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Hello, everyone. Thank you for joining us and welcome to Xeris Biopharma XP 8121 program overview. After today's prepared remarks, we will host a question and answer session. If you would like to ask a question, please press star one to raise your hand. To withdraw your question, press star 1 again. Those on the webcast can submit a text question by clicking the Q&A button on the bottom right corner of the screen. I will now hand the conference over to Allison Way, Senior Vice President of Investor Relations. Allison, please go ahead. Good morning, everyone, and welcome. I'm Allison Way. I am the Senior Vice President of Investment Relations. On behalf of the entire Xeris team, thank you for joining us today for XP8121's program overview. We will start the presentation today with John Shannon, Chairman and Chief Executive Officer of Xerris, who will set the stage for everything you're about to hear, including why we believe our candidate drug product, XP-8121, a once-weekly subcutaneous injection of levothyroxine for the treatment of hypothyroidism, has the potential to be a blockbuster. From there, you'll hear from Dr. David Robertson, a leading endocrinologist and an investigator in our Phase III registrational study. Dr. Robertson will share his clinical perspective on why XP-8121 has the potential to be a game-changer for people living with hypothyroidism and the physicians working to treat them. Dr. Ang Nguyen, our Chief Medical Officer, will cover our comprehensive integrated evidence generation program for 8121 in detail, including Cornerstone, our Phase 3 study, Capstone, Our Pediatric Study, Touchstone, Our Special Population Study, and Our Real-World Evidence Strategy. Josh Bennett, our head of strategy, will reinforce the unmet need, the competitive moat, and highlight our commercial readiness. After a quick summary by John, we'll wrap up today with a question and answer session consisting of the full XERIS team. Before we begin, this presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Please see slide 3 of the accompanying presentation and our SEC filings for important risk factors that could cause our actual performance and results to differ materially from those expressed or implied in these forward-looking statements. We undertake no obligation to update or revise the information provided on this call as a result of new information or future results or developments. that, I'll turn the call over to John. Thanks, Allison. A year ago, we set out our ambition to become the next great biopharmaceutical company. Today, we're here to show you exactly how we're delivering on that ambition. Let me start with where we stand today. Our strategy is straightforward and it's working. The first part of our strategy is to build a fast-growing commercial enterprise. RecorLiv, GVoke, and Cabeas are performing, with RecorViv leading the way towards our goal of $750 million in total revenue by 2030. Second part of our strategy is to execute on our pipeline. Layered on top of our strong commercial momentum is XP8121, our lead pipeline asset, and our next big catalyst that we believe will deliver Xeris' long-term growth. These are the two core elements of our strategy, a commercial engine generating growth today and continuing investment in our own organic product development. This is how we become the next great biopharmaceutical company. XP8121 is the reason we're here today. We want you to understand exactly why we believe this asset has the potential to deliver continued growth reserves well into the next decade. In a few moments, our team will take you through how we see 8-1-21 solving a serious unmet medical need impacting millions of patients. To understand why we are so confident in 8-2-1, you need to understand the real problem it may solve for patients. Hypothyroidism is a prevalent condition where the body does not produce enough thyroid hormone. approximately 20 million americans are diagnosed and treated today with daily oral levothyroxine but here's a very important data point three to five million of those patients are failing to achieve biochemical control with the current oral therapy these patients are diagnosed they are on medicine but because of challenges such as gi absorption their medicine is failing them This is not a small clinical inconvenience. Uncontrolled hypothyroidism may lead to heart disease and increased mortality. The consequences are real, and physicians and patients deserve a better solution. XP-8121 is just that, an innovative and patented once-weekly subcutaneous levothyroxine formulation that bypasses GI absorption challenges. For the millions of patients who fail to achieve biochemical control with current therapy, 8121 has the potential to impact their clinical outcomes and improve their lives. This is exactly the kind of opportunity that fulfills our company's mission and vision to raise the standard of care by uniting scientific advancement and genuine human connection. You will hear today that we will execute a comprehensive clinical development program aimed at achieving registration and differentiation. You will hear we are leveraging our formulation technology, our drug device expertise, along with our existing medical and commercial infrastructure to bring an innovative, important solution to millions of patients. You will here we are on track. We intend to initiate Cornerstone, our phase three pivotal study before year end, fully aligned with FDA on endpoints and statistical power. Based on our enrollment assumptions, we expect data in late 2028 and then FDA approval and launch in 2030. And Cornerstone is just the beginning. We're executing a comprehensive clinical program in hypothyroidism, Cornerstone, Capstone, Touchstone, along with real-world evidence, all