Acelyrin, Inc. (SLRN) Earnings Call Transcript & Summary

Good afternoon, and welcome to Acelyrin's Lonigutamab Investor Event. This event is being recorded today, January 6, 2025. I would now like to turn the call over to Tyler Marciniak, Vice President of Investor Relations and Corporate Operations. Please go ahead, Tyler.

Thank you, Tara. Hello, everyone, and thank you for joining us for today's event to review new data from our ongoing Phase Ib/II trial of lonigutamab in thyroid eye disease and the planned design for our registrational program. We issued a news release earlier outlining the information to be reviewed today. And before we begin the presentation, I'd like to remind the audience that our remarks may contain forward-looking statements, including, but not limited to, those related to the progress of our planned Phase III clinical trials for lonigutamab, the potential safety and efficacy of lonigutamab, the potential benefits of loniglutamab, including versus other treatment options, the potential commercial opportunity for lonigutamab and our cash runway. We urge you to review the Risk Factors section of our Form 10-Q for the quarter ended September 30, 2024, which is available on our website at acceleron.com, along with today's news release, which identifies certain factors that could cause our actual results, performance and events to differ materially. Finally, our statements are based on information available to us today, January 6, 2025, and we undertake no obligation to update them as circumstances may change. We have an exciting agenda today, so let's get started. With me are Mina, Shep and Ken, who will review for you the multiple reasons we believe lonigutamab can win in thyroid eye disease. We are also fortunate to be joined by 2 esteemed TED clinicians and members of our Scientific and Patient Advisory Board, Dr. Andrea Kosler of the Stanford University School of Medicine and Dr. Prem Subramanian of the University of Colorado School of Medicine. We are thankful to have both of you with us today. Finally, we'll close with analyst Q&A and try to take some questions from the audience time permitting. If you'd like to ask a question, please submit it in the box within the web platform, and we'll take as many as we can. We'll also follow up individually afterward on any submitted questions that we don't have time to take. And now I will turn the call over to Mina.

Thanks, Tyler, and thanks everyone for joining us today. Acelyrin is coming into 2025, fully focused on executing the Phase III program for lonigutamab in TED. Having successfully completed our end of Phase II meeting with the FDA and dose-ranging in TED patients, we plan to start both Phase III trials this year, so they run concurrently. We're on track to dose the first patient this quarter, and we expect our time lines to be competitive with other programs. Acelyrin continues to be well capitalized with $560 million at September 30, 2024, with our cash runway expected to extend into mid-2027. This means the Lonigutamab Phase III program is fully funded with current cash, eliminating any financing overhang on the program. In addition, we expect our cash runway to enable selective pipeline expansion. Now I'd like to provide a brief overview of what we think makes Lonigutamab so exciting. First, Lonigutamab has a unique MOA with noncompetitive peripheral binding. We've seen evidence of rapid internalization of IGF-1R and limited increase in circulating IGF-1. We also believe that Lonigutamab's high potency is important in driving efficacy that's in line with other anti-IGF-1Rs, but at much lower plasma exposures with lower C-max and volumes necessary to drive efficacy. We've dosed more than 75 subjects. This work has enabled us to select a dose that we believe can deliver efficacy with an optimized safety profile and derisks execution of the Phase III program. We believe that the adverse event profile seen with other anti-IGF-1R agents to date is not an unavoidable consequence of achieving efficacy. We believe that Lonigutamab can deliver a better therapy for patients that does not trade off safety for efficacy. Our Phase III program is informed by extensive input from KOLs and patients and also aligned with the FDA. TED is a chronic autoimmune disease that may require longer, more flexible treatment than the current standard of care. We have alignment with the FDA to dose out to 52 weeks, enabling long-term flexibility to ensure patients can receive the duration of care they need. Fundamentally, we believe that addressing the unmet needs of patients is what drives an ideal TPP. We hope to deliver IV-like efficacy with reduced safety barriers to adoption. That includes hearing liabilities, but also common AEs like hyperglycemia, and importantly, in a disease that impacts mainly women menstrual disorders. We also expect to launch Lonigutamab in a convenient 1-mill auto-injector that's self-administered by the patient. The prevailing assumption may be that IV like efficacy can only be achieved at the expense of safety. We think we can do better for patients in a couple of ways. First, because of lonigutamab's potency, we can achieve efficacy at exposure levels that are orders of magnitude below that of other anti-IGF-1Rs, so we may be able to limit exposure in the ear where IGF-1 has an important role in protecting the hair cells responsible for hearing. These hair cells are finite in number and do not regenerate. So protecting these hair cells is important in ensuring no permanent hearing loss or damage occurs during treatment. Second, we've now seen that treatment with lonigutamab maintains more homeostatic levels of IGF-1 compared to other agents. The data we will present today with lonigutamab, a noncompetitive antagonist clearly shows that robust efficacy can be obtained without the large several fold increase in IGF-1 levels seen with other anti-IGF-1Rs. This is important because elevation of IGF-1 may impact multiple systems in the body in a negative way. For example, by impacting growth hormone regulation and insulin receptor signaling. The safety data we will present today does not show mental disorders or hyperglycemia in the patients who have received lonigutamab to date. Certainly, we need to further characterize the safety profile of lonigutamab in our Phase III program, but it's an exciting prospect for patients who may one day have a therapeutic option that can deliver IV-like efficacy, in a broader patient population due to lonigutamab's, unique MOA and potency. So let's step back and consider how lonigutamab could change the TED treatment paradigm? Today, not dissimilar from outpatient chemotherapy for cancer, TED patients receive IV infusions every 3 weeks for a fixed course of 24 weeks in an outpatient health care facility. This is a legacy of the oncology setting from which the current standard of care originated and does not reflect the actual needs of TED patients. Our vision is to deliver the next generation of anti-IGF-1R therapies, which allow for IV like efficacy with reduced safety liabilities and barriers to adoption in a convenient, self-administered 1 mil auto-injector, with a flexible and personalized duration of therapy. In designing our development program, we're grateful to have the input of numerous KOLs, including those on our scientific and patient advisory board. There is nothing more important than understanding the real world experiences and needs of patients and doctors to drive the next generation of therapy. Along those lines, we'd like you to hear from Christine Gustafsson, the patient advocate on our Advisory Board. [Presentation]

I'd now like to introduce Dr. Andrea Kossler, who's been a tireless advocate for TED patients and whom we're honored to have on our SAB. Dr. Kossler.

