SPRB

Welcome to the Spruce Biosciences Investor Call [Operator Instructions]. Please note, this conference call is being recorded. I'll now turn the floor over to Samir Gharib, President and CFO of Spruce Biosciences. Samir, the floor is yours.

Thank you, operator. And thank you all for joining us this morning. With me on today's call are Dr. Javier Szwarcberg, Chief Executive Officer; and Dr. Kirk Ways, Chief Medical Officer. This morning, Spruce issued a news release announcing its new corporate strategy and the acquisition of Tralesinidase Alfa for the treatment of Sanfilippo Syndrome Type B or MPS IIIB. Please note that certain information discussed on the call today is covered under the safe harbor provisions of the Private Securities Litigation Reform Act. We caution listeners that during this call, Spruce management will be making forward-looking statements. Actual results could differ materially from those stated or implied by these forward-looking statements due to risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the cautionary statements contained in Spruce's press release issued today ad the company's SEC filings, including its annual report on Form 10-K filed today. This conference call also contains time sensitive information that is accurate only as of the date of this live broadcast, April 15, 2025. Spruce undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. Finally, during today's Q&A session, we ask that you please direct all questions to Javier and he will process Spruce management and elaborate as appropriate. Now I'd like to turn the call over to Javier. Javier?

Thank you, Samir. Today, we unveil our new corporate strategy, including a new pipeline focused on the developing and commercializing of first-in-class therapy for a neurological disorder with a significant unmet medical need. In connection with our new strategy, we also announced today that Spruce has acquired Tralesinidase Alfa Enzyme Replacement Therapy or TA-ERT for the treatment of MPS IIIB. We we anticipate making a BLA submission in the first half of 2026. The focus of today's call is on TA-ERT for MPS IIIB. Our other programs will be discussed at a later time. Historically, Spruce's efforts have been primarily directed towards the development of Tralesinidase for CAH. And although we executed the program well, the product failed to achieve its primary efficacy measures in clinical studies and we discontinued this development for CAH in December of 2024. Following that decision, we initiated a strategic review process. In the course of the review, the company evaluated a number of strategic options and identified and successfully acquired Tralesinidase Alfa, an enzyme replacement therapy for MPS IIIB, a devastating pediatric neurodegenerative disease that is ultimately fatal. MPS IIIB is a rare, inherited autosomal recessive disease caused by a deficiency in the activity of NAGLU or an N-acetylglucosaminidase, a lysosomal enzyme required for the degradation of the ammunoglycan heparan sulfate and the MPS IIIB specific nonreducing end of heparan sulfate. In the absence of NAGLU enzyme activity, heparan sulfate accumulates in many tissues and organs, particularly in CNS. Over time, MPS IIIB results in irreversible neurodegeneration and that is why early treatment is so critical. TA-ERT is a fusion protein comprised of recombinant human NAGLU and a truncated human IGF-2 connected via an amino acid linker. This structure is believed to enable adequate penetration into cells in lysosomes. TA-ERT is intended as an enzyme lasting therapy for the treatment of patients with MPS IIIB and is expected to restore NAGLU and thematic activity levels in the range following intracerebroventricular injection. We believe TA-ERT is largely derisked BLA radio acid. And this enzyme is known, we can make it and previous clinical trials show that when given in the brain normalized heparan sulfate in nearly all patients at all stay time points. Alignment has been achieved with the FDA that the MPS-IIIB non-reducing end of heparan sulfide can be used as a biomarker that may reasonably predict clinical benefit and serve as the basis for accelerated approval. Based on the existing clinical and nonclinical data, we anticipate submitting a BLA for TA-ERT to the FDA in the first half of 2026. Alignment was also achieved with the FDA on the key design elements for our Phase 3 confirmatory trial, which must be initiated prior to potential accelerated approval. TA-ERT has received fast track designation, rare pediatric disease designation, which will qualify TA-ERT for our PRV, if approved by December 2026, and orphan drug designation in the US and in the European Union. The FDA encouraged the prior sponsor to apply for breakthrough designation, which we intend to do. With that, I'll pass it on to Kirk to discuss our MPS IIIB program. Kirk?