designed from the ground up to establish 8.121 as the definitive differentiated standard of care for patients with poorly controlled hypothyroidism. And you will hear how this clinical development program has a high probability of success. You will hear our program is protected. Our IP strategy covers composition of matter and the methods of use and our formulation technology and the science underpinning that protection is solid. You will hear we are ready. This is a program we are executing now. The development plan and full-scale commercial launch are entirely self-funded. We have the science, the people, and the innovation to run a comprehensive clinical program of this scale. And when approval comes, we plan to launch quickly and efficiently using the commercial infrastructure we have already built and proven. We are not waiting to develop capabilities. We have them. And you will hear, most importantly, the commercial opportunity is substantial. We are targeting a defined reachable population of three to five million patients who are already diagnosed, already treated, and still not controlled on oral therapy. Once approved and launched, We believe that XP8121 will achieve $1 to $3 billion in peak sales potential. And we believe the clinical and patient communities are waiting for exactly what XP81201 has to offer. Before we go deeper, I want to bring in a thought leader whose perspective means more to me than any financial model or market research report. Dr. Robertson has spent nearly three decades on the front lines of endocrine medicine at Atlanta Diabetes Associates and Piedmont Hospital, treating patients with exactly the kinds of complex thyroid and metabolic conditions we're focused on, and we're grateful he could join us today. Physicians who treat hypothyroidism see inadequate thyroid control every day. The patients do everything right, and their thyroid-stimulating hormone, or TSH, is still out of range, visit after visit. Clinicians have been waiting a long time for a treatment like XP8121, and Dr. Robertson is one of them. When a clinician of his caliber tells us he is excited about an entirely new approach and is willing to join the study himself, that really means something. And now I'll hand it over to Dr. Roberttson. Thanks for having me, John. As you mentioned, I'm an endocrinologist based in Atlanta where I care for, over the last 30 years, literally a thousand or more patients with hypothyroidism. I'm also a clinical investigator and I've been involved in 35 to 45 endocrine trials over the last two to three decades, including my plan to be an investigator in the upcoming Cornerstone trial. When I first learned about XP-8121, I was excited. In my practice, I see patients every day who are still struggling despite being on standard therapy, and the truth is there haven't been very many meaningful advances in how we treat hypothyroidism in a long time. The idea that XP-8121 could potentially offer something different for my patients, that's what drew me in. In my practice, there's a group of patients who just can't achieve TSH normalization on existing oral medications, despite my best efforts. The reasons vary. Unreliable absorption, GI disorders, drug interactions, and in some cases, no clear explanation at all. What it leads to is a cycle of dose escalations, repeated testing, and persistent symptoms, and ultimately, long-term comorbidities. It's frustrating to me, and it's frustrating to the patient. When we still can't get to goal, my treatment options are limited. I can switch generics, I can try a brand-name product, or I can move to an oral liquid solution. They help some patients, but ultimately, all of these options still rely on the GI tract for absorption, and thus, have a low likelihood of changing the outcome. For the first time in decades, XP8121 offers a new approach to levothyroxine. It bypasses the GI tract, which may help difficult-to-treat patients achieve biochemical control and reach their treatment goals. Based on the phase 1 and phase 2 data, I'm reassured by its safety profile and those dose conversion results. LevothyroXine is still levothyroid, but I can see how this approach could help some of my patients today. Before XP8121 can become available, it must complete a phase 3 trial as part of the FDA approval process. That is why I'm an investigator in the Cornerstone trial, to help evaluate this potential treatment and hopefully move it one step closer to the patients who need it. And when I think about patients who could benefit, one comes to mind right away. A 38-year-old female with hypothyroidism and Crohn's disease who has frequent flares. Each episode alters absorption of her thyroid replacement, resulting in hypothyroid symptoms. When I make a dose adjustment, her gastrointestinal symptoms improve, absorption once again improves, and then there's a risk of developing hyperthyroid phase, which could again impact her Crohn's disease. The up and down dose adjustments of thyroid replacement is resource intensive and disruptive to her quality of life. And she's certainly not alone. Many of my other patients with inflammatory bowel disease and also celiac disease find themselves in similar scenarios, and an injectable therapy that bypasses absorption issues could provide an important new option for GI patients. I look forward to participating in and completing the cornerstone study. I also appreciate that Xeris is planning future studies in uncontrolled patients, giving me further guidance and confidence in XP8121. With that, I'll turn it over to Ang Nguyen, Xerox Chief Medical Officer, who can take you through the developmental program in greater detail. Thank you, Dr. Robertson, for detailing the everyday clinical concerns of hypothyroidism medical management. The clinical challenge in hypothyroidism