Thank you so much, Mina. So I will talk about the unmet need of thyroid eye disease from a provider perspective, and I have my 2 patients here that are going to help me to tell the story of thyroid eye disease. As you can see from these patient photographs, this disease is, in fact, a debilitating and vision-threatening condition, and every patient is impacted in a different way. This disease can present with many different types of symptoms and phenotypes, but what these patients all have in common is that it does have a significant impact on their quality of life. Patients with thyroid eye disease typically start with aggressive and inflammatory condition that worsens over time. And eventually, they can burn out into this chronic phase of the disease where the inflammatory symptoms may subside, but they're left with fibrosis and oftentimes irreversible damage to the periocular and ocular tissues. Now common symptoms that we see with patients with thyroid eye disease include things like bulging of their eyes, as you can see very clearly in my 2 patients here. Double vision, which you can see in the bottom right patient very clearly. And that's probably one of the more debilitating signs that our patients complain of. It can really impact their function. And many patients live with pain and redness and swelling and that's not common. Most of us don't feel our eyes. And when we think about and feel our eyes every single day, it really can drive patients mad. Now when the disease progresses to a more severe stage, patients can have compression or stretching of their optic nerve, which can impact their vision or they can have breakdown of their eye and of their cornea, because their eye lids can't close to protect their eye, and we call that severe exposure keratopathy. Now both the optic neuropathy, exposure keratopathy can lead to permanent vision loss in about 5% to 8% of patients. So this disease is chronic, it's debilitating and vision threatening. Unfortunately, this disease impacts more than just the eye as our patient advocate previously said, this is a big quality of life killer for our patients. Studies have very clearly demonstrated that patients living with thyroid eye disease experience not only changes to their physical health, but also to their mental health, their wellness, their psychologic health. And this disease poses many social challenges for these patients. And if not properly treated, this can impact them for the rest of their lives. Studies have demonstrated that patients with thyroid eye disease have depression and anxiety more frequently than matched controls. In fact, when you compare patients with thyroid eye disease, they have anxiety and depression on par with patients suffering from chronic angina or chest pain. Patients suffering from pulmonary disease where they cannot breath. So again, this very much impacts their quality of life. Oftentimes, this is because of their vision changes, but also because of their appearance changes, the way they feel about themselves, the way that they experience the world and the way that they're presenting themselves to the world. In addition, these patients can have difficulty sleeping. Oftentimes, our patients will have eye lid retraction that happens in 90% of patients. But at nighttime, they can develop nocturnal [indiscernible]. It means that they can't close their eyes at nighttime. And as a provider, I ask my patients to wake up in the middle of the night and put drops or ointment in their eyes or sleep with a moisture chamber or saran wrap around their eyes just to keep the moisture in. This can really impact their sleep further worsening their physical well-being and their psychological well-being. Now I also know that while the eye disease is the most common extrathyroidal manifestation of graves disease, there are many other systemic implications. As our patient advocate previously said, this is not just an eye disease it's a facial disease. Studies have demonstrated that the buccal [indiscernible] and the tempo and the eyebrow in many other parts of the face are impacted by this disease. Also our skin to be impacted. Patients can experience dermopathy, which can be painful and also it can be disfiguring. Patients develop changes to their fingers and their joints, which we call [indiscernible]. They can also have changes to their finger nails. And we know that this disease has many important hormonal implications. Now the current paradigm of treating thyroid eye disease includes a fixed term therapy. So we take this chronic long-standing disease. And we somehow think that 24 weeks of treatment is going to be enough, and it really just isn't for many of our patients. What we need is a customized treatment plan where providers are able to treat patients for the durations needed for these patients. We need to be able to customize treatments for their individual phenotype of disease, the severity of the disease. And we also may need to think about the systemic implications and the other health conditions that the patients may be experiencing. Now in the past, the way the thyroid eye disease was treated was very black and white. It was thought that patients either were in an active state of disease or in a stable state of disease. And in the active stage of the disease, we used to only offer patients treatments for the inflammation like steroids or radiation or other nonsteroidal anti-inflammatory medications. And it was thought that we could only treat them early in the active phase of the disease. And then once they've had disease for long periods of time or were stable, we would only offer them surgical rehabilitation. Teprotumumab has really changed the paradigm for the way that we treat thyroid eye disease. And we've really started to understand the thyroid eye disease is not black and white. It is not active or stable. Instead, there seems to be a continuum of disease and a new equilibrium that is reached over time. And what we know from teprotumumab is that some of the changes to the orbit can be reversed medically regardless of the duration of the disease. Now teprotumumab, again, has been game changing, and it is quite effective drug, but adverse events are concerning. As a provider, I spend a lot of my time making sure that I'm treating these patients safely and effectively. It requires very strict screening and monitoring guidelines to make sure that we can treat our patients safely. The other issue that we have with current treatment options is that the long-term durability is adequate. Studies have demonstrated that up to 50% of patients are experiencing significant regression. Oftentimes, these patients need retreatment and it leaves us as providers unsure of the next step. The other issue with the current treatment paradigms is the burden of IV administration. Oftentimes, our patients don't want to have to come into the health care system every 3 weeks. It can be sometimes hard to find infusion centers to get insurance approval, and it does plug up our health care system. So having a more convenient treatment option would be a nice convenient thing for our patients. What I can tell you, as a provider that while new biologics have changed the way that I treat thyroid eye disease, I find myself using off-label biologics more commonly now than I ever did before because of the issues of durability, regression and just poor reliability. Let's talk a moment about the adverse events of current IGF-1 inhibition. At our institution, we did a study on hearing-related changes with teprotumumab. And what we found was that when we asked our patients about side effects, we found that 80% of them had subjective changes to their hearing. Now most of this was things like ear ringing or ear plugging or middle-ear symptoms. However, about 40% of patients experienced actual hearing loss or muffled hearing. So what you can see in the left graph there is that the yellow is the muffled hearing or the hearing loss, whereas the blue, orange and green are showing you tinnitus or middle ear symptoms. Now we can see that the tinnitus and the middle ear symptoms resolves in the majority of patients. Over 90% of patients had resolution at 40-week follow up after treatment. But the yellow line, you see about 40% of patients are experiencing hearing loss or muffled hearing and only about half of them had resolution of those hearing loss symptoms at about 40 weeks after finishing drug. We also took a look at hyperglycemia, and we found that about 50% of patients treated with teprotumumab experienced significant hypoglycemia. When we broke that down into patients that had prediabetes or diabetes -- you can see in this figure that patients with prediabetes shown in blue had a significant increase in their hemoglobin A1c over time and patients with diabetes had an even higher significantly worsening of their hemoglobin A1c with treatment. And their changes were really quite severe and unpredictable. Sometimes patients can even have such high sugars that we've had patients that have experienced DKA and other very serious endocronologic conditions. Now hearing loss, hyperglycemia, have received a lot of press about side effects for teprotumumab. But there are many other off-target effects of anti-IGF-1 receptor drugs. So I just really want to make it clear that there are other things that can happen when we're inhibiting the IGF-1 receptor, such as neurologic or psychiatric changes, of course, muscular skeletal changes other endocrinologic changes, reproductive and menstrocycle irregularities, changes to our skin and nails, our kidneys and even GI system. So IGF-1 is ubiquitous throughout the body, and it's very important that we're careful at how we're inhibiting this important molecule. So there remains a significant unmet need in our thyroid eye disease patients. And as a provider, what I would really love to see is a treatment option that would embrace the long-term chronic nature of this disease, I want to be able to provide individualized treatment plan for my patients. I want to be able to decide how long I need to treat a patient, I want flexibility in treatment. And I also want to know that I'm treating my patient safely. For me, that is one of the most important things that I can do for my patients. I really want a safe and reliable drug, which would make me feel comfortable treating my patients earlier and also treating my patients for longer periods of time, which is typically needed in these patients. And of course, it would be nice to have a convenient treatment option for these patients, in the safety of their own home. So I'm excited to see the results of this drug and to be able to offer my patient an effective and safe option.