Thanks, Javier. As Javier mentioned, MPS Type IIIB is an autosomal recessive disorder. The incidence is about 100,000 and 200,000 live births. The disease is due to a deficiency of a single enzyme and this enzyme breaks down the compound heparan sulfate and with that the enzyme heparan sulfate accumulates in cells, which ultimately kills neurons in the brain and impairs the renal development, leading to neurodegeneration and an early death in these children. And the figure you see here, the black perpendicular line represents a child's normal development progression as they age. The blue line represents children with MPS Type IIIB. Children start to fall off the development curve as early as one year old and they peak in their development at about two to three years of age. After that, they regress. They lose the ability to communicate. They lose the ability to feed themselves or to be fed and ultimately have to be fed with feeding tubes. They lose the ability to ambulate and become bedridden and they die usually by the mid-teens. This is a terrible disease for the patients as well as for the families and there are no treatments available. There was a Type C meeting with FDA in March of last year, three key things came out of that meeting. One, the FDA reiterated that MPS Type IIIB specific nonreducing end of heparan sulfate can be used as a biomarker that may reasonably predict clinical benefit and as the primary endpoint for the BLA accelerated approval submission. So that's really key. The FDA also said that the clinical and nonclinical programs that have been done are sufficient for BLA filing. We don't have to do any more studies outside of the confirmatory trial. And importantly, they agreed on the design of a Phase 3 confirmatory trial in 14 patients that needs to be started prior to approval. TA-ERT would also be eligible for a priority review voucher, assuming we can get the BLA submitted and approved by September of 2026. This is a brief summary of the Tralesinidase clinical development program. Human exposure to TA-ERT has occurred in three clinical studies, Studies 201, 202 and 401. Study 201 was a completed Phase 1/2 first-in-human multicenter, multinational open label dose escalation study. Study 202 was an extension study for patients who completed study 201 and study 401 was an extension study for patients who completed the study 202. The patients entered study 201 by either completing study 201's Part 1 dose escalation study or by completing study 901, an observational study of progressive MPS Type IIIB symptomatology. In studies 201 and 202 TA-ERT was administered weekly by intracerebroventricular infusion and patients were evaluated in terms of neurocognitive function, behavior, sleep, quality of life, both of the patient and of the family caregiver, MRI imaging characteristics, biochemical markers of disease burden and in some cases, hearing. The primary objectives of these studies were to evaluate the safety and tolerability of TA-ERT administered to patients with MPS Type IIIB via an ICV reservoir and catheter and to evaluate the impact of TA-ERT on cognitive function in patients with MPS IIIB as assessed by the RAL score and age equivalent quotient or AEq. Patients in study 202 were eligible for weekly or every other week dosing after week 96. 22 patients enrolled in study 201 and a total of 21 patients completed the study. 20 of these patients transitioned to study 202 for up to 240 weeks. Study 401 was a Phase 3b/4 study to allow patients that completed study 201 to continue receiving TA-ERT for up to an additional three years. The study was discontinued in October of 2023 due to financial constraints of the product's prior sponsor. Study 901 was a prospective nontreatment study of MPS Type IIIB open to one to 10 year old patients with cognitive development quotients of greater than or equal to 50 as determined by the daily scales of infant and toddler development third edition or Kaufman Assessment Battery for children second edition upon entry in the study based on age. This study aims to quantify MPS Type IIIB disease progression over time to correlate changes in clinical features of the disease, in particular, cognitive decline with MRI characteristics and biochemical markers of disease burden and to serve as a comparator for studies 201 and 202. Following a screening period, patients were assessed every 12 weeks up to 96 weeks and 22 patients and 20 patients maticulated into 201. Study 902 was a prospective nontreatment study of MPS Type IIIB that aim to quantify the progression of cognitive decline in pediatric patients with MPS Type IIIB over time. The study enrolled patients regardless of age or baseline development quotient. To this end, data collected from study 902 will augment and extend data from study 901. Data was prospectively collected from 44 patients for up to 192 weeks with study visits occurring every 24 weeks. This slide shows the results of the primary endpoint, which is intended to serve as the basis for accelerated approval, which is cerebrospinal fluid heparan sulfate levels. Those levels are shown on the Y axis and time on treatment is shown on the X axis. The plot on the left is total heparan sulfate levels, the right plot is a heparan sulfate moiety that specifically accumulates when the enzyme is deficient. And this is a fraction of the total CSF heparan sulfate levels shown on the left chart. Tralesinidase Alfa treatment normalized heparan sulfate levels as early as six months and that normalization was maintained over a five year period. It's important to note that therapies that are approved to treat other types of MPS diseases that have elevations in heparan sulfate have not demonstrated normalization of heparan sulfate levels as is seen with this drug. Now if you reduce heparan sulfate, you would expect the organs that it accumulates in to be reduced in size. And this is data from MRI assessments of liver volumes on the left and cortical gray matter in the brain on the right as a function of time shown on the X axis at baseline and after 24 and 48 weeks of treatment. The shaded area across the plots are the normal range. Let me direct your attention to the liver volume at baseline, it is elevated. That's known to be the case for MPS Type IIIB and other types of MPS diseases as heparan sulfate accumulates in the liver. Tralesinidase Alfa treatment normalize the size of the liver by removing heparan sulfate from it along with the water that accumulates due to an osmotic effect and the resulting inflammation that occurs. On the right is cortical gray matter and this is a different story at baseline. So here rather increased volume, cortical gray matter volume has decreased. This is known to be the case because this is a neurodegenerative disease, neurons die and the brain shrinks over time. The children coming into this trial had a lower cortical gray matter volume than normal. Tralesinidase Alfa treatment caused an expected decrease at 24 weeks followed by stability at 48 weeks. So basically, what this is showing is that you're removing heparan sulfate, reducing inflammation and removing the water that accumulates with it and effectively stabilizing the real cortical gray matter volume in these patients. Here, you see the clinical outcome associated with the reduction in heparan sulfate. If I could direct your attention to the left side the plot, which is a natural history study. On the X axis is a chronologic age and on the Y axis is the cognitive age equivalent. The cognitive age equivalent is derived from the Bayley Scales of Infant and Toddler Development Third Edition, which ask a number of questions to the caregivers regarding the child's cognitive development. This is the endpoint that FDA would like to be used in our upcoming Phase III confirmatory trial as the primary endpoint for clinical benefit. In the plot, you'll see a line that goes up diagonally, which represents normal childhood development. So just to explain this, if I'm a 24 month old child on the X axis and I go up to that line and come over at 24 months at an age equivalent cognition score, you would ideally want to be close to that line. Open circles are children with MPS IIIB from our natural history studies and close circles are children with MPS Type III and other natural history studies. So you can see here by year one, they're starting to fall off to the right of the curve. Their cognition growth is slowing. They still accumulate the ability to cognate up to about the three years or so when they reach their peak. They then are stable from every year or so and then they regress. So then if you look at a child that's say 10 years old that child has the cognitive age equivalent of about a six month old child. This is due to the neurodegenerative nature of the disease. We had 22 patients that were enrolled in study 201 and the inclusion criteria were rather broad. We had children from one to 11 years old enrolled in the study. And the average age of children enrolled in the study was approximately six years old. If you look over at the plot on the left you're on the downward trend of cognition and these children are regressing. And that was the midpoint indicating that many children are older than six and some are even younger. We separated the population into what we consider to be early disease are those kids that have cognition that's closer to normal development at baseline and those with later stage disease. We had 10 patients that we characterized as early disease. Of those 10 patients, seven demonstrated either our stability in cognition. We had 12 patients that were characterized as later stage disease. Of the 12 later stage disease patients, only three patients demonstrated either improvement or stability in cognition, reflecting the challenges of later intervention. The drug has demonstrated that it can lower heparan sulfate, which is the pathogenic metabolite in this disease and children who have fairly normal cognition to start with we can stabilize or allow them to improve their cognition. So those would be the type of children we'll enroll in the confirmatory trial. Now I focused on cognition here but cognition is only one attribute that needs to be treated in this disease, and it's probably not the most important one to parents and caregivers. Caregivers want their kids to be able to eat independently, to walk and to be able to communicate with them. So what we're doing now in the number of questionnaires that we've used in the studies is pulling out that type of data, which addresses these attributes. But what we anticipate is in these kids who don't have much cognition and who are older, we might be able to stabilize these other functional attributes that are really important to patients and their families. In Study 201, the drug was generally well tolerated. There were no discontinuations due to drug or device related adverse events and no deaths in the study. There were device related adverse events, some of which were serious. The type of device events and the instance rate is very similar to what's been described in the literature using the Ommaya reservoir and also in the Brineura program, a drug that's been approved for treatment using an intraventricular route. We observed some hypersensitivity reactions but none of these were severe, antidrug and neutralizing antibodies could occur. But if you recall back to the cerebrospinal fluid heparan sulfate levels, which were stable over five years, the antibodies did not affect the pharmacodynamic effect of the drug's ability to reduce and normalize heparan sulfate. Now I'll turn it over to Samir to review our financials and TA-ERT commercial opportunity. Samir?

Thank you, Kirk. Today, Spruce reported financial results for the year ended December 31, 2024. As of December 31, 2024, Spruce had cash and cash equivalents of $38.8 million. The company expects its cash runway to fund its current operating plan through the end of 2025, which solely reflects ongoing development of TA-ERT. As our partner, HMNC is fully financing the Phase II [indiscernible] study, which is a Phase II proof-of-concept trial for the use of Tildacerfont as a treatment to improve depressive symptoms in patients with major depressive disorder, no resources are currently being allocated to that program. As of December 31, 2024, 42.2 million shares of common stock are outstanding and 60.7 million common shares are outstanding on a fully diluted basis. For our full 2024 financial results, I would refer you to our 2024 annual report on Form 10-K filed with the SEC this morning. Now in connection with our acquisition of TA-ERT, we assumed the exclusive worldwide license to that and other enzyme replacement therapy products from BioMarin Pharmaceutical. As we progress development of TA-ERT, we are obligated to pay BioMarin up to an aggregate of $22.5 million upon the achievement of certain developmental and regulatory milestones and up to $100 million upon the achievement of certain sales milestones. In addition, we are required to pay to BioMarin tiered royalties on annual worldwide net sales ranging from the high single digit to low teens during the applicable royalty term subject to certain customary reductions in force. Now moving on to the commercial opportunity for TA-ERT. There is a clear blueprint of how to market and commercialize ultra rare drugs based on approved drugs for other MPS diseases, which are listed on the table on this slide. Epidemiology is usually inaccurate and underrepresents how common these conditions are. For the first and second year following the launch, the focus is on the prevalent patient population. But as neatness in the cases emerge and are treated life expectancy increases, which in turn increases the pool of prevalent patients on treatment over time. Prior to our product launch, there are typically less of an appreciation of the condition and there's less patient awareness. And when a drug becomes available, many things happen. Education ramps up, newborn screening becomes adopted, drug availability lures patients into treating centers for drug access, and there's also sibling and family testing. There's much more awareness in general and as patients are increasingly identified, launches succeed. If the BLA is approved, Spruce intends to build a highly specialized commercial organization to support the launch of TA-ERT. Given that a relatively small number of clinicians and specialists treat most of the patients with MPS IIIB, we believe this market can be effectively addressed with a modest size and targeted patient centric field team alongside various high-touch patient initiatives. A very important element in the launch is to keep commercial infrastructure rightsized and focused on patient identification, patient support and market access. We believe that a commercial team between five and 10 people will be sufficient to successfully launch TA-ERT in the US. Based on health claims data, there are approximately 3,000 MPS patients in the US, including 1,000 pediatric patients diagnosed and managed across five NPS centers of excellence and 26 lysosomal disease centers, which speaks to the high degree of concentration of these patients among centers of excellence and treating specialists. We estimate that there would be at least approximately 135 prevalent cases of MPS IIIB in the US and at least half, if not more, of those patients as potentially addressable with TA-ERT therapy. We also intend to commercialize TA-ERT throughout the developed world, including North America, the EU, the UK, Latin America, Turkey, Asia and other international markets. Beyond the US, we intend to establish our own commercial organization in the EU and in the UK and seek regional partnerships in a network of third party distributors in other international markets. We are incredibly excited about the commercial potential of TA-ERT and its potential to help patients and families impacted by this devastating disease. With that, I'll pass the call back to Javier.