extends beyond diagnosis and treatment initiation. Maintaining patients within their optimal therapeutic range remains difficult, and both undertreatment and overtreatment are associated with meaningful health consequences. We believe the next frontier in thyroid hormone replacement is to enable consistent thyroid control over time. XB8121 is being developed to improve the reliability of thyroid hormone placement, helping patients maintain target thyroid levels more consistently. By addressing the critical limitations of current management, we aim to unlock better long-term outcomes and maximize the benefits of effective thyroid control. The thyroid hormone replacement landscape has seen limited therapeutic innovation and clinical evidence generation over the past several decades. Yet, inconsistent thyroid control continues to expose patients to the risk associated with both under- and over-treatment by pairing an intuitive therapy such as subcutaneous levothyroxine with a comprehensive clinical data generation program, we intend to build the evidence-based clinicians need to drive confidence, accelerate adoption, unlock patient demand, and support long-term growth. Our development strategy for XP8121 is defined by three reinforcing pillars and together they form the foundation for a transformative new approach to therapy. Our first pillar is regulatory approval At the heart of our Phase 3 program is Cornerstone. Our registrational trial is designed to secure regulatory approval. Cornerstone is designed to establish that weekly subcutaneous XP8121 is therapeutically equivalent to daily oral therapy, while at the same time supporting the comparative advantages of this new approach from a label perspective. I will share more about the Cornerstone study in a moment. Our second pillar is extending safety and dosing across all ages through capstone. XP-8121 thus far demonstrated a compelling safety and tolerability profile confirmed through completed Phase I and Phase II trials in adults with repeat dosing. We extend that confidence to the pediatric populations through our capstone study with an aim to confirm dosing and safety in children. and our third pillar, clinical differentiation. Clinical differentiation is where XP8121's full promise becomes most visible. Our touchstone study is designed to demonstrate that consistent thyroid control is achievable even in patients who have had historically been difficult to treat. Importantly, these findings will address a population that remains underserved despite existing therapies. Complementing Touchstone, our real-world evidence programs document the significant unmet need in hypothyroidism, with many patients continuing to experience persistent symptoms, impaired quality of life, and reduced functional well-being despite current treatments. To accelerate this work, we are also committing significant grant resources towards investigator-initiated research with details to be unveiled at the annual meeting of the American Thyroid Association this November. Together, these efforts reinforce XP8121 as a potential new therapy for improved thyroid control that addresses the outcomes that matter the most for people living with hypothyroidism. We've designed a robust Phase III pivotal study named Cornerstone. To approve XP-8121, the FDA requires that we demonstrate that once a week subcutaneous XP-8121 is therapeutically equivalent to daily oral levothyroxine in well-controlled hypothyroid patients. Cornerstone will enroll 500 adults and adolescents with well-controlled hypothyroidism at more than 50 U.S. clinical trial sites that represent both community and academic settings. Subjects will be randomized one-to-one to receive either oral levothyroxine or subcutaneous XB8121 for 54 weeks. Both treatment changes and lab assessments will be recorded every six weeks throughout the 54-week study, building a robust data set. The primary endpoint will be the proportion of subjects with TSH within normal range at both 48 and 54 weeks. Our most important secondary endpoints are the proportion of time that TSH and free T4, which is the primary hormone made by the thyroid gland, are each within normal range during the last 30 weeks of the study. The most compelling differentiation versus daily oral lipothoraxine may come from the support of secondary PKPD endpoints as they quantify the advantages of once-weekly subcutaneous delivery. Cornerstone's design enables a clear and predictable regulatory pathway and a strong probability of success. Following alignment with FDA on a 15% non-inferiority margin, we've sized the study to 500 patients representing over 90% power. A study of this size allows us to evaluate highly meaningful secondary endpoints like time range and thyroid control consistency. It also allows us to evaluate outcomes that match to patients and providers, including symptom burden, quality of life, functional status, and treatment preference. Together, these endpoints are expected to build a differentiated evidence package that supports regulatory approval and broad clinical adoption. We're on track to initiate Cornerstone by year end. We are engaged in clinical trial site activation activities, and investigators are telling us they are excited about this new approach to therapy and that patients are ready to enroll. The Cornerstone study alone gives us a promising path towards drug approval. In addition, our continued focus is to further support clinical adoption through clear clinical differentiation and established XP8121 as the preferred therapy. An estimated three to five million patients continue to struggle with inadequate thyroid control on their daily oral levothyroxine, yet the field has generated remarkably little new evidence or innovation to address their needs. We believe that this unmet need represents