Thanks, Dr. Kossler. I'd now like to hand it over to Shep to review lonigutamab's unique MOA.

Thank you, Mina. While there are many putative therapeutic targets being explored in thyroid eye disease ranging from target upstream with CD20, BAF and FcRn inhibitors to the use of various anti-inflammatory compounds on the downstream side. It is clear the IGF-1R a pathway is central to thyroid eye disease and drives both fibrotic and inflationary components of thyroid eye disease. Blocking of stimulation of IGF-1R TSHR signaling complex via the anti-IGF-1R monoclonal antibodies has proven to be remarkably effective at treating thyroid eye disease across various stages of disease and regardless of disease duration of the patients thyroid status. Lonigutamab is a next-generation anti-IGF-1R with differentiated mechanism of action. Lonigutamab is unique in that it binds IGF-1R peripherally with high affinity. Unlike other anti-IGF-1R agents, it is a noncompetitive antagonist that rapidly eliminates IGF-1R and bound IGF-1 from the surface of cells through rapid internalization and degradation in lysosomes. Lonigutamab effectively eliminates overly expressed IGF-1R from the surface of orbital fibroblast and shuts down IGF-1R/TSHR crosstalk signaling and associated thyroid eye disease pathophysiology. It does this with lower exposures in comparison to other anti-IGF-1R agents. Other IGF-1R agents are competitive antagonist that's preventing ligand induced activation of the receptor, a consequence of preventing the ligand from binding to its receptor, is elevated serum IGF-1 levels. In contrast, because lonigutamab is a noncompetitive antagonist IGF-1 serum is maintained closer to homeostatic levels. This slide shows the change in the levels of regulating IGF-1 at weeks 2 to 3 and at week 12 for lonigutamab and other anti-IGF-1R agents. With this unique mechanism of action and noncompetitive binding, lonigutamab maintains homeostatic IGF-1 levels, even at doses up to 250 milligrams. Lonigutamab maintains IGF-1 levels, as you can see, near base line with even prolonged continued treatment, whereas increases in IGF-1 with teprotumumab are evident at weeks 2 and 3 and increased even more over time suggesting lonigutamab has a more stable and controlled effect. Of not published levels of IGF-1 following teprotumumab treatment continued to increase through week 24. Although more research is needed, there is already a substantial body of evidence in published literature implicating elevated IGF-1 levels in abnormalities of glucose metabolism and reproductive hormone function. I'll hand it back to Mina to provide an overview of our strategy for dose selection.

