, to approval with the Neurocrine product, where do you think tildacerfont really stands out? If you had to go ahead and kind of market it to CAH docs.
I mean, I think that there's a lot of work to be done between now and launch. I think that there's a lot of market shaping and disease education. I think that. You know, Abnormalities that we're seeing both in 203 and 204 at baseline are fairly remarkable, and in my mind highlights an unrealized unmet need, right? And people feel they're fine, but in reality they're not. And I think once the community understands that living with a very high BMI, living with high degrees of hypertension and dyslipidemia and bone demineralization, and so on, right? will actually be kind of a wake up call for people. I think that the differentiation between the two compounds will be driven primarily by.
You know, surrogate measures, which are A4 and GC, but as well as the more clinical measures, which will take a little time to pan out. We haven't seen any of those data being presented on our end. We haven't yet generated it. So, I think that, you know, it's a little early to highlight differences, aside from, as I said earlier, the work we are QD under BID. But again, the market is a very large market, and I think the more drugs that are available for patients, the better the patient choice, and the better the patient well-being.
Yep. And then, you know, I think that there's some IP action going on, right, Javier, between Spruce and Neurocrine. Could you just address that really quickly?
Yeah. Spruce has currently composition of matter protection through 2028, with patent term extensions will extend through 2032, and with method of use for 2038. Hartaj . We have a number of method of use patents that are specific to tildacerfont. We also had a few of the patents that were more broad to CRF1 receptor antagonist class. Those two of those patents were actually challenged, and are back into with a patent office being reviewed. So there will be the court is meeting in September, and the outcome of those patents will be determined at that time. They're currently being litigated.
Great. And then, you know, the other question I just want to ask here is that, you know, we had talked a little bit about your potential, you know, for partnering. You know, do you still see, assuming you get a positive 203 and 204 study? Do you still see, you know, this as an initially as primary U.S. market where you're gonna be, and then maybe kind of roll it out over the EU, ex-U.S., or would you rather stick to the U.S. and then try to partner out the rest of the world?
Yeah, probably the latter. I think we'll be. We are very committed in and have strong conviction that. We can, with a limited sales force, commercialize tildacerfont in the U.S. We've been very open to seeking ex-US partners at the moment. We've actually closed a deal with Kaken Pharmaceuticals back in February of 2023. For Japanese only rights, and are exploring, you know, multiple other options in the context of ex-US opportunities.
Yep. Got it, Javier. And then you know. I guess if we just kind of step back, you've got a really important March coming up, you know, hopefully also ENDO. You know, what does your cash runway look like, Javier, right now? And then how would you think about with a positive 203 and potential, and you know. Let's say a good 205, and then also 204. How would you want to kind of buff up your cash runway, I guess, or would you want to.
Yeah. So we closed the year with 2023 with $96 million in cash, which gives us our cash runway into the first half of 2025. I think that, depending on the data that we see post-203, there might be an opportunity to capitalize the company there. And you know, the size of it will obviously depend on the data, and where the stock is at the time, and maybe an opportunity to do another one. That will bring us all the way through launch post-204. But we'll take that, you know, one step at a time, and the good thing is that. You know, we really have enough cash to actually read through all of our key catalysts in 2024 and position the company.
You know, in the right way, ideally.
Yep. Yep. No, no, that's very, very fair, Javier. Let me just see, you know. That's the extent the questions. We had, Javier. This is really, really comprehensive. Anything else? You know, we've got basically just a couple of minutes left, but anything that you know. I, you know, we were at the Oppenheimer CEO winter conference last week. You met some investors there. I know you've been meeting, you know, a lot of investors on and off. Are there any sort of, you know, any things out there that you know that you're asked about that you think, you know, it, you know, leave people a little bit confused about Spruce, or anything out there that you just like to kind of clear up, or whatever's the biggest pushback you face from investors.
Yeah, I think we have. We're frankly past the period of execution, right? And I think that's it's really nice to have that behind us. We've actually executed quite well, and I really I'm super thankful for the team here at Spruce that drove the enrollment of CAHmelia and CAHptain forward. I mean, the interest is actually accelerating, I think, as we approach our first catalyst in March. A lot of investors are frankly paying a lot more attention to our story, and I probably want to be part of it. So, I mean, from my point of view, Hartaj, it's been all about patience, and it's all been about addressing their unmet need. And I think that.
You know, that's why I do what I do, right, to be able to bring a therapy and hope to their care. So it will be incredibly rewarding to feel that tildacerfont can be added as another drug in the toolkit.
Yep. You know, Javier, it's a real pleasure. Always is. You know, and like roughly the two years are, you know, that we've known each other. It's just great to see how much Spruce has achieved, and how much of what you know you promised to get done has been done. And now we look forward to, you know, knock on wood, good 203, 204, 205, and then later on 204 readouts, and we'll, you know, go look forward to kind of keeping the conversation going.
Thank you, Aneka, for your support.
No, no. Always, Javier. A pleasure. Give our best to Samir and the team.
I will. Thank you so much, Hartaj. Thank you. Bye-bye.