a compelling opportunity for a differentiated therapeutic solution. Touchstone is our prospective single-arm clinical study designed to establish efficacy within the inadequately treated patient population who will most benefit from XP8121. We will enroll patients who have inconsistent control despite being on maximal oral therapy, convert them onto XP8 121, and measure the rate of TSH formalization over six months. The touchstone study will be completed in time for inclusion with our NDA submission. Beyond the XP81-21 clinical program, we are building a comprehensive real-world data set designed to accelerate clinical adoption, support market access, and define the patients most likely to benefit. Working closely with leading endocrinology experts. We are leveraging claims and real-world data sets to quantify the burden of inadequate thyroid control, characterize poorly controlled patient populations, and demonstrate the clinical and economic consequences of current treatment limitations. This data will give providers a strong evidence-based framework to identify appropriate patients, strengthen payer value discussions and create a compelling foundation for strong uptake of XP8121 into clinical practice. Importantly, our real-world evidence strategy is already working. We have already presented data at multiple congresses, and those presentations have catalyzed deeper, more substantive conversations with key opinion leaders about the persistent unmet need in hypothyroidism and XP-8121's potential to address it. This recurring engagement reinforces our confidence in both the clinical value proposition and the commercial opportunity. Together, Cornerstone, Capstone, Touchstone, and the Real World Evidence Program provide a clear and predictable path towards drug approval, establish meaningful clinical differentiation, and position XP-8121 as the preferred therapy for patients who need reliable, sustained thyroid control across all stages of life. The critical path for XP-8121 is clear and well-defined. Cornerstone, initiated by year end, completes in 2028, delivers top-line results in late 2028 and positions us for an NDA filing and regulatory approval in 2030. Touchstone and Capstone advance in parallel. Running alongside all of this is our real-world evidence program, continuously generating the outcomes data that will inform clinical practice, strengthen payer conversations, and support guideline discussions well before launch. The result is a steady cadence of clinical and real- world evidence milestones from now through 2030. Each study progressively strengthens the evidence base and drives the path forward. By 2030, we will not simply have an approval. We will have a strong label, a robust real-world evidence package, a well-prepared market, a patented product, and the foundation for clinical adoption and payer access. Now, I'll turn it over to Josh to walk you what it means for the commercial opportunity. Thank you, Ang. Our approach to developing 8121 has been laser focused on patients like Dr. Robertson described. Not only does her Crohn's disease impact how levothyroxine is absorbed, but the impact varies over time. For patients like her and the healthcare professionals striving to help them, an injectable therapy that bypasses gastrointestinal absorption could offer an important new treatment option. When treating hypothyroidism, the clinical guidelines are clear. Treat with levothyroxine until thyroid hormone levels measured by TSH are normal. Keeping levels in range is so important that both guidelines and product labels require regular monitoring. And yet, look at the numbers. Currently, three to five million patients are diagnosed, treated, but not well-controlled. That is roughly 20% of all hypothyroid patients. The standard is clear. One in five patients isn't eating. A major reason is the oral route. Absorption of oral levothyroxine is disrupted by underlying GI conditions, interacting medications and supplements, food and administration timing, patient-specific physiology, and the sheer complexity of treatment. Any one of them can push a patient out of range, but when more than one is present, it's a daunting challenge. The answer? Subcutaneous administration bypasses GI absorption entirely. Our team has accomplished something no one else has. We've created a product that can solve this high unmet need. Turning levothyroxine into a product that meets all requirements is a formidable undertaking. Levothyroxine is inherently unstable. It's a narrow therapeutic index drug, which means the FDA holds manufacturers to a stringent dose accuracy standard, and it must be available in a wide range of doses to meet the needs of all patients. The barrier to entry is solving all these simultaneously. Our solution is novel, but the ingredients are not. The key components of 8121 are already on the market. Levothyroxine has been approved for decades. Our proprietary Xerosol technology, already used in our approved GIVO product line, produces a stable, high-concentration formulation. We modified a pen injector that was designed for accuracy and already approved in Europe. The device is adjustable across the range of doses the patients need and similar to commonly used injectors. And our progress to date increases our confidence. We're building on a strong clinical record. Across phase one and phase two, 8121 showed an acceptable safety and tolerability profile, predictable PKPD with sustained weekly exposure, biochemical efficacy, and strong patient preference, the key elements typically required before a pivotal trial. The regulatory pathway is well-defined. Cornerstone was designed in close collaboration with KOLs and the FDAs aligned with its design and statistical powering. and 8121 is protected. Issued patents covering methods of use and composition