Thanks, Shep. Our Phase III program benefits from data from more than 75 healthy volunteers in TED patients. Today, we will review the clinical data from the Phase Ib II dose-ranging trial in TED patients, which demonstrates that maintaining C-max throughout the treatment period optimizes efficacy without producing safety liabilities. In addition, we've seen a differentiated safety profile so far with no audiology changes, no hypoglycemia and no menstrual disorders. Our Phase III program is based on a positive end of Phase II meeting with the FDA, during which the agency aligned with key design elements of the program, including patient population and sample size, dose selection and duration of treatment. We know efficacy and safety both matter. So we're focused on minimizing C-max while maintaining exposure within the therapeutic range throughout the treatment period. We also know patients care about convenience. We expect to launch within the auto-injector that patients can self-administer. Our Phase Ib/II trial was designed based on our Phase Ia clinical data from healthy volunteers who received various doses of subcutaneous lonigutamab. This data provided us with our initial clinical evidence that maintaining Cmin at 3 was likely to maintain IGF-1R saturation. As shown on the left, at a dose of 50 mg Q4W at 12 weeks, the Cmin of 0.1 suboptimal efficacy when compared to the robust efficacy shown across endpoints with 50 meg loading dose followed by 25 megs weekly. At this dose and regimen, lonigutamab maintained a C-min of 3.6 throughout the dosing interval. This Cmin produced robust clinical activity at week 12 across all manifestations of Chad, with approximately 63% improvement in proptosis response, 100% response in CAS, 50% response in diplopia and clinically meaningful improvement on [indiscernible] up to 27.7 points. These data provided the insights around PK/PD correlation leading to the evaluation of cohort 4 to confirm the Phase III [indiscernible] dose selection. We previously announced that we had added a final cohort of patients to our Phase Ib/II study. Although we originally planned for a monthly dose based on clinical data and the half-life of lonigutamab, monthly dosing is insufficient to achieve and maintain optimal therapeutic concentration levels throughout the dosing interval, and could therefore lead to suboptimal efficacy. Cohort 4, which is the last cohort of the Phase Ib/II confirms the PK and safety of selecting a 100 mg loading dose for Phase III. We're pleased the initial data from the first 4 patients enrolled in this cohort shows PK data consistent with our modeling. As shown by the data, the 100 mg loading dose achieved therapeutic concentration within days, while not exceeding the C-Max. Given the strong clinical data across endpoints with the 50 mg loading dose and 25 mg weekly dose and along with the confirmatory initial PK data we've seen from our loading dose cohort. We're confident in our Phase III dose selection. The Phase III dose will be a loading dose of 100 mg followed by a 50 mg Q2W maintenance dose. This dosing regimen is supported by the correlation of C-Min greater than 3 throughout the dosing interval to efficacy. We believe Q2W dosing is convenient for patients and appropriately balances benefit risk. With that, I'll turn it back to Shep to review the data.

Thank you, Mina. The Phase I/II trial was designed to provide data on the safety and efficacy of various doses and regimens of subcutaneous lonigutamab in active thyroid disease patients with consideration of pharmacokinetics and efficacy to inform the Phase III program. Our adaptive approach focused on identifying and establishing an optimal dose and a therapeutic concentration with higher to drive efficacy. In addition, given the potence of lonigutamab, we wanted to explore the potential to enable IV-like efficacy at lower exposures, thus improving the benefit risk profile by minimizing or avoiding on-target IGF safety liabilities, i.e., hearing impairment, menstrual disorders and hyperglycemia. Note that this adaptive design was open label and allowed us to test both the dose and the regimen and utilize these learnings in an iterative way. Screening and eligibility were consistent with other trials in active thyroid eye disease, including proptosis of greater than 3 millimeters above NOMA and a CAS greater than 4. Baseline characteristics and demographics across treatment groups were well balanced and consistent with other previous active thyroid eye disease trials. Patients on average were 10 to 15 months since the onset of TED and more than half identified as having never smoked. Baseline line values of proptosis, CAS, diplopia were in line with other studies in this patient population, including about 2/3 of patients with diplopia at base line. Baseline characteristics were similar in patients enrolled from the U.S. and Australia. This slide shows the result of the placebo-controlled part of the Phase Ib/II study, which we have previously shared. Patients received only 2 doses of placebo or lonigutamab 40 milligrams at week 0 and 3 during the 6-week treatment period and then entered post-treatment follow-up with the final efficacy assessment at week 12. As you can see, rapid and meaningful responses were observed at 6 weeks across all thyroid eye disease manifestations and were maintained throughout week 12 of treatment. We use this proof-of-concept data to inform the doses and regimens we tested in subsequent cohorts, which range from 25 to 100 milligrams and weekly to monthly regimens. This next slide highlights the importance of achieving and maintaining therapeutic levels of exposure to achieve robust efficacy. On the right, thyroid eye disease patients who received a loading dose of 50 milligrams and a weekly dose of 25 milligrams achieved and maintained a C-Min of 3.6 micrograms per ml. These patients, had a rapid improvement in proptosis as early as week 4 at the first time of assessment, with the responses improving over time and maintained through week 12 and for 3 months of treatment. On the left graph, thyroid eye disease patients who received an infrequent dose of 50 milligrams every 4 weeks or monthly achieved and maintained a low C-Min of 0.1 micrograms per ml. These patients are comparatively suboptimal proptosis response. It is evident from this data that less frequent dose interval, Q4W or monthly produce a low C-min below the therapeutic concentration resulting in suboptimal efficacy. This observation is supported by the higher proptosis response rate observed at week 6, which is 2 weeks after the second dose when plasma concentrations are high. However, past that time point at week 8 just before redosing [indiscernible] concentrations are below the level of target-mediated drug disposition. The target was not fully saturated and therefore is waning of the proptosis response. We are very pleased with our Phase II data which show the potential of lonigutamab to achieve IV-like efficacy at substantially lower plasma concentrations. The left graph on this slide shows subcutaneous lonigutamab produces substantially lower plasma concentrations when compared to IV-teprotumumab and IV [indiscernible]. We will demonstrate in the next few slides that similar clinical efficacy achieved with lonigutamab at lower plasma exposure when compared to tepro and [indiscernible], it is clear these levels of efficacy can be achieved while maintaining homeostatic IGF-1 levels in contrast to teprotumumab and [indiscernible], where total IGF-1 levels increased in a dose-dependent manner. Using IGF-1 as a proxy for target engagement does not correlate with proptosis response as a pharmacodynamic marker and may instead contribute to potential safety liabilities associated with elevated IGF-1 levels. The lower exposure with lonigutamab is an important lending of having explored dose ranging with a subcutaneous formulation in thyroid eye disease patients to establish an optimum and minimum target exposure efficacy while I'm really avoiding the undue overexposure that potentially impacts benefit list. As we can see here, patients who receive the 50 milligrams weekly maintenance dose of lonigutamab, showed a rapid onset of proptosis response with a commensurate reduction in mean change of proptosis. Importantly, the onset and time course of response in subcutaneous lonigutamab was similar to the kinetics of response of IV-teprotumumab in [indiscernible] a significantly higher exposures. It is clear from the patient level data that achieving and maintaining therapeutic concentration drives deeper mean change in proptosis from baseline. Here, we see profound change in proptosis individual patients from baseline, some patients improving by minus 3 to minus 4 millimeters, 7 of 8 patients achieved a change equal to or greater than 2 millimeters within 12 weeks. Notably, the 1 patient with partial mean proptosis response improved in CAS and [indiscernible] quality of life. Thus, these bar charts demonstrate the potential therapeutic impact of lonigutamab on proptosis and show that individual patients can achieve deep change in proptosis that is not evident when looking only admin change in proptosis. Lonigutamab potency enables IV like efficacy, but with a subcutaneous formulation at lower exposures. Notice the rapid kinetics of response across all thyroid eye disease manifestation shown here in this slide, as early as week 4 in patients receiving 50 milligram loading dose and 25 milligrams weekly dose regimen. This tracks nearly in the same trajectories and magnitude of response as IV-tepro and [indiscernible]. Notably, 40% of patients achieved an improvement in diplopia or double vision, a well-recognized debilitating symptom in thyroid eye disease patients, not just the similar rates of improvement on this end point compared to IV-teprotumumab. The [graph] of the total quality of life improvements were clinically meaningful as early as week 4 and over time. Overall, safety was favorable with a total of almost 75 subjects dosed with lonigutamab to date, as you can see across the different dose groups, there were no treatment in major serious adverse events, 1 patient on placebo had optic neuropathy and discontinued the study and no other patients who received lonigutamab across different dose strengths discontinued the study. Overall, as we have previously reported, 4 patients at the lowest doses tested had mild tinnitus that was transient that fully resolved without treatment interruption or discontinuation from the study. Importantly, there were no new [indiscernible] findings compared to baseline and over time in any of the patients that were dosed with lonigutamab. To date, we have not seen any [hybrglycemia] or menstrual disorders in patients exposed to lonigutamab. Overall, this data gives us confidence in the safety profile of lonigutamab and the potential for differentiated risk benefit. We believe this -- this is enabled by the unique mechanism of lonigutamab that enables a robust therapeutic impact with low levels of exposure and it's noncompetitive binding that maintains homeostatic IGF-1 levels, critical for maintaining integrity across different organs. I would like to note that in this slide, we separated tinnitus from auto toxicity in our safety table. Tinnitus is a subject of symptom that is self-reported and generally transient and self-resolving. We measure auto toxicity objectively as a change on pure tone or geometry compared to baseline and over time to determine any hearing loss. While these results are preliminary, they show adverse events of special interest across 28 thyroid eye disease patients on lonigutamab to date. We feel very encouraged by the very favorable safety profile that we believe has the potential to make lonigutamab the best-in-class. I will now turn it back to Mina.