Thank you, Samir. We consider it an honor and a privilege of being able to partner with the entire MPS IIIB community and through innovation, open a new chapter in the treatment of MPS IIIB with a possible life changing medicine. I recognize the potentially transformative impact of Tralesinidase Alfa and having a strong sense of urgency to deliver on our commitment to patients and families who suffer with MPS IIIB. Across the landscape, this is an incredibly important and exciting time for patients and families affected by neuropathic MPSs and making progress in a therapeutic area that is underserved requires doing things differently and in partnership. We have a clear purpose and that is to ensure access and to transform the lives of patients and families that we serve. That is our true north. Looking ahead, we're eager to pursue accelerated approval of Tralesinidase Alfa and file the BLA in the first half of 2026. Around that time, we plan to initiate a confirmatory study and enable expanded access program to ensure that patients have access to therapy. In conclusion, I would like to extend our gratitude to the patient and caregiver advocates clinicians and industry leaders who have contributed to the TA-ERT program. With no FDA approved treatment currently available, TA-ERT has a potential to be groundbreaking advancement for patients and families impacted by MPS IIIB. I also want to express my gratitude to all employees for their contributions and tireless dedication to advancing our mission of bringing forward new and innovative therapies for MPS IIIB and other neurological disorders. Operator, we may now open the line for questions.

[Operator Instructions] Our first question comes from Joe Schwartz with Leerink Partners.

I guess my first question is, I was wondering about your read on the depth of the buy-in for accelerated approval pathway at CBER currently. What additional work did you do beyond the March 24 meeting? Obviously, given everything that's going on, a lot of us are wondering how sacred anything is at the FDA. And so to that end, I was wondering if you could give us your read on the accelerated approval pathway, the realistic likelihood of that currently? And then I have a follow-up.

So let me give you a little bit of the historical perspective here. So the prior sponsor of the drug tried to approach the FDA multiple times. And for a number of years, the FDA was resistant to accepting a surrogate endpoint for accelerated approval. It wasn't just the prior sponsor. It was also other companies doing work in the neuropathic MPS space, including Ultragenyx, REGENXBIO, Orchard, JCR, Denali and a few others. And it wasn't until the FDA, along with academia, patients, patient groups in the industry got together under the roof of the Reagan-Udall Foundation in February of 2024. At that time, the surrogacy of heparan sulfate was endorsed and accepted by the RUF -- through the RUF workshop and that resulted in the FDA's becoming more amenable and more willing to use heparan separate sulfide as a viable surrogate. Following that meeting, companies like Ultragenyx have actually submitted a BLA under CBER in December, the FDA filed the application in February and they're expecting an approval PDUFA date on August 18th. Denali has also -- and that's based on heparan sulfate as a surrogate for accelerated approval. Denali has initiated the rolling submission for MPS II or Hunter syndrome on April 2nd. So they will be fully filed. I think they guided to sometime in May under also accelerated approval. So there's a precedent, there's a regulatory precedent. The FDA is honoring their prior commitments. We have not reengaged with the FDA since we acquired the asset. To confirm our review division is under CDER, same division that is SIMGroup or SIMGroup of FDA that's regulating the Denali filing as well. Ultragenyx is under CBER, Denali is under CDER. We are under CDER as well given our route of administration. So we have confidence. I mean, we have no reason to believe that the FDA will not honor the prior agreements made with the prior sponsor.

And then I guess in terms of the financing plan here, what are your latest thoughts given the limited financial resources and the market environment? Can you give us some insight into how you plan to actually be able to advance this development plan from a financial perspective?

I'll pass it on to Samir. Clearly something that is top of mind for us, but Samir will expand further.

So as we mentioned in the release, we have current cash resources that will extend our current operating plan and fund that plan through the end of this year. And clearly, between now and then, we will need to tap into additional resources to advance the program beyond that date. And I'd say amidst the backdrop of, as you sure can appreciate, a very volatile market environment. I think the one thing that stands out in particular with this asset is the fact that it's highly derisked. I mean we have guidance from the FDA that charts a path to an accelerated approval. We have very strong clinical data against the biomarker, which would serve as a basis for approval. And we think that this asset fits the profile of the types of investment opportunities that investors are currently looking for in a volatile market with a high degree of unpredictability. And so from that standpoint, we have a great deal of confidence that we'll be able to advance this program ourselves and tap into those additional resources as we need to do so.

Your next question comes from Gregory Renza with RBC Capital.

It's [Anish] on for Greg. Congrats on the refresh, and thanks for sharing the updates. Just a couple from us. First, if you could walk us down the funnel of these MPS Type IIIB patients starting from the top of the TAM down to how many patients may actually be able to take the enzyme replacement therapy, what are the filters here in terms of biomarker screening assets, eligible patients, et cetera. And I have a follow-up.

So to walk you down through the funnel. So based on claims database, there are about 3.3k patients with MPS in the US. Of those 1,000 of those are MPSs that affect pediatric patients of those 1,000 about 300 patients have MPS III. Now that's as far as the claims database goes because there are no codes that actually separates MPS IIIA, IIIB, IIIC and IIID. So based on overall global prevalence, MPS IIIB is anywhere between 25% and 40%. So we believe that the prevalent patient population in the US is about 165 patients, 135 patients, rather. We believe that we will be able to address about 50% of those and perhaps more. If you look at the distribution of patients based on claims, about a third of the patients with MPS III are under the age of 10 and we think we can have a penetration of about 85% and we'll have a penetration of about 30% in older patients. Given that the indication for this drug and frankly, when you look at other labels for other MPS drugs tends to be very general for the treatment of MPS IIIB to reduce heparan sulfate, and we think that we actually check both boxes. Patients will be diagnosed through either enzymatic or molecular diagnostic measures or testings and we know the drug has a very profound effect on heparan sulfate. So ultimately, at the end of the day, there's going to be -- the decision on whether to treat and to maintain a patient on treatment will be based on neurocognitive stabilization or improvement but also on other functions like Kirk was alluding to earlier in the call, on whether patients can ambulate, on whether patients can perform social skills, can they toilet themselves, can they eat by themselves, can they have a more engaging live and those -- that decision will be based on whether parents and caregivers and physicians see tangible benefit.

And then I guess just as we think about -- just kind of a follow-on to the previous financing question. As you think about spend, it looks like for the fourth quarter, R&D spend ticked up quite a bit from the third quarter. Maybe if you could just comment on the cadence over 2025, I know the focus is on TA-ERT, but if you could give some granularity there.

So I'll ask Samir to answer that question. Before I do that, let me add something more to your prior question. The response I gave you touches on the prevalent patient population but a very important piece here that Samir touched towards the end of his talk was there is an incidence patient population that occurs year-over-year. And we believe the incidence of MPS IIIB is about 100,000, 200,000 lives that will result in about 18 new patients per year. And those patients that are diagnosed early are likely to benefit to therapy the most. And that becomes a patient pool that is treated for a much longer time because their cognition, their brain function becomes more preserved and those people have -- could have, I wouldn't say normal, but near normal life expectancy. So we're projecting for them to be able to live longer 20, 30, perhaps 40 years if the drug is tolerated and they do well. So I'll pause here and I'll pass it over to Samir to address your financial question.

So you referenced sort of the uptick from Q3 to Q4 of last year. Just as a reminder, that largely reflects the spend of -- on the legacy program for tildacerfont for the treatment of CAH. Obviously, those programs have now been wound down. So on a go forward basis, which reflects our continued development -- ongoing development of TA-ERT, I would guide you to for this year roughly $10 million a quarter of spend. And as we enter the next fiscal year, probably an uptick to $15 million a quarter again, reflective of the BLA enabling activities but also the uptick in terms of the commercial build required to launch the product successfully. Hopefully, that addresses your question.

Your next question comes from Jon Wolleben with JMP.

Can you talk a little bit about the confirmatory trial, what is FDA said about the surrogate heparan sulfate endpoint and what clinical endpoint you need to look at? And what are your thoughts about starting that trial, patient numbers? Any details on that confirmatory would be helpful.

So as you know, as part of an accelerated approval, typically, it comes with the need to confirm the clinical meaningfulness of a surrogate endpoint. And so the prior sponsor had agreed on the key elements for the confirmatory trial. Ii will be a 14 patient trial who have -- it will be 1:1 randomization with seven patients on each of the arms. There will be a active treatment arm, which will be Tralesinidase Alfa. There will be a comparer arm that's going to be standard of care, which is, in essence, palliative medicine, blending will be done as best possible. And there will be a rescue criteria in the protocol that will include some type of decline, which will prompt rescue with Tralesinidase Alfa treatment. There's currently agreement with -- there was agreement between the prior sponsor and the FDA on that study design. We intend to approach the FDA and perhaps offer an alternative to the current protocol in terms of rescue criteria and try to optimize some of the elements of that study, I think that is going to be very, very important for us to engage with the FDA and gain clarity. We intend to initiate the trial while we're under review and that's frankly accepted by the FDA, there is recent guidance for rare diseases actually. You also asked me about the primary outcome. So the FDA has wanted a neurocognitive outcome and that's going to be the BSID, the Bayleys questionnaire cognitive raw score as a primary outcome for the study. It is the same outcome required for Ultragenyx' trial, a similar outcome required for the Denali program. Denali used a combination of heparan sulfate at week 24 and the Vineland questionnaire at week 96, I believe.