of matter provide IP coverage through at least 2043. The combination of a known API, phase 1 and 2 safety data, and clear regulatory path is why we believe 8121 has a higher probability of success than a typical phase 3 program. XP-8121 is innovative, addresses a well-defined unmet medical need. Backed by positive phase one and two clinical data, aligned with the FDA based on a well-designed clinical program, and protected through at least 2043. Now, let me share why we believe 8121 can be a one to three billion dollar product for Xeris. To achieve that, our job is to ensure that it reaches all the patients who can benefit. A readily identifiable population defined by a single lab value already in their medical record. We don't need to find them, and we don't need to persuade anyone they exist. They are already diagnosed, already treated, already failing, and their physicians already know it. We've confirmed this in market research. 75% of physicians we surveyed reported high intent to prescribe XP8121. This level of interest is rare and points to a community ready for a solution. And we're already planning for a successful launch. Everything required to make 8121 a blockbuster is a capability that already exists in Xeris. First, HCPs need to be prepared. Clinicians understand the problem. They live it every day. Our job is to quantify it and ensure the broader clinical community sees it as clear. That means data defining the unmet need paired with KOL engagement to bring these insights to the community. It is the same approach behind every brand we've commercialized, and as you heard today, those efforts are well underway and driving KOL enthusiasm. Then we need to reach HCPs, especially the endocrinologists who see the greatest concentration of poorly controlled patients. We call on them today for our commercial products and understand their needs. And finally, patients need to be able to get 8121 through their insurance, including when prior authorizations are required. Our market access and patient services teams understand this space and navigate coverage and access across our three currently marketed brands. This is a space we know, technology we own, and a team that is proven and will get it done. That is why we believe peak sales of $1 to $3 billion are achievable. The market is big. The need is real. The clinical and regulatory path are clear. The technology is differentiated and protected. Patients need 8121, and clinicians are ready for it. And with that, I will turn it back to John. Thanks, Josh, Ang, and Dr. Robertson. Before we turn to Q&A, let me bring it all together. What you heard today is not just a vision. It's a strategy we are executing right now. The case for XP8121 comes down to four key points. First, there is a well-established unmet need. Three to five million patients are diagnosed, being treated, and are not achieving biochemical control on the current standard of care. We believe we have the answer to solve this unmet needs. Second, our development program has high probability of success. Our Phase 1 and Phase 2 trials give us strong confidence going into our Registrational Phase 3 Cornerstone trial. We will enter the study with the go-to-market formulation and device, putting us on track for launch in 2030. Third, we are investing in data generation that will differentiate XP81-21 and maximize target population adoption. With cornerstone, capstone, touchstone, and real-world evidence running in parallel, we are building the data, evidence, and outcomes now to support every prescriber conversation, every payer discussion, and every treatment guideline. Market leadership requires more than a strong label. And lastly, we have everything we need to execute. We are self-funded. We have our proprietary Xerasol technology. We have strong IP. We have a proven medical and commercial infrastructure. We're not building capabilities, we're deploying them. This is why we are confident that XP8121 will reach one to three billion in peak sales and cement Xeras as a leading biopharmaceutical company. And most importantly, why once approved, 8121 has the potential to meaningfully improve the lives of millions of patients. Before we turn to Q&A, it must be noted that we could not achieve our objectives without the support of our patients, caregivers, investigators, employees, and you. Thank you for joining us today. And with that, I'll hand over to the operator. We will now begin the question and answer session. Please limit yourself to one question and one follow-up. If you would like to ask a question, please press star 1 to raise your hand. To withdraw your question, press star 1 again. We ask that you pick up your handset when asking a question to allow for optimum sound quality. If you are muted locally, please remember to unmute your device. Those on the webcast can submit a text question by clicking the Q&A button on the bottom right corner of the screen and will be answered should time allow. Finally, all questions asked on today's call should pertain to today's material only. Please stand by while we compile the Q&A roster. Your first question comes from the line of Leyland Gershel with Oppenheimer. Leyland, your line is now open. Great. Good morning. Thank you for holding this very informative session and for taking our questions. Two questions, if I may. First, one for Dr. Robertson. Thank you for your commentary. You know, understanding that 3 to 5 million patients were uncontrolled, I wanted to sort of better understand who among those patients would be kind of the most at risk and therefore the most in need of a product like XP8121. What sort of, you know, given that there is different degrees of uncontrolled wondering your thoughts on, you know, among let's say your patients, what would that have to look like in terms of, you