Thanks, Shep. We're excited to share the full design of our Phase III program today. We will be running 2 concurrent trials with top line data expected in 2026. The first trial LONGITUDE-I, has a study within a study design to establish efficacy in active tad, while at the same time, allowing for accelerated enrollment of the total number of patients needed to support our safety database for treatment out to 52 weeks. We are especially excited to tap out the potential to deepen responses beyond 24 weeks and believe this is a significant change in the TED treatment paradigm. The primary endpoint in LONGITUDE-I is proptosis response rate in active patients, similar to the active TED trials run with other agents. This will facilitate a comparison across agents for this population. We plan to enroll at least 81 active TED patients. Proptosis response rate in all patients is a secondary endpoint. We expect to enroll 175 patients in LONGITUDE-1. The second trial LONGITUDE-2, maybe read as more like the chronic TED trials run with other agents. We do think the active versus chronic labels are not fully reflective of TED, but it can be a shorthand to describe these trials. We expect to enroll 175 patients in this trial with proptosis response rate in all patients as the primary endpoint. Both trials will have the standard secondary endpoints of CAS, diplopia and [indiscernible]. We will also be using optional MRIs in both trials. LONGITUDE 1 and 2 have similar designs with the primary difference being the minimum of 81 active TED patients required in LONGITUDE-1. Otherwise, these studies have been designed with broad inclusion criteria, which reflect the real-world TED patient population and the significant unmet need that remains. We're aware of the competitive dynamics of enrolling these trials and think several features will help us win in terms of enrollment. There's a 2:1 randomization of drug to placebo, and all patients cross over to active drug after 24 weeks. So importantly, while patients will remain masked as to whether they were on placebo or active for the first 24 weeks, all patients will receive lonigutamab for at least 28 weeks. We believe this will be especially attractive for patients in a global study and especially in places where teprotumumab is not yet approved. We also believe that the data we're sharing today around efficacy as well as safety will generate enthusiasm from KOLs in patients and may lower the barrier to study participation for some patients who are concerned about potential safety liabilities associated with other anti-IGF-1R therapies. Subjects randomized to the lonigutamab group who complete both treatment periods will receive a total of 26 doses, in subjects randomized to the placebo group who complete both treatment periods will receive 14 doses of lonigutamab. With that, I'll turn it over to Ken to walk through the commercial opportunity.