And one more, if I may. Looking at the curve you guys had, I think, on Slide 8 for the heparan sulfate levels. When we look at the end, when we get down to six patients for about five years out, is that patients still earlier in the study at the earlier follow-up period or the people drop off and then how many patients are on TA-ERT today?

It's a combination but for the most part due to financial considerations, the prior response ended up discontinuing the program. So not very many patients were able to roll into the 401 study, didn't have -- really have the opportunity to roll into the 401 study being to a 240-week duration follow-on study to 201. And what was the last part of your question, Jon? [Technical Difficulty] how many people on drug. So the prior sponsor discontinued all patients on drug in October of 2023 due to financial consideration. So at the moment, we have -- we only have two patients at a site in Germany receiving ongoing treatment but that's not under the auspices of a trial rather on a compassionate use basis.

Can you tell us how many identified patients you have in the US?

Those are the numbers that I quoted before of about…

Well, not the prevalence of actual patients that may have been on TA-ERT that are still potential candidates for treatment…

We haven't gone down and map out those issues yet, Jon. With all the activity that we do, I just want to highlight that it is foundational for successful rare disease launches, the one goes out and maps out the eligible patient opportunity as well as offer eligible patients access through an early access program prior to commercial launch. And we have -- we intend to have a very similar effort in the EU4 countries as well as the UK through new patient self programs or other type of programs there that we assemble that using different names.

Your next question comes from Leland Gershell with Oppenheimer.

And thanks for this update and great to see this asset in your hands after having seen its progression at prior companies. Just a question from us, Javier and team. With respect to the capital needs for your plans going forward in the kind of two parts, right, you have to do inventory build for the presumptive commercial launch and then also Spruce would have to fund the confirmatory study. Just wondering given that, that study would run several years and obviously extend much past when you could be approved and launched Tralesinidase. Would the company be willing to start that study even if capital remains limited i.e., you may not have enough capital to complete it with perhaps another financing round just given the capital markets we're in, obviously, the environment is very challenging.

Let me start with some elements of your question, and then I'll pass it on to Samir. I mean, we were lucky to be able to have a meaningful inventory of drug substance. Our drug manufacturer company or vendor is Samsung Biologics in South Korea. With that drug substance we'll be manufacturing drug product and developing registrational badges and putting those on stability to support the six month stability required for the BLA. In parallel, we'll be making new drug substance and making new drug product and developing PPQ batches in the required workloads to be able to launch the compound. So I just wanted to provide you some context in the context of CMC. But I'll pass it on to Samir, perhaps you can address, Samir, the capital spend related to CMC and the confirmatory trial and how do we think about that?

So as we think about -- I will just address your question just from a prioritization standpoint, and that prioritization initiative will be primarily directed towards the BLA submission. We have some work to do with respect to manufacturing a drug product campaign and accumulating stability data from that campaign. As both Javier and Kirk highlighted, we have all the clinical and nonclinical data we need for that submission but we'll spend the money to get the required CMC data. As we move forward, obviously, the spend will then be directed towards pre-commercial activities. And to your question on the confirmatory study, from a timing standpoint, the requirement there will be prior to a potential accelerated approval. So we're not really discussing here any near term spend. And now we haven't done formal costing yet. But I would just point you to the fact that the number of patients in the study including roughly 14, 15 patients. And as you think about spend over, call it, a five or six year period, inclusive of enrollment time lines, you're really thinking about 20 million to 30 million over that six year period and so we don't expect this to be really a drag on resources over the long term. And so hopefully, that will address the question, at least from a capital need perspective.

Your next question comes from Ram Selvaraju with H.C. Wainwright.

So with respect to the sort of path forward from here, can you just clarify what level of spend would be required simply to get through the period from where your current cash runway ends and the actual submission of the BLA as well as the period of BLA review according to the accelerated approval time frame? And then secondly, with respect to the commercial perspective, I was just wondering if you could comment on two things briefly. Firstly, perspectives on eligibility for a priority review voucher. How has that changed, how might that change in the future? Because under normal circumstances, one would imagine that a project like this would be PRV eligible. And also, if you can comment on whether pricing perspective might, in any way, be influenced by the near term market introduction of another product candidate. For example, you mentioned UX111 during your prepared remarks. I was just wondering whether whatever pricing gets set for that product, if it gets approved by the PDUFA date in August, would have any implications on how you approach pricing determination for this candidate as and when it gets to the market.

Let me start addressing the latter part of your question first, and then I'll pass it on to Samir to cover some of the financials. So obviously -- I'll start with the PRV and then cover pricing and Samir will do the financials. So I mean, obviously, getting the PRV would be really important for us. The VRV regulation with the PRV reauthorization hasn't really happened as of now. So given that the product has received rare pediatric disease designation, we are under the current framework, which expires on September 30, 2026. We obviously would thrive and we'll do our very best to be able to fit that time line and are working very closely with our CMC vendor to be able to accomplish that. That will inject further cash into the company, which can be used towards performing life cycle management efforts in the context of our CMC activities, meaning scaling up 2,000, 5,000 liters bioreactors, potentially, but also changing the formulation to lyophilized formulation, for example, to simplify some of the call chain required to administer the product as well as injecting cash into other aspects of our pipeline. I think to your point, it is expected that the PRVs will get reauthorized. There is strong impetus from both chambers of Congress as well as the FDA and the patient community to get that deal go through. But at this stage, we're still operating under the September 30th deadline for the program. From a pricing point of view, the compound would convey very meaningful benefit to patients that are suffering for a neurodegenerative fatal disease. So we think that is going to be commanding high price, very similar to other MPSs. Exactly where we land is still yet to be determined. Ultragenyx' drug is a gene therapy. So in theory will be a one and done deal for the patients that would qualify. So I'm not sure that it's going to be the perfect analog. Denali's drug could potentially be a good analog to benchmark the gains. It's a drug that addresses more effectively a neuropathic piece of MPS II, and I think that that's going to be likely priced at a premium to ELAPRASE. Sarepta's drug Zolgensma has a WACC price of approximately $750,000 typically paid without discounts by payers. It's a very bad disease. It's also administered intrathecally into the central nervous system every few weeks initially. That's typically not been a drug that has been heavily negotiated either in the US or Europe. So that could provide a meaningful anchor for our drug. I'll pause here and pass it on to Samir to discuss some of the financial questions that you all had.

Ram, I think you had asked about capital needs but also in relation to some key inflections points and milestones. So as we mentioned in the release today, we had -- we ended 2024 with $38.8 million in cash and cash equivalents. We would need roughly incremental capital, call it, 60 million to get to a potential approval for TA-ERT and, call it, roughly half of that number of incremental capital would be needed to get to the actual BLA submission.

At this time, there are no further questions in queue. Ladies and gentlemen, thank you for your participation. This concludes the Spruce Biosciences investor call. You may now disconnect your lines at this time. Have a wonderful rest of your day.

Greetings! Welcome to the Spruce Biosciences conference call. All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on your telephone keypad. To withdraw your question, please press star, then two. Please note, this conference is being recorded. At this time, I'll now turn the floor over to Samir Gharib, President and CFO of Spruce Biosciences. Samir, you may begin now.

Thank you, operator, and thank you all for joining us this afternoon. With me on today's call are Dr. Javier Szwarcberg, Spruce's Chief Executive Officer; Dr. Will Charlton, Spruce's Chief Medical Officer; Dr. Irina Bancos, Principal Investigator in the CAHmelia-203 study and Associate Professor of Medicine and Endocrinologist at the Mayo Clinic; and Dr. Paul Thornton, Principal Investigator in the CAHptain-205 study and Medical Director of the Endocrine and Diabetes Program at a CAH Center of Excellence. This afternoon, Spruce issued a news release announcing top-line results from its phase 2B CAHmelia-203 clinical trial of tildacerfont in adult classic congenital adrenal hyperplasia, also known as CAH, and its phase 2 CAHptain-205 clinical trial of tildacerfont in pediatric classic CAH. Spruce also announced its financial results for the year ended December 31, 2023.

