Xeris Biopharma Holdings, Inc. (XERS) Earnings Call Transcript & Summary

Hello, everyone. Thank you for joining us, and welcome to Xeris Biopharma XP-8121 Program Overview. [Operator Instructions] I will now hand the conference over to Allison Wey, Senior Vice President of Investor Relations. Allison, please go ahead.

Good morning, everyone, and welcome. I'm Allison Wey, Senior Vice President of Investor Relations. On behalf of the entire Xeris team, thank you for joining us today for XP-8121's program overview. We will start the presentation today with John Shannon, Chairman and Chief Executive Officer of Xeris, 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. Anh Nguyen, our Chief Medical Officer, will cover our comprehensive integrated evidence generation program for 8121 in detail, including Cornerstone, our Phase III 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. With 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. Recorlev, Gvoke and Keveyis are performing with Recorlev 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 XP-8121, our lead pipeline asset and our next big catalyst that we believe will deliver Xeris' long-term growth. These are the 2 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. XP-8121 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 for Xeris well into the next decade. In a few moments, our team will take you through how we see 8121 solving a serious unmet medical need impacting millions of patients. To understand why we are so confident in 8121, 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 is a very important data point, 3 million to 5 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 hear we are on track. We intend to initiate Cornerstone, our Phase III 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 an 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 8121 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 3 million to 5 million patients who are already diagnosed, already treated and still not controlled on oral therapy. Once approved and launched, we believe that XP-8121 will achieve $1 billion to $3 billion in peak sales potential. And we believe the clinical and patient communities are waiting for exactly what XP-8121 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 3 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 XP-8121, 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. Robertson.

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 1,000 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 2 to 3 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. While 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 absorption and thus have a low likelihood of changing the outcome. For the first time in decades, XP-8121 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 I and Phase II data, I'm reassured by a safety profile and its dose conversion results. Levothyroxine is still levothyroxine, but I can see how this approach could help some of my patients today. Before XP-8121 can become available, it must complete a Phase III 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 XP-8121. With that, I'll turn it over to Anh Nguyen, Xeris' 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. XP-8121 is being developed to improve the reliability of thyroid hormone replacement, 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 overtreatment. By pairing an intuitive therapy such as subcutaneous levothyroxine with a comprehensive clinical data generation program, we intend to build the evidence base clinicians need to drive confidence, accelerate adoption, unlock patient demand and support long-term growth. Our development strategy for XP-8121 is defined by 3 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 III program is Cornerstone. Our registrational trial is designed to secure regulatory approval. Cornerstone is designed to establish that weekly subcutaneous XP-8121 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 in completed Phase I and Phase II trials in adults with repeat dosing. We extend that confidence to the pediatric population through our Capstone study with an aim to confirm dosing and safety in children. And our third pillar, clinical differentiation. Clinical differentiation is where XP-8121'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 XP-8121 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 1:1 to receive either oral levothyroxine or subcutaneous XP-8121 for 54 weeks. Both treatment changes and lab assessments will be recorded every 6 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 a 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 levothyroxine may come from the supportive secondary PK/PD 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 in range and thyroid control consistency. It also allows us to evaluate outcomes that matter 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 the patients 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 establish XP-8121 as the preferred therapy. An estimated 3 million to 5 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 XP-8121. We will enroll patients who have inconsistent control despite being on maximal oral therapy, convert them on to XP-8121 and measure the rate of TSH normalization over 6 months. The Touchstone study will be completed in time for inclusion with our NDA submission. Beyond the XP-8121 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 provide us a strong evidence-based framework to identify appropriate patients, strengthen payer value discussions and create a compelling foundation for strong uptake of XP-8121 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 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 initiates 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 through what it means for the commercial opportunity.

Thank you, Anh. 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 health care 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, 3 million to 5 million patients are diagnosed, treated but not well controlled. That is roughly 20% of all hypothyroid patients. The standard is clear, 1 in 5 patients isn't meeting. 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 XeriSol technology already used in our approved Gvoke 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 I and Phase II, 8121 showed an acceptable safety and tolerability profile, predictable PK/PD 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 FDA is aligned with its design and statistical power 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 I and II safety data and clear regulatory path is why we believe 8121 has a higher probability of success than a typical Phase III program. XP-8121 is innovative, addresses a well-defined unmet medical need, backed by positive Phase I and II clinical data, aligned with the FDA based on a well-designed clinical program and protected to at least 2043. Now let me share why we believe 8121 can be a $1 billion to $3 billion 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 XP-8121. 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 3 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 billion 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, Anh 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 XP-8121 comes down to 4 key points. First, there is a well-established unmet need. 3 million to 5 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 need. Second, our development program has high probability of success. Our Phase I and Phase II trials give us strong confidence going into our registrational Phase III 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 XP-8121 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 XeriSol 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 XP-8121 will reach $1 billion to $3 billion in peak sales and cement Xeris 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.

[Operator Instructions] Your first question comes from the line of Leland Gershell with Oppenheimer.

Two questions, if I may. First one for Dr. Robertson. Thank you for your commentary. I'm just saying the 3 million to 5 million patients who are 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 XP-8121. What sort of -- given that there's different degrees of uncontrol, wondering your thoughts on among, let's say, your patients, what would that have to look like in terms of pushing you over the edge to prescribe the medication?

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 amongst the 3 others. Anh, do you want to try that one?

Thank you, Leland. So overall, at any one time, 20% of people are out of range, even if they're considered within consistent control. And this issue becomes one of undertreatment and overtreatment. So we are doing activities in order to identify and clinical community about these concerns of both the clinical and economic consequences of undertreatment and overtreatment.

Great. 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 announcement that you may need to run or you'd like to run even just to modernize the trial?

Yes. Leland, it's John. The package -- 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.

Your next question comes from the line of Roanna Ruiz with Leerink Partners.

So 2 questions for me. For the first one, can you talk a bit more about your expected penetration rates for 8121 in the first couple of years of launch, if you started to think about that? And what strategies could drive you to the higher end of your estimated peak sales range?

Thanks, Roanna. I'm going to let Josh take that one.

Yes. Thanks for the question, Roanna. So just to frame this, our forecast assumes that we get no more than 10% of the 3 million 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 Anh said, not only are the 3 million 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 premised our goals on what we believe is an achievable market share.

Got it. That helps. And a quick follow-up. Could 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?

Yes. Thanks for the question. I think it starts with one of the things we mentioned, which is that because this is a narrow therapeutic index drug, patients are required to be tested at least annually and often more often, 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 none of the -- no education is needed to point that out. On top of it, some patients are asymptomatic, they still need to be brought into range and some suffer symptom burden and are especially motivated to seek new options. So what we've seen in all of our research as well as our Phase II studies is a highly motivated physician and patient population. It really struck us that in our Phase II study, when we took patients who were well controlled and converted them to 8121, 72% said that they would prefer to stay on 8121 moving forward. That was a really positive signal. And as we study the uncontrolled population more, we expect that to increase.

The next question comes from the line of Chase Knickerbocker with Craig-Hallum.

Maybe just first on Touchstone. Can you just describe how inconsistently controlled is defined, just kind of the enrollment criteria for where these patients are, how far they are out of range, if they're on kind of maximum oral dosage, et cetera?

Yes, we'll let Anh answer that question.