Thank you, Mina. So I want to highlight the unique aspects of our differentiated Phase III development plan and how it enhances the opportunity for lonigutamab to benefit more patients with thyroid eye disease. As Mina mentioned, key features of our program really stand out. Firstly, a broad inclusion criteria beyond just the most severe and curated groups that we see in other trials. We're evaluating prior teprotumumab responders, patients with longer disease duration and age appropriate hearing loss patients, patients with which are typically excluded from other trials. This approach ensures we address a broader range of real-world patient needs as well as opening the funnel for significantly more patients to become candidates for anti-IGF1 therapy. We're also focusing on patients with diplopia. And as you heard one of the most bothersome symptoms of TED, improving upon limited historical trial data sets. We've been encouraged by our prior results for diplopia resolution and believe the lonigutamab profile is well suited to address this challenging symptom and in particular, one that may benefit from more thorough treatment. Patients with controlled diabetes are also now eligible as lonigutamab's unique mechanism of action has avoided hyperglycemic events to date. And we believe these patients can also benefit from lonigutamab without concern over exacerbation of their condition. These differences in design may lead to a broadened label at launch with data in hand to be able to immediately address incremental populations that have historically been left on the sidelines due to lack of information about specific benefit or side effects in these groups. In addition, given the more inclusive criteria we've heard from and hope to capitalize on increased investigator enthusiasm for enrollment into our trial, in addition to the encouraging clinical data produced to date and lonigutamab's unique MOA. Our trial also involves continuous dosing for up to 52 weeks, aligning with TED's chronic inflammatory nature. This long-term approach offers physicians flexibility in treating patients over time, providing the ability to tailor the therapy to individual patient needs and addressing the asynchronous nature of symptom resolution while improving upon the depth of response. Fixed durations of therapy as seen in IV regimens just don't make sense in that scenario because a one-size-fits-all approach does not fit the true nature of the disease. Now regarding the overall opportunity, TED affects around 100,000 patients in the U.S., but today, less than 10% or so receive advanced current -- advanced therapy currently. Despite the minimally penetrated market, this still represents a $2 billion opportunity for the standard of care. We believe subcutaneous lonigutamab has a safety profile that has the potential to shift the benefit risk equation for patients and providers. which can expand this market, especially for patients that aren't the most severe or active in their disease course, but are still symptomatic. Alongside other emergent subcutaneous options, we expect lonigutamab can grow the treated patient population substantially from broader acceptance of therapy as well as blur the lines of distinction between active and chronic disease. We believe that what was previously considered 2 distinct forms of TED is really a single disease that can be treated with the same safe chronic treatment regardless of activity, severity or disease duration. Our recent market research highlights the needs of patients, physicians and payers. And we believe the subcutaneous lonigutamab profile aligns with the needs of all 3 groups of stakeholders. For patients, lonigutamab may offer effective, safe therapy with longer-term dosing that addresses the full spectrum of symptoms as well as provides an opportunity for deeper symptom resolution. In addition to patients today being increasingly aware of the safety risk of the standard of care, our research suggests that only a minority of patients on teprotumumab have the totality of their symptoms resolved after treatment. Our research also showed that an overwhelming preference for subcutaneous at-home dosing versus IV with the caveats of having an improved safety profile. In other words, subcutaneous delivery in and of itself, may not be enough to overcome a specific known safety concerns of other anti-IGF1 agents. For physicians, the safety and convenience of the subcutaneous delivery make it easier for doctors to offer treatment and improve patient adherence with minimal disruption to their lives. A safer option that physicians can more confidently offer and more patients accept allows for more HCP to deliver on the promise of advanced therapies for TED. And for payers, the potential to reduce the need for retreatment and address the chronic nature of TED aligns with the payer goals to improve cost effectiveness. Payers are interested in a therapy that more fully addresses the multiple symptoms of the disease through a more complete treatment of what is a chronic condition and obtaining a better understanding of performance in broader patient populations. In addition to delivering on what may be a best-in-class clinical profile, a lonigutamab auto-injector is positioned to be the smallest, fastest, lowest volume subcutaneous auto-injector in the class to be available at commercial launch. As mentioned earlier, our dosing will be every other of the week for as long as the patients need therapy. And this is a regimen similar to many of the most successful therapies in the world, adalimumab, dupilumab, even GLP-1s. It's a regimen that's not only easy to remember, but also easy to stop and wash out of a patient system quickly should there be a need or an adverse event, potentially leading to reversibility and specifically limiting the potential for any permanent adverse events. Extending half-life of these agents might appear advantageous. However, this could prove to be highly problematic for benefit-risk should a safety concern emerge and the very long time it takes to clear from the system. So in summary, we believe that lonigutamab is a highly differentiated de-risked program that features robust efficacy, comparable to standard of care and emerging anti-IGF-1 agents. We feature the first subcutaneous data in TED patients, which effectively derisks the Phase III program. We feature an optimized safety profile with no evidence of hearing impairment, hyperglycemia or menstrual disorders, and features a profile that is well suited for chronic and flexible use to address the full range of TED symptoms and improve upon the depth of response. We've talked about our inclusive trial design that answers important scientific questions, and expands the patient population. And lastly, we believe we have a best-in-class auto injector. So we are very excited that subcutaneous lonigutamab will expand the addressable patient population and enable more patients suffering from TED, regardless of disease activity or duration to experience the benefit of an optimized anti-IGF-1R therapy. I'll pass it back now to Mina.

Thanks, Ken. Before we turn it over to Q&A, I thought we'd take advantage of having Dr. Kossler and Dr. Subramanian in here with us today. One, I wanted to thank you both for being on our Advisory Board and for all the sage wisdom and advice along the way as we've been working to develop lonigutamab. And maybe Dr. Subramanian, I'll start with you. Just a general question. I wanted to get your general thoughts and impressions on the content we covered today.