Please note that certain information discussed on the call today is covered under the safe harbor provisions of the Private Securities Litigation Reform Act. We caution listeners that during this call, Spruce management will be making forward-looking statements. Actual results could differ materially from those stated or implied by these forward-looking statements due to the risks and uncertainties associated with the company's business. These forward-looking statements are qualified by the cautionary statements contained in Spruce's press release as issued today and the company's SEC filings, including its most recent annual report on Form 10-K and subsequent SEC filings that it has made. This conference call also contains time-sensitive information that is accurate only as of the date of this live broadcast, March 13, 2024.

Spruce undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call. Now, finally, during today's Q&A session, we ask that you please direct all questions to Javier, and he will request that either Spruce management and Doctors Bancos and Thornton elaborate as appropriate. Now, I'd like to turn the call over to Javier. Please go ahead, Javier.

Thank you, Samir, and thank you, and good afternoon to you all. As a physician and drug developer, I have dedicated my career to advancing new and innovative solutions for underserved patients, families, and communities suffering from rare orphan diseases. At Spruce, we focus on transforming the care of patients with rare endocrine disorders, including CAH. For nearly a decade, our team of innovators and drug developers has sought to advance new therapeutic options. Today, our focus is on tildacerfont, a once-daily tablet in development that we believe has the potential to transform the treatment paradigm in CAH and positively impact the lives of patients and their families. CAH is a rare genetic disorder that impacts patients throughout their entire lives from birth. It's estimated that the total classic CAH population is approximately 20,000-30,000 people in the U.S. and 50,000 in the EU.

CAH affects the adrenal glands and, due to an enzymatic deficiency, leads to an inability to make cortisol and an overproduction of adrenal androgens. Due to the severity of the disease, every state across the U.S. and most developed nations have established newborn diagnosis screening programs. From birth, newborns are placed on glucocorticoid replacement therapy, also known as steroids or GCs, to correct for the missing cortisol. If left untreated, patients become susceptible to adrenal crisis, which can be life-threatening. This risk continues over the person's lifetime and never goes away. The overproduction of adrenal androgens is also an important issue, as it can lead to life-compromising effects such as early puberty, obesity, short stature, acne, facial hair in females, psychiatric problems, and impaired fertility in both sexes.

Elevated adrenal androgens levels are generally managed with above physiologic doses of GCs, which over a lifetime carry several well-known debilitating effects, including obesity, cardiac problems, hypertension, insulin resistance, high lipids, Cushingoid appearance, bone loss, which may result in excess bone fractures, sleep issues, and anxiety. Unfortunately, for patients, there has not been a steroid-sparing treatment option and frankly, minimal innovation since GCs became available in the 1950s. So why, for the past 70 years, has science been unable to make meaningful advances in the CAH therapeutic landscape? Well, key to the problem is the perception that chronic GCs at above physiologic doses, along with chronically elevated adrenal hormones, will not result in significant chronic consequences to one's life. That's simply untrue, and this perception must change. It is a cumulative lifetime overtreatment that creates problems and matters.

Better options are desperately needed that allow for physiologic, meaning more balanced steroid use, while controlling the elevated androgens. At Spruce, we are focused on changing this treatment paradigm by developing tildacerfont as an oral, once daily, non-steroidal treatment option. It is a corticotropin-releasing factor type one, or CRF1 receptor antagonist, designed for androgenic control while on physiologic doses of GCs, which was not possible until now with the current steroid therapies. We are committed to unlocking the full therapeutic potential of tildacerfont and developing a quantifiable and meaningful improvement over today's standard of care in CAH. Which is why we were disappointed by the results from the CAHmelia-203 program in adult CAH patients with severe hyperandrogenemia. Though the study did not achieve the primary endpoint, we garnered important data about the challenges of treating severe hyperandrogenemia within this patient population.

CAHmelia-203 is the first study of its kind to focus on a very difficult-to-treat patient population with poorly controlled disease, as evidenced by the mean androstenedione, or A4, levels of patients who enrolled in this study, which was over 5 times above the upper limit of normal. This was an important study to learn how best to address this refractory and difficult-to-treat group of CAH patients with severe chronic hyperandrogenemia, often attributed to challenging real-life compliance with daily glucocorticoids. Despite our efforts and strong study conduct standards, overall compliance with study medication and GCs was low in CAHmelia-203, resulting in lower than expected tildacerfont exposures. However, after consultation with experts and advisors, as well as our internal analyses, we remain confident in the therapeutic activity and potential of tildacerfont. We will explain why today.

We are hopeful and look forward to reviewing the results of CAHmelia-204, which is expected to read out in the third quarter of 2024. The CAHmelia-204 study is focused on assessing GC reduction, a potentially registrational endpoint in a less severe patient population of adult CAH patients with relatively controlled A4 levels and historically better adherence to daily GC therapy, which gives us further confidence. A recent phase 3 study investigating another CRF1 receptor antagonist in a patient population similar to that of CAHmelia-204, demonstrated statistically significant responses to treatment based on recently released data. Additionally, we are encouraged by the initial positive top-line results from our CAHptain-205 study in children and adolescents. The therapeutic activity we observed in this study suggests that tildacerfont, even at lower doses, may enable clinically meaningful reductions in A4 and allow for GC reduction in children and adolescents with CAH.

I will now turn the call over to Dr. Will Charlton, our CMO, to review our top-line study results. Will?

Thank you, Javier, and good afternoon all. As a pediatric endocrinologist, I've cared for people living with CAH and have a very personal connection to this community. I've dedicated my career to making scientific progress and improving the lives of patients suffering from rare endocrine disorders. The global CAHmelia program in adult classic CAH is comprised of two phase 2B studies designed to address the unmet medical needs of two subpopulations of adults. CAHmelia-203 assesses A4 reduction in adult CAH patients with severe hyperandrogenemia, while CAHmelia-204 assesses GC reduction in adult CAH patients that are on supraphysiologic GC doses and have normal or near normal A4 levels.

Our program underscores our initial strategy to address the entirety of the adult classic CAH patient population by targeting two distinct groups with differing challenges: those with excessive adrenal androgen levels, the CAHmelia-203 study, and those with excessive GC usage, the CAHmelia-204 study. CAHmelia-203 enrolled 96 participants, A4 level of 1,151 nanograms per deciliter, which is over five times the upper limit of normal. The study did not achieve the primary efficacy endpoint of assessment of dose response for the change in A4 from baseline to week 12. 200 milligram once daily of tildacerfont demonstrated a placebo-adjusted reduction from baseline in A4 of -2.6%, with a non-significant P value at week 12. Tildacerfont was generally safe and well tolerated at all dose ranges, with no treatment-related serious adverse events. Most adverse events were recorded as mild to moderate.

The results from CAHmelia-203 highlight the challenges of treating severe hyperandrogenemia within this patient population, many of whom were ineligible for other CAH clinical trials... and underscores a potentially different treatment paradigm that may be necessary to affect, to effectively address the unmet need in these patients. In fact, the effective treatment of CAH in the context of severe hyperandrogenemia may be different from the approach needed to manage GC excess in patients with normal or near normal levels of androgens. The differences between these two patient populations are quite evident when you review the baseline characteristics for CAHmelia-203 and CAHmelia-204. The mean adrenocorticotropic hormone, or ACTH level, was nearly 7 times the upper limit of normal, while the mean A4 level within CAHmelia-203 was above 5 times the upper limit of normal.

Compare that to the levels in CAHmelia-204, which were at or near the upper limit of normal. 17-Hydroxyprogesterone, or 17-OHP, in CAHmelia-203, was more than 80 times the upper limit of normal, compared to the level in 204, which was approximately 28 times the upper limit of normal. Further, patients enrolled in CAHmelia-203 have severe and refractory disease as a result of patient-specific physiology, such as degree of 21-hydroxylase deficiency, or inability or unwillingness to tolerate high doses of steroids, which makes them more susceptible to being in a hyperandrogenic state in the first place. We know from clinical practice that patients with hyperandrogenemia generally require increases in their background steroid therapy, and in some cases, changes to their dosing schedule or their type of GC to reduce adrenal androgens.

When adrenal glands are highly overstimulated, especially for a long time, they become increasingly hyperplastic and more difficult to control. In these cases, short-term treatment with higher steroid doses is sometimes required to involute adrenal tissue and to reduce adrenal androgen production. This, combined with results from our study, offers us insights into a potentially different treatment paradigm needed for this population, and considerations for optimizing the combination of tildacerfont and steroid dosing to address the ACTH overdrive in CAH patients suffering from severe hyperandrogenemia. Now, this is in very stark comparison to patients in our CAHmelia-204 study, who are more controlled by virtue of their higher GC doses and likely suffer from less hyperplasia of the adrenal glands.

Patients with higher GC doses and normal or near normal androgen levels are also generally more consistent with GC therapy and easier to manage, but they carry a higher risk of steroid-associated comorbidities. We believe that for this group of relatively well-controlled patients in CAHmelia-204, the goal should be to sustain ACTH suppression, which would allow for a gradual decrease in steroid dosage, ideally to physiologic replacement levels. For this reason, we do not believe that results from CAHmelia-203 are necessarily suggestive of potential results from CAHmelia-204. This, along with feedback from many experts as well as our internal analysis, reinforces our confidence in the therapeutic potential and activity of tildacerfont, and we look forward to the 204 results in the third quarter of 2024, which will provide a critically important and more complete picture of its efficacy.

Moving forward, we plan to continue our analysis of CAHmelia-203 and plan to use our study learnings to potentially inform a future phase 3 program. Now, let's discuss the positive initial top-line results from our pediatric CAH program. The phase 2 CAHptain-205 study is focused on addressing the unmet medical need in pediatric classic CAH patients, which represents approximately 25% of the total patient population. CAHptain-205 enrolls 30 children between 2 and 17 years of age. They had a mean baseline GC dose of 14 mg/m²/day, and a mean baseline A4 level of 372 ng/dL. The study characterized both the safety and pharmacokinetic profiles of tildacerfont in children, as well as changes in androgen levels over 12 weeks of treatment and the ability to reduce daily GC doses in patients achieving normal A4 levels.

During the initial four weeks of the trial, glucocorticoid treatment was not modified. 73% of all patients, or 22 of 30, met the efficacy endpoint of A4 or GC reduction at baseline, or rather, from baseline at week 12 weeks of treatment with tildacerfont. 70% of patients with elevated baseline A4 values, or 16 of 23, demonstrated an A4 reduction at week four. Tildacerfont was generally safe and well-tolerated at all dose ranges, and no treatment-related serious adverse events were reported. Although the CAHptain study met the efficacy endpoints, the results were less consistent than anticipated and without clear dose response. Pharmacokinetic results suggest that children clear tildacerfont more rapidly than adults do, which is common with many drugs due to differences in drug metabolism across age and developmental stages.

It is not uncommon for children to require relatively higher doses than adults in order to achieve optimal exposures of drugs. So we are encouraged by the activity observed thus far at suboptimal doses in this phase 2 dose ranging study, and we plan to continue to evaluate the optimal dose, with top-line results anticipated in the fourth quarter of 2024. Overall, as a pediatric endocrinologist, I've witnessed firsthand the unmet medical needs and challenges of people with CAH who lack steroid-sparing treatment options. I remain encouraged by our results today and the potential of tildacerfont to deliver transformative care for patients and families living with CAH.

Thank you, Will. I will now ask Samir Gharib, our President and CFO, to briefly review our 2023 financial results. Samir?

Thank you, Javier. Our cash and cash equivalents as of December 31, 2023, were $96.3 million. The company currently has over $81 million in cash and cash equivalents. We have made the difficult but necessary decision to streamline our operations and have implemented cost reduction measures, including termination of the CAHmelia-203 study, and a reduction in force of approximately 21%, which has extended our cash runway through the end of 2025, beyond top-line data readouts for CAHmelia-204 and additional dose ranging data from CAHptain-205.

Collaboration revenue for the year ended December 31, 2023, was $10.1 million, compared to nothing in 2022, reflecting the partial recognition of the $15 million upfront payment received from Kaken Pharmaceutical in connection with the company's strategic collaboration with Kaken to develop and commercialize tildacerfont for the treatment of CAH in Japan. R&D expenses for the year ended December 31, 2023, were $49.4 million, compared to $35.2 million in 2022. The overall increase in R&D expenses was primarily related to the advancement of our CAHmelia and CAHptain clinical studies. G&A expenses for the year ended December 31, 2023, were $12.7 million, compared to $12.1 million in 2022.

Total operating expenses for the year ended December 31, 2023, were $62.1 million, compared to $47.3 million in 2022. These include non-cash stock-based compensation expense for the year ended December 31, 2023, of $4.6 million, which compared to $3.6 million in 2022. Net loss for the year ended December 31, 2023, was $47.9 million, compared to $46.2 million in 2022. Now finally, common shares outstanding as of December 31, 2023, were 41 million shares and 61.3 million common shares on a fully, fully diluted basis.

Thank you, Samir. We consider it an honor of being able to partner with the CH community, and through innovation, open a new chapter in the management of CH with a possible life-changing medicine. I recognize the potential transformative impact of tildacerfont, and we have a strong sense of urgency to deliver on our commitment to the CH community. Across the landscape, this is an incredibly important and exciting time for CH patients and families. Making progress in a therapeutic area that is underserved requires doing things differently and in partnership with them. We at Spruce have a clear purpose, and that is to improve the standard of care for the communities we serve. That is our true north.

Looking ahead to the third quarter, we're eager to report top-line results from CAHmelia-204, which is focused on assessing GC reduction in potentially registrational endpoint in adult CAH patients with relatively controlled A4 levels and better GC compliance. Assuming positive results from the CAHmelia-204 and CAHptain-205, we plan to meet with the U.S. FDA and comparable foreign regulatory authorities to outline the design of a registrational clinical program in adult and pediatric classic CAH. In conclusion, I would like to extend our deep appreciation to all the patients, families, study team, and investigators who participated in the CAHmelia-203 and CAHptain-205 clinical trials. Your support advances our understanding of the disease and our mission to deliver a meaningful improvement over today's standard of care in CAH.

I also want to express my gratitude to all of our employees, including those departing Spruce, for their contributions and tireless dedication to advancing our mission and bringing forward new and innovative therapies for CAH and other rare endocrine disorders. Operator, will we now open the line for questions?

We will now begin the question and answer session. To ask a question, you may press star, then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. Our first question today is from Joseph Schwartz with Leerink Partners. Please go ahead.

... my condolences on these results. I was wondering, it sounds like you're not just attributing the miss to poor compliance, but also the patient population which was enrolled in 203 with their severe and refractory disease. So I was wondering, how much did tildacerfont reduce A4 in patients who were compliant to their regimen and, or who had less extreme A4 levels in study 203? Have you done any analyses looking into the data to see such things in order to explore whether there's any data supporting your hypotheses to explain the miss in study 203? And then I have a follow-up.

Hi, Joe. This is Javier. Yeah, we're in the process, Joe, of really understanding the relationship between exposure and response in the trial. Clearly, we see that upon increased levels of different doses of tildacerfont in the 203 study of 50, 100, and 200, we've seen increased levels of exposure. But overall, the overall exposures were multiple folds below the exposures that we had seen in the 202 study, which was a proof of concept trial that informed the design of the 203 program. And it is because of that that we attributed, you know, the kind of - you can actually attest the sequence, right? Lesser compliance, less exposure, lesser overall benefit.

I would like to, you know, pass on some of this response to Dr. Bancos. Irina, perhaps it'd be great if you can, you know, provide your point of view on the type of patients that we treated in the 203 study and how that translates into your clinical practice.

Yes, thank you for this question. So clearly, patients enrolled in 203 were not quite representative of, majority of patients with CAH, at least seen in adrenal centers. And what I mean by that, that these are the patients who were less likely to be controlled, as you have shown based on their androstenedione levels. So, it's a bit difficult to apply the results of, the study to the whole population with CAH, considering that these are very unique patients on low glucocorticoids and with more uncontrolled androstenedione.

Okay. And why do you think you're seeing an inverse baseline effect when Neurocrine saw a strong positive baseline effect in CAHtalyst, where patients with higher A4 baseline benefited more with a larger reduction in A4 on a related molecule?

Well, I wouldn't say that... Thank you, Joe, for the question. I wouldn't say that the baselines between the Neurocrine program and the 203 study are similar. Rather, I consider them quite different. The baseline A4 value was 620. Our baseline A4 value is 1,151 nanograms per deciliter, and overall GCUs in the 203 study was 27 milligrams relative to a 32 in the Neurocrine program. You know, I think that the explanation that we have given, or at least the current hypothesis, is that it's related to the overall compliance and the overall exposure of drugs.

So we didn't really achieve the exposures in the 202 study that we were hoping to achieve, and hence the lesser overall impact on the biomarkers that we have tested. I think that part of the reason why we didn't achieve the exposures is because of the compliance rates, which were remarkably low, and I think they reflect, frankly, what typically happens in practice, right? And you just heard what Dr. Bancos had to say. The compliance rates in the 203 study were, you know, approximately 50% of patients were about 80% compliance.

And we know that 80% compliance isn't terrific, and patients are missing 2 out of 10 doses, and we know how sensitive it is for patients to you know how sensitive A4 is in the context of missed doses. So, yeah.

Right. I guess, assuming A4 didn't change much in the placebo arm, and knowing that around half of patients were generally compliant, this would still imply that A4 only decreased by around 5% amongst compliant patients. So I'm just trying to understand, are you attributing the miss to both the poor compliance and just the drug not working in really high A4 levels at baseline? And I'm just a little bit confused by that, because Catalyst, I thought, showed us that crinecerfont worked better in people with A4 that was higher in baseline in that trial, recognizing that the A4s overall were lower in Catalyst. So why would that relationship break down, you know, at much higher A4 levels?

... Yeah, the way we understand this, Joe, is that the exposures need to be adequate to control patients with CAH, right? I mean, this patient population tends to be generally more difficult to control. The 2 or 3 patient population is more severe, is more advanced, tends to be more refractory to treatment, therefore, requiring adequate levels of CRF1 receptor antagonism to induce a response. I mean, the comment that we made earlier that patient -- maybe this patient population requires more intense management with corticosteroids to first control the disease and later to, for the disease to be maintained on a more on the CRF1 receptor antagonist alone, may frankly hold true.

It is definitely a fact that, you know, we did not achieve the exposures that were necessary to control this patient population in the 203 study. And it is also a fact that the exposure seen in the 203 study are folds lower than the exposures that we saw in 202, in the same patient population of elevated androgens and characterizes as poor control. Now, the patient population in 204 is very different, right? This is a group that generally has adrenal a little more under control, that have lesser extent of hyperandrogenemia, that tend to be more compliant with therapy. And we have, you know, strong reasons to believe that the 204 study will behave differently.

Okay. Good luck. Thanks for taking my questions.

Thank you, Joe.

The next question is from Gregory Renza with RBC Capital. Please go ahead.

Hey, good afternoon, Javier. Thanks for holding the call, taking the question also. Yeah, apologies on the, sorry about the ultimate result here. Javier, just as you think about the design that you had for 2 of 3, certainly, with respect to the screening and the run-in, I'm just curious if you could talk a little bit about, you know, how that's fair to your expectations, what could have been done to maybe, you know, mitigate for this or, or not, as you think about the compliant or non-compliant population?

Maybe just as you talk about, you and the docs talk about the 2 of 4, can you just walk us through a little bit about the rationale about why the compliance expectation would be better? Certainly, you've touched on that, but just expand a little bit about anything quantitative that you see that gives you confidence in those areas. Thanks so much.

Thank you for the question, Greg. So, with regards to two or three, frankly, we've designed, I think, a very thoughtful study. On the front end of the trial, there was a run-in period of about six weeks. During those six weeks, we assessed compliance with study drug and compliance with corticosteroids and didn't allow patients in the trial that were less than 80% compliant. Frankly, that was done to ameliorate and reduce the possible placebo effect, and with the hopes that we were going to dismiss from entry patients that weren't going to be compliant during the trial.

Certainly that wasn't enough, and we, you know, despite doing that, we were not able to attain the levels of compliance that we were hoping. The study was conducted to the highest standard, with great robustness and very significant oversight, with you know, I'll let Will talk a little bit about the efforts that we put in place to ensure that people stay compliant during the course of a trial. Before I pass it on to ... Actually, Will, why don't you cover that, and then we can address the question that Greg had on 2 or 4?

Sure. So it became evident early that people were having trouble understanding how to take tildacerfont with food and the right time. So we launched some campaigns, some educational campaigns around how to take it correctly, how to take it with food, and also around compliance with steroids. In spite of those efforts, we do see a meaningfully lower compliance rate in this study than in other studies, and I think that's reflected in our exposure levels that we've seen.

Yeah. Thanks for that, Will. So let's talk about the 204 question that you had on compliance, and why do we have confidence that things are going to be different for the 204? I'll ask Irina in a moment, Dr. Bancos, in a moment to comment on her experience in patients in her practice that are more similar to the 204 patient population. But we've looked at compliance in 204, Greg, and all along, compliance in the 204 study has been much, much better than the compliance that we've seen in 203. As of now, the ongoing compliance rate based on recent data appears to be north of 80%.

And that frankly gives us the reassurance that we'll achieve the tildacerfont exposure that are required to demonstrate efficacy. And as I said before, you know, I firmly believe that probably what will be needed to control - to maintain a patient in control in two or four is likely very different, and the CRF exposure necessary to induce control in a refractory two or three patient like. But I'd like to ask Dr. Bancos about her point of view here and how this relates to her practice.

So I guess in relation to, 203 population and high androstenedione levels and, compliance. So first, why would we see elevated androstenedione in CAH? It's really one or more than three things. Number 1, taking low glucocorticoid dose than is needed. Number 2, being noncompliant with your glucocorticoid dose. Or Number 3, severe CAH needing high glucocorticoid dose. So considering that the average dose of glucocorticoids in 203 study was not particularly low, clearly it's one of the other two, right? So it's either severe CAH or noncompliant. Earlier when I said, it's a bit of a sort of unique population of patients with CAH in one of the three categories. So I hope that answers your question.

Thank you, Irina. Perhaps, Irina, if you can, comment on 204 patients, the type of 204 patients that you see in your practice, and whether they tend to be different than the patients that we enrolled in 203 with a focus on compliance. Do they tend to be more compliant with therapy?

Yeah. Well, so by describing the population that went into 203, we just can contrast the one that went into 204. Well, that those were the people on slightly higher glucocorticoid dose, clearly more compliant with lower androstenedione levels, reflecting the compliance. So you, you have sort of like a natural division here between, you know, two types of population. And definitely the 204 population is what, probably is more representative of most patients followed by adrenal centers.

Thank you, Dr. Bancos. Rick, I hope our response addresses your question. Perhaps we can pass it back to the operator to see if there are any more phone call, any more questions.

The next question comes from John Wolleben with JMP Securities. Please go ahead.

Hey, thanks for taking the question. A couple on 205 and then one to circle back to 204. Can you tell us what the actual A4 and GC reductions were in 205?

We'll be, we'll be disclosing those results, probably in an upcoming meeting later in the year, John. You're talking about specifics?

Yes. Yeah. Okay, so we'll stay tuned there. And it sounds like you don't think that 204 is gonna be sufficient to submit to regulatory authorities on its own. Is that correct?

Well, it will depend on the strength of the evidence from 204, but I think it is quite likely that we will be required to conduct a confirmatory phase III trial to support the results from 204.

Last one for me. Can you talk a little bit about the titration regimen in 204? If patients are coming in near the upper limit of normal at baseline, will they be able to start titrating down their GC dose immediately? Can you just speak a little bit about that algorithm in 204?

Yeah, they would. So patients that come in. So we titrate. We have a titrating algorithm that's based on A4 values. When the A4 values fall within the upper limit of normal, or when patients come into the trial with A4 values that are within the upper limit of normal, they are readily eligible for a GC down titration. So we have, you know, patients come in, and there's a visit schedule that dictates when our A4 is to be drawn and, upon assessment of the A4 value, then the GC gets titrated down, maintained, or increased following the protocol-specified algorithm.

Okay. All right. That's helpful. Thanks again for taking the questions.

Thank you, John.

The next question is from Hartaj Singh with Oppenheimer. Please go ahead.

Great. Thank you for the questions and really tough results to see today. You know, just a couple of questions. One was just going to, I guess, through 205 study, what were the A4 and GC reductions seen in the pediatric study? And then, you know, were there any discontinuations in the 203 study? And then what were the reasons for that? And I got a quick follow-up.

Hi, Hartaj. Thanks for your questions. We will be reporting, you know, the actual GC and A4 reductions at an upcoming medical conference later in the year for 205, so stay tuned on that. Regarding 2 or 3 discontinuations, the actual retention rate was actually quite high. We were able to achieve over 90% of patients completing the trial. Frankly, there was nothing related to safety matters that explain the discontinuations, you know, personal reasons and a couple of adverse events that were deemed non-related to study drug. I'll pass it on to Will to see if there's anything else to add.

There were a handful of discontinuations, but there was really no pattern. As Javier said, there was no safety concern. There were personal issues like changing jobs or moving.

Great, thank you. And then just a couple, just questions on, you know, if you did see reductions in A4, in two or three, about how long did it take? And, you know, was that correlated with adequate drug levels in two or three?

Yeah, that's a good question, Hartaj. So we didn't really see a correlation with time. We looked at week 4, week 8, and week 12, and, you know, frankly, the exposures were low throughout. We haven't yet, we're in the process of examining an exposure-response correlation. If there is one, it will be very weak, because even the max exposure was meaningfully lower than the exposures that we achieved in 202 study, where we saw a fairly strong signal on biomarker reduction, both in ACTH 17-hydroxyprogesterone A4. So it, it's disappointing, and I know that, you know, we here at Spruce tried to find explanations and find reasons as to why this happened.

The current hypothesis of lesser compliance leading to lesser exposure of drug, in my mind, explains what's going on. And I wanna make it very clear that we see a very different reality in 204 patients, and that's why we believe that 204 study hopefully will read out different results.

Yeah. Great, Javier. And my last question is just again, going to 2 or 4. You said you might need a confirmatory phase 3. That would be basically just like a 2 or 4? I mean, I guess these poorly controlled patients is not an area that you would look at further, right?

Well, I think that upon unveiling the 204 study and upon looking at the totality of the 203 data, we'll develop a firmer point of view. But currently, our approach is to frankly pursue a broad indication for tildacerfont, just like we have pursued so far, which includes adults and children. And frankly, you know, there is a possibility that that study that we've been alluding to will be a study that includes both adults and children. We currently have a dose response study in 205 that's ongoing. Because of safety, we wanted to expose first adults to 200 milligrams BID, and then adults at 400 milligrams BID before we expose children to those doses.

Again, to just make sure that the things were okay from that regard before we venture into children. And I think that those two doses will be incredibly important as we design and think about that follow-along study. So I think that, you know, there's still the possibility of us being able to address the more severe, the more difficult to treat patient population enrolled in two or three.

Yeah, Javier, that makes a lot of sense. Thanks for the comprehensive answer, and tough day today, but looking forward to more updates.

The next question is from Evan Wang with Guggenheim Securities. Please go ahead.

Hey, guys. Thanks for taking the question. Had a couple, you know, just trying to understand some of the 2 or 3 dynamics a little bit more. Were you able to take a look at, you know, those maybe that were more compliant and better controlled, if you were seeing A4 that was more like the 202 studies, and whether the exposure there was more similar? And then in terms of, you know, the regulatory path forward and a potential phase 3, can you expand a little bit more in terms of what a design could look like? It sounds like there could be a possibility of, like, a different dosing regimen. Just wanted to confirm. I'll start there. I have a follow-up.

Yeah. Thanks, Evan, for the questions. I think we're in the process of really understanding our 203 data in depth. The data that we released, or the data that informs this release is frankly top-line data, so we're in the process of conducting more analysis on the data. So stay tuned on that. In terms of phase 3 design, frankly, we'll be dictated by the outcomes of those response arms that I mentioned in adults and in children. Those, those arms are currently ongoing. And also the results of the 204 study. I don't discard at this stage that we might need a higher dose and possibly a BID dose of tildacerfont to address this more severe, more difficult to treat patient populations.

But that will depend on the data that we see. Like I said earlier, our intent is to bring forward the 205 and 204 study results to the FDA, hold an end of phase two meeting, and at that time propose, you know, a development program that makes sense for both adult and peds. You said you had a follow-on question, Evan?

Yep. I was just wondering, with the cost savings initiative and cash runway, I guess, is that looking at both for the development of adult and pediatrics? Or is there kind of prioritization of maybe one first?

Yeah, I'll let somebody take on that question.

Yeah. Hey, hey, Evan, thanks for taking the time to join us today. So our current operating plan contemplates sort of the scenario of events that Javier has outlined, which is, you know, reading out the 204 study, garnering additional dose-ranging data from the 205 study, taking that to an end of phase two, and commencing, assuming positive results from both studies, a single phase three study in both populations. So when you look at our new extended current cash runway, those assumptions and plans are contemplated in those estimates.

Great. Thanks, guys.

The next question is from Aidan Husanov with Ladenburg. Please go ahead.

Good afternoon, everyone. Thank you for taking, the questions. So I have a couple. So Neurocrine will likely launch the drug in 2025 in both pediatric and adult population. So if you are to run phase 3, how do you plan to enroll these patients, given the prior challenges in the phase 2 enrollment?

Hi, Aidan. This is Javier. Thanks for the question. You know, I think that, frankly, I know that our competition is intending to launch or at least express a desire to launch in 2025. I think that, you know, we still need to learn more about their data, more about the regulatory pathway and details about the launch. I feel that, launches are typically not, you know, especially early on in rare diseases, not global launches, so there might be regions and areas of the world where the studies can be conducted. Adoption of therapy probably will be throughout. There will be an element of patients that will qualify for the Neurocrine drug, and those might be eligible patients to come into a trial.

So I think it's gonna—we're gonna have to wait and see. I think that, you know, our studies, all of them, 203, 204, and 205, ended up being oversubscribed with very strong patient interest. And frankly, the results of 204 and 205 will frankly dictate the appetite of patients to be part of our program. You know, we'll definitely make it, you know, I think part of competitive landscapes and I've had to enroll clinical trials in the past where a competitor has been approved, and, you know, that often creates the right momentum for patient participation into research.

Javier, do you think the FDA will be selective in terms of the potential specific label indicating the baseline GC levels?

Are you referring to GC levels in the context of 204, potentially?

I'm referring to the potential kernicterus on the approval. Do you think they'll be specific in terms of the GC levels, or they'll be broad?

Yeah, I don't, I don't really have, you know, frankly, much vision into, into what, what Neurocrine will do, or what frankly, what the FDA will do. My response will be speculative, so I'd rather not do that.

Okay, understood. The last one: Could you share any changes in the characteristics, additional characteristic in 203 studies, such as 17-OHP or ACTH levels in 203 study?

Sure. I will, I will pass on that question to Dr. Willis Altman.

Androstenedione, or A4, is the most reliable of the biomarkers that we have in CAH, so that's our primary. But the both ACTH and 17-OHP were dramatically elevated in 203 relative to 204. So the 17-OHP, for example, in 203, was more than 80 times the upper limit of normal, compared to 204, which was 28 times the upper limit of normal. Important to keep in mind that 28 times sounds high, but actually, if you The treatment goal is never to normalize 17-OHP. In fact, you wanna be severalfold above normal to be in what's considered the appropriate range, so just for a little context.

Similarly with ACTH, in 203, it was close to 7 times the upper limit of normal, and in 204, it was pretty close to normal. So that's a meaningful difference that carries it over across all the biomarkers in a consistent way.

Understood. Thanks so much. Thank you for taking the questions.

Again, if you have a question, please press star, then one. The next question is a follow-up from Jonathan Wolleben with JMP Securities. Please go ahead.

Hey, Samir, thanks for taking the follow-up. You mentioned the 202 data a few times, and, you know, there you had pretty high baseline levels of A4 as well, and you mentioned that the exposures was greater, but that was a 400 mg dose. So can you talk a little bit about what you know about the 400 mg versus the 200 mg exposure levels, if it is, if patients do take the drug as intended?

Yeah. Hi, John, Javier. So the exposures in 202 were clearly, you know, greater between 2 and threefold, the exposures we've seen in the 203 study. And it is our current hypothesis that that delta in exposures, you know, explain away the current effect sizes that we saw in 203, which are very different than the effect sizes we saw in 202. I completely agree with you that the exposures in 202 are greater because, you know, one possibility is not just because the drug is greater, but also because compliance rates in 202 were greater. I mean, over 95% of patients took 100% of their study drug in 202.

Again, a smaller study, more manageable, lesser sites, less complexity probably. So, you know, at this stage, it's really difficult to attribute, you know, whether the effect is solely compliance or solely exposures. You know, but what we, what I can tell you is that there was a meaningful delta between 203 and 204 -- sorry, 202 and 203 exposures. And, and there was a, you know, real separation between effect sizes in the two studies. And, and, so that's frankly all we know.

I mean, you know, I can tell you that if we would've achieved, the speculation is that if we would've achieved exposures, seen in 202 within the 203 study, we think that we would've seen the same effect sizes, given that the patient population was very, very similar. As you said, A4 values were comparable between the two the two studies and, and GC use was comparable. The major difference between 202 and 203 was the age group of the study participants in the full control group in 202, which was around 42, and in the 203 study, which is on average 32 years of age.

Okay. That, that's very helpful context. Thanks again, Javier.

Ladies and gentlemen, thank you for your participation. This concludes today's teleconference. You may disconnect your lines at this time, and have a nice day.