know pushing you over the edge to prescribe the medication? Thank you. Hey, Leland. This is Allison. So Dr. Robertson couldn't be with us for the Q&A session here, but I'm sure we can answer that question unless the three others present. Thank you, and you want to try that one? Good morning. Thank you Leland, so overall, at any one time, but 20% of people are out of range, even if they're considered consistent within consistent control. And this issue becomes one of undertreatment and overtreatment. And so, we are doing activities in order to identify and teach the clinical community about these concerns of both the clinical and economic consequences of undertreating and overtreating. Thank you. And then, just a question on the package for the FDA. Just given that oral levothyroxine was approved some time ago, wondering if there are any other studies in addition to the ones you outlined. in your announcements that you may need to run or you'd like to run even just to modernize the file. Thank you. Yeah. Hey, Leland, it's John. The comprehensive program we put together will get us what we need from a regulatory approval as well as allow us to maximize the commercial opportunity and really get after the true unmet need in this space. So we think we've got everything laid out here today. and no need to do any additional work. Excellent. Thanks very much. Your next question comes from the line of Roana Ruiz with Lear Inc. Partners. Your line is now open. Hi, everyone. Morning. So two questions for me. For the first one, could you talk a bit more about your expected penetration rates for 81-21 in the first couple years of launch, if you've started to think about that, and what strategies could drive you to the higher end of your estimated peak sales range? Thanks, Rana. I'm going to let Josh take that one. Yeah, thanks for the question, Rona. So just to frame this, our forecast assumes that we get no more than 10% of the 3 to 5 million patients on therapy at peak. And I think what you've highlighted is correct in that the range primarily reflects a degree of penetration. So that's why we are investing aggressively and early in the real-world data package that brings the highest unmet need patients, especially those with underlying GI disorders like Dr. Robertson talked about, really quantifies the burden that those patients face and brings them to life to make sure that we're powering adoption in the early phases of launch. And then as we think about the total opportunity, as Aang said, not only are the 3 to 5 million patients not meeting their goals, but guidelines don't distinguish the reason. They say bring them into range. So we believe that the opportunity is large, but we've premised our goals on what we believe is an achievable market share at peak. Got it. That helps. And quick follow-up, can you talk a bit more about the patient experience currently with standard of care. Do they notice when they're uncontrolled and actually are actively seeking better options? And do you expect any education that needs to happen either with the physicians or the patients as 8121 launches? Yeah, thanks for the question. I think it starts with one of the things we mentioned, which is that because this is a neurotherapeutic index drug, patients are required to be tested at least annually and often more often, and sometimes physicians test more frequently. So the evidence of being out of range is in the chart today and they're reminded of it every year they get a negative result. So no education is needed to point that out. On top of it, some patients are asymptomatic but still need to be brought into range and some suffer symptom burden and are especially motivated to see new options. So what we've seen in all of our research, as well as our phase two studies, is a highly motivated physician and patient population. It really struck us that in our phase two study, when we took patients who were well-controlled and converted them to 81-21, 71% or 72% said that they would prefer to stay on 81- 21 moving forward. That was a really positive signal. And as we study the uncontrolled population more, you know, we expect that to increase. Very helpful. Thanks. The next question comes from the line of Chase Knickerbocker with Craig Hallam. Your line is now open. Good morning. Thanks for taking the questions. Maybe just first on Touchstone, can you just describe how inconsistently controlled is defined? Just kind of, you know, the enrollment criteria for where these patients are, how far they are out of range, you know, if they're on kind of maximum oral dosage, et cetera. Yeah, we'll let Ang answer that question. Thanks, Chase. So Touchstone focuses on the patients who need therapy correction the most and where they have inconsistent control, which is defined by having at least two TSH ranges out of range. Got it. And then just as we kind of shift to how you might be treated from a payer perspective, I mean, is this kind of how you think a potential step edit might look? Is it, you know, is two kind of reads out of range going to be sufficient, do you think, for a future step edit, or how should we be thinking about, you know, the potential right patient population for you, if approved, as it relates to how payers will treat you? Yeah, Josh, he's going to jump in. Thanks, Jay. So, great question, right? And I think, you know, first, you implied something that we believe is we're planning for step edits to be the norm. And as Aang and John said, we're in a position in which the failure is documented in the chart. So we don't need to generate any data that exists today. We just have to activate it with the patient. And I think you're right to say that the initial adoption is especially going to be concentrated in patients with the highest unmet need when they're not only out of range, but being out of range is tied to a known underlying reason like a GI malabsorption disorder. The other thing I'd say, though, is that this is, 8121 is essentially the definition of a medical necessity. We'll be treating patients where the only available option has already been demonstrated to fail. Failure is proven with the lab. The lab doesn't meet guidelines. And it's a neurotherapeutic index drug, which payers recognize as signaling both a higher unmet need and the need to try new options more aggressively. do you think there'll be um you know a document a need for documented um kind of call it max titration or you know where do you Think that'll fall and just kind of along those same lines um do you thing about any sort of consideration um with potential kind of workup required I mean just how how kind of in-depth do you perceive it to be um You know you talked about some of comorbidities h pylori etc do you think a workup there will be required yeah i don't think so and i think that we're we're really anchored on the fact that being out of range by itself represents health risk having an underlying condition speaks to a mechanistic and known reason for why that's happening and emphasizes the unmet need but it doesn't really matter i think you heard dr robertson say that patients can be out of range for a variety of reasons, sometimes not even identifiable. The reason doesn't change the health risk, right? Patients who are out of range face real long-term morbidities, cardiovascular, osteoporosis, even mortality on top of the burden to the system. So our strategy is premised on being out of reach is the problem. Everything else is additive data to enable clearer diagnosis and treatment. And we think that that'll be sufficient to navigate payers. Very helpful, Josh. Thanks. Maybe just last for me, just on the cost for the program, Steve. You know, previous expectations were 1,000 patients, you know, now 500, but we've got some ancillary studies that we're also going to do as well. Just maybe your thoughts on overall incremental costs for the programme relative to current R&D run rate. Yeah. Thanks, Chase, for the question. So the total cost for the clinical program that the team covered today is approximately $70 million over the next several years. And you mentioned the step-up in R&D spend this year. So some of that's factored into the step up this year, and then the balance is really split evenly between $27 and $28. THANK YOU. YOUR NEXT QUESTION COMES FROM THE LINE OF DENNIS DING WITH JEFFRIES. YOUR LINE IS NOW OPEN. GOOD MORNING, GUYS. THANKS FOR THIS UPDATE. ONE QUESTION AND THEN ONE FOLLOW-UP. SO LOOK, I APPRECIATE NONINFURIORITY MAYBE THE REGULATORY BAR, BUT DO YOU THINK THAT WILL be enough humans payers to reimburse for this product appropriately you know and on you know stats specifically how much power do you have to hit the key secondaries and in what hierarchy will they be tested because it seems really important for the secondaries to hit because if you show non-inferiority but then miss on the secondaires payers might not reimburse for that profile yeah look we're going to have josh answer the payer question first and then i can come back on the secondaries? Yeah, great question, Dennis. So let me start with the prescription intent that we saw in our research. Prescription intent, 75 physicians, after we adjusted for the typical over-response that physicians say, said that they were likely to prescribe 8121. And that was based on only having non-inferiority data without any proven superiority out of cornerstone and without touchstone. So we see a clear signal from physicians that because they understand how levothyroxine works, and because the idea of the subcutaneous route is so intuitive, that they're likely to prescribe with only non- inferiority. And when we combine that with what we discussed earlier that the patients have a demonstrated failure to meet their goals. The physician enthusiasm combined with the demonstrated lack of reaching treatment goals with orals is sufficient to navigate payer access and prior authorizations. So all of the things that we're building on top of it, whether it's the secondary endpoints in Cornerstone, Touchstone, or our real-world evidence are really designed not to secure payer access, but to increase confidence and enthusiasm for faster adoption and launch. And Dennis, thanks again. And Josh, I want to reiterate your comments is that at the end of the day, the 8121 program, this is a therapy which is highly intuitive to the clinical community, right? This is a known molecule through an entirely different route of administration given at a different cadence, once a week versus daily, which, because, as we've seen in the Phase I-II programs, has a very consistent, reliable, predictable PAPD. And this will be re-evaluated and demonstrated within the context of the phased and registrational program. Now, mind you, just at the end of the day, this is highly intuitive, right? I think the clinical community understands it. This is a drug approval pathway, which allows us to show durability, consistency, reliability of the PGPD, which has not been observed in the very little data generation across the oral therapy landscape, right? And so, you know, our primary endpoint, the six-week difference, which is consistent with treatment guidelines, is designed in order to demonstrate that there could be differences there between the oral and us. Now, the overall program, 500 study participants, has well over 90% power in order to hit on the primary endpoint, and that same statistical power will be applied to the key secondary endpoints, i.e., the proportional time and range. And as you, I think, have implied, Dennis, yes, we also agree that this proportional time and range is a critical component. But in itself, the program hitting on the primary endpoint is differentiated in itself. And mind you, again, because even on the label, you're not going to have all the oral drug interactions and whatnot. And I think again, very intuitive for the clinical community. Got it. That's very helpful. But what do you tell doctors who say that, you know, they treat the symptoms and not the biomarker? And in your market research, do you think that doctors would prescribe 8121 essentially to subclinical hypothyroid patients based on your research? Thanks so much. Yeah, thanks for that, Dennis. Let me start with, you know, we've spoken to over 500 physicians just in the last year, and I've personally spoken to over 100. And the conversations we have are amazingly consistent. First time somebody's exposed to 8121, they say, oh, what's this? Oh, subcutaneous levothyroxine? That makes sense. And then they name a patient. And each one names a different patient, but they have the common thread of not meeting their biochemical treatment goals, usually with an identified reason. And then they think of other reasons why a patient may not reach their treatment goals biochemically that justifies use of 8120. So we've been struck by the consistency. And that's why our strategy is really clear. there are, this is a large, diverse condition, and we're not focused on the patients where the unmet need is debatable or marginal. We're focused on Thanks. Two quick ones for me. First, on your sales organization, I know you were already calling on endocrinologists, but was wondering about the extent to which you will need to expand headcount in order to more fully capture the target prescriber audience. And also, how are you thinking about potentially calling on general practitioners, given that there are GPs that do write for levothyroxine? So that's number one. And then number two is on pricing. And I know this is perhaps early to talk about, but can you maybe talk generally to where you think a good range could be on pricing? Would a good analog be, say, a branded levothyroxine or a levothyrosine product like amniosunithroid? Is that a good way to think about pricing? Any kind of guidance you can provide on that would be helpful. Thank you. Yeah, thanks, David. So let me start with the Salesforce question. So as we said, 8121 perfectly leverages the capabilities we've built. and the endocrinologists that our GVOC team calls on today are the exact same physicians who are going to write 8121. In fact, as Dr. Robertson talked about treating a thousand patients over his career, there are individual endocrineologists who have over a thousand hypothyroid patients treated at any one time and many, many that have hundreds. So they have the highest concentration of the high-end-need patients. And so we're very confident that our existing capability to reach them is leverageable. Of course, we're going to expand our capacity, including into primary care. And all of that is captured with what Steve said and John said about this being part of our plan and cell phone. So then turning to pricing, it's a great question. And let me start out to say that we are absolutely not thinking of any oral therapy as the reference for price, because oral, these are priced for therapies that are failing for these patients where we intend to provide a solution. So we're going to be in a different price category. Our pricing assumptions, we believe, are reasonable. And as you said, obviously, we're not going to guide on price specifically before initiating phase three. that's something we'll do closer to launch. But I will say that when you think about the revenue ranges we've given and anchor on that our share requires no more than one out of 10 of the 3 to 5 million poorly controlled patients, I think that can guide to the range of pricing that we think is achievable, is supported by analogs we see in the market, and analogs that are similarly treating a subset of patients where a cheap generic therapy is currently failing and give you a reasonable range of how we're thinking about this. Okay, thank you. The next question comes from the line of Brandon Folks with H.C. Wainwright. Your line is now open. hi thanks for taking my questions and thank you very much for this today um just want to follow on so in terms of the 10 penetration of the three to five million out of control patients to get to peak sales any color in the subset of that three to four million patients you're assuming you have the biggest uptake um you know are those mainly patients who have maxed out on levo or drug drug interaction concerns. And then any color in terms of what your peak sales that you've put out represent in termsof penetration of that subset of patients? And then along the same line, any color on the three to five million patients who are out of control that don't respond to Levo at all or are maxed out on Levo therapy? Thank you. Yeah, thanks for the question. There a few pieces of this. So let me kind of take them in turn. The 10%, you know, our peak sales is premised on no more than 10% of the three to five. When we think about the three-to-five and kind of the subdivisions within it, I think that's something we'll share a lot more as our real world evidence program advances and we bring on more quantification and color to that. But go back to what we hear from physicians is we don't hear them identifying a single etiology for why a patient's out of range. We hear a variety. And all of our research, as well as informal discussions, are consistent about that. So we think the 10% is going to come from a variety of etiologies of patients who are not meeting the treatment goals. And that's what we base the launch on. That is all the time we have for the Q&A. This concludes today's call. Thank you for attending. You may now disconnect.