Thank you, Mina. There's a tremendous amount of data and really exciting information. And I'll offer the perspective of a physician who has treated patients with thyroid eye disease for 25 years. We have all seen how the development of IGF-1 receptor antagonist drugs and their institution over the past 5 years has change our perspective on thyroid eye disease has changed our patient expectations that -- previously, when I would offer the medicine, it was to temporize them until someone like Dr. Kossler or I could take them to the operating room to do surgery on them. And the ultimate goal of treatment was maybe I can make you look a little bit better. Maybe I can make your eyes closed, but there was this acceptance that I could never do anything to really try to make them normal again. And so it's exciting as we look at the potential of a therapy that is designed to both be safe and effective to take advantage of what we know is the efficacy of an IGF-1 receptor antagonist pathway and then try to address some of the downsides of that, some of the things we have seen with respect to side effects, hearing impairment and hyperglycemia were mentioned, the menstrual irregularities. I would say the hyperglycemia in particular is one that seeing it not occurring in the cohort of patients that has been treated so far is really quite exciting to me because hyperglycemia is dangerous, hyperglycemia can kill people. And so if you have a drug that has a better side effect profile in that regard, that to me, is a potential real benefit. But going even further than that and saying that we have a treatment that potentially can be modified to treat patients at different stages of their disease to tailor a therapy that may prevent some of the bad things from happening with thyroid eye disease, but also can be continued to give them perhaps a more durable response to therapy and take my role as a surgeon out of the equation. I have plenty of other surgeries to do. And if I can help my patients with thyroid eye disease in another way. And again, shifting that risk-benefit profile and the durability profile in a way that may be more favorable than I'm really excited by those things.

Great. Thanks, Dr. Subramanian. Maybe Dr. Kossler, I'll ask you the same question. Any general thoughts or impressions from the content today?

I'm very excited about this drug. I think that in this class, efficacy is an expectation. So I'm impressed with the early data on efficacy, but I do expect that. What was unexpected to me, and one of the reasons I decided to join a Scientific Advisory Board was the safety potential. And with the data that's been shown really the safety results. One of the most challenging things that I have when I'm using the current FDA-approved IGF-1 receptor inhibitor, I know that it works, especially in patients with active moderate to severe thyroid eye disease, but it's been the screening and the monitoring and the safety. So to understand this mechanism of action and how it's slightly different and how it's not competitively binding to the IGF-1 molecule, it really does make sense, and it really does excite me that by decreasing the circulating IGF-1 and perhaps not allowing for that feedback loop inhibition happening at the hypothalamus and the pituitary, so that we're not having that impact on growth hormone, which can then cause insulin resistance and then cause that hyperglycemia or can have an impact in the menstrual cycle. By understanding that, it really makes me believe that this drug could be more safe. And if I'm treating my patients with the drug that I know is effective, but is also safe, then that really expands the patients that I'm going to be able to help. So now I feel more comfortable if, in fact, all of this plays out, I would feel more comfortable treating patients with more mild disease or treating patients with risk factors for severe disease early in the stage of their disease and also, of course, treating patients further out in their disease process that have more chronic forms of the disease, and also treating patients that have some baseline hearing loss that maybe are of childbearing potential, et cetera. So I'm really excited by the safety potential of this drug and the amount of patients that I can now treat and be able to sleep well at night time because of the safety.

Great. Thanks. And Dr. Subramanian, I mean maybe just to build on the safety theme. From a patient perspective, in your practice, what do you hear from patients? And do you think that this -- if lonigutamab delivers what we've seen to date, would it change anything in patient perceptions or the way that you treat patients?

Our patients today are really savvy. They have read the literature. They talk to each other in person and in Facebook and other groups. And so they have understandable concerns about potential side effects of medications, and they've heard about all of them. And it does make them hesitant to undergo a treatment, especially in the paradigm of fixed dosing regimen where they then have concerns that not only might they experience side effects from the medication that would then lead them to having to discontinue it. But ultimately, they're concerned that the effect of the treatment that they get might wane down the road. And so they are very cognizant of that, and it's a very detailed discussion that I have. Every drug has potential side effects, of course. But again, as we know, since this is a pathway that seems to work, if there is the potential to be able to say to them, this is an option for you that should work at least as well as another drug in this class but has a better safety profile, then that is very appealing. And that doesn't even get at the aspect of how the drug is delivered to them, whether it's given through an IV infusion or through a self-administration. As was noted, patients greatly prefer the idea of a self-administered drug.

Great. And maybe just to continue on a little bit. I know you and I have discussed in the past other end points other than proptosis, for example, diplopia. I mean how do you think about the data today with respect to those kinds of other end points?

As a preliminary data set, it was certainly encouraging to see that there was improvement in diplopia. Diplopia is one of those things that can be a bit tricky because it's related not only to the eye alignment but how well the eyes move. And it would be interesting to know if that significant increase in the GO-QoL, in part may have been related to some improvement in eye movement and not so much again just on a strict definition of diplopia. So it is really disabling symptom, and it is reflected in some of the more qualitative things that we look at in terms of patient outcome. So I think, again, it is encouraging to me that there is the potential here to lead to an improvement in the quality of life of those patients, and they're functioning that may be hard to capture through some other mechanisms.

Great. And Dr. Kossler, I guess same question to you. I mean what do you hear from your patients? And what do you think could change with the therapy that's got the potential profile that lonigutamab does?

Yes, I agree that this disease can be devastating for our patients, their quality of life. And -- what I'm most excited about is, yes, I'm impressed that it improves double vision, but I would prefer prevent double vision, right? So I get excited about drugs that we can use earlier in the course of their disease rather than improving 50% of patients that have double vision. It would be nice to prevent those patients from ever having to deal with that sequela in the first place. So I really think that the safety profile, again, is what excites me because I feel more comfortable treating patients earlier. The other thing that I like about the design of this study is the duration. As an ophthalmologist, we know from our retina colleagues, this treat and extend journey that all of our AMD treatments went through, where they tried all of this fixed dosing and then they try it every month. And then they came to the understanding that every patient is different and that when you're treating AMD, macular degeneration, that there's this kind of treat and extend. You really have to use your art and your experience to be able to treat these patients in a customized way. So I like that this drug is going to be studied over 52 weeks. I would envision that when insurance companies later approve this drug that would give a lot of power to the providers to treat the patients the way we believe that they need to be treated. And that really, I'm excited about because when I'm treating patients with the current FDA-approved option, when they do fantastic on the drug, but then 9 months later regress, fighting with insurance is a pain. They oftentimes say no. And now I have nothing to do for my patient to get them back to that improvement that they experience with drugs. So I'm very excited about having some power back in the physician's hands to treat the patients the way that we believe that they should be best treated. I'm excited about that customized treatment, that longer-term treatment when necessary. And also, there's been times where I have a patient that did really well on teprotumumab. But they did experience side effects. And then when they have the regression, I get worried about putting them on it again because I don't know if there are long-term implications of repeated IGF-1 inhibition over time. So I'm excited about this study because it is for 52 weeks of treatment. And so I'm excited to find out, can I treat patients for this long amount of time and not have to worry about those safety concerns. As an ophthalmologist, I'm not the best person to be treating hearing loss or hyperglycemia or the myriad of other side effects that these patients have. Now I'm fortunate enough to work really closely with an endocrinology colleague, but not every ophthalmologist has that benefit. So to have a drug where we can focus on our expertise is really going to be really fantastic for ophthalmologists treating this condition.

Thanks. And Dr. Subramanian maybe to build on that a little bit, I think Dr. Kossler touched a little bit on the Phase III design, right, and dosing out to 52 weeks and also sort of the broadened inclusion criteria. But any additional thoughts on the Phase III design or on the trial design?

I like the fact that it is capturing patients at different stages of their disease being more inclusive of letting patients enroll if they do have age-related hearing changes that are mild. And what it does to me as a physician when I look at data that come out of clinical trials like this, it does, as Dr. Kossler was just saying, give me the confidence to say, this drug works ideally and that it is safe if the safety data are replicated in this larger population. And I think that's one of the really powerful things about this study design -- is that we don't have to wait for some years down the road with real-world experience in older patients or patients with other medical comorbidities or things like that to have the experience and the ability to say to a patient sitting in front of us, I think you would be a good candidate for this drug. I don't have to say, well, you don't quite fit the category of people who were studied. So I'm a little concerned as to whether or not this is the right thing for you. I don't want to underestimate the importance of including more people like that. That's really, to me, a key aspect of this along with the longer duration of treatment. And this optimized dosing that has been done, the work that has been in the Phase I and II to really intelligently come to a treatment strategy, a Phase III treatment strategy that both maximizes the likelihood of success but also minimizes the potential for side effects. I think that really speaks to some good science behind this.

And I think we've got a couple more slides before we go into Q&A, and we're going to ask you both to rejoin us for the Q&A. But Dr. Kossler, any last thoughts?

Well, one thing that wasn't mentioned is kind of the big obvious thing, the auto-injector. I think that our patients would love to have an auto-injector, I know at least at Stanford, it can be really challenging to try to coordinate with the infusion centers and to get the approval and to get the chair that they can sit in and just having to come in for these infusions every 3 weeks be very onerous on our patients and on the health care system and honestly, on the physician as well, trying to coordinate all of this. So I think that the auto-injector approach is going to be a very welcome thing for our patients and for the providers. And I would agree with the last thing that was mentioned, which was the care that was taken into the dosing regimen. I think, Mina, you had mentioned right before we got on this call, that it could go to 4 weeks, but then that would sacrifice safety. So that really was a big deal for me to hear that. We would rather be safe than go to Q4. And we know with the success of the Ozempic and the other GLP-1 inhibitors. Q week is standard nowadays. So to do Q2 is even better. So I think that at the end of the day, it's really all about safety and efficacy. And then as long as the injection is easy to do for our patients, I don't think that the frequency will really matter.

Great. Thanks. And yes, last question, Dr. Subramanian, any final thoughts for us?

I would just echo this idea that we're in an era now where we have knowledge that IGF-1 receptor antagonism is a good way to treat thyroid eye disease. I think it's really exciting that we have now a potential new mechanism of action with a drug that is opening up doors. I really look at it that way as something that has the potential to broaden our patient base to broaden our ability to modulate this disease and to really just continue to make progress in a field that has seen a lot change over the past 5 years.

That's great. Thank you both so much. I think we've got just a couple of more slides and then we're going to come back for Q&A. Okay. Thanks for listening today. We believe lonigutamab has the potential to shift the paradigm of treatment for TED patients. Based on it's unique MOA, delivering IV-like efficacy with the convenience of a self-administered auto-injector and a favorable benefit/risk profile. We're also really excited to start the trial this year. We will be launching the first trial this quarter and with -- we expect to dose our first patient in the first quarter with the second trial following close behind. We will be reading out top line data in 2026, and I said -- as I've said before, the program is fully funded. I want to just take a moment to thank all the participants today. Dr. Kossler, Dr. Subramanian, thanks so much for joining us, and we look forward to having you on the Q&A. I also want to thank all the patients and clinicians who were part of our Phase II trial and those who will be joining us for the Phase III program. We're incredibly excited to launch this trial. Finally, I want to thank all of the employees at Acelyrin. We are working very hard every day to improve treatment for thyroid eye disease patients, and we look forward to providing updates along the way. With that, we'll open it up to questions.

[Operator Instructions] So our first question comes from Derek Archila at Wells Fargo.

Thanks for the update and Happy New Year. I was wondering if you could provide some additional color on Slide 33. And I guess what's happening to the proptosis responses between week 8 and week 12? We see it falling off even though they're getting weekly dosing. Are we to assume -- I guess it's maybe patients 6 and 7 on Slide 36. Is the drug concentration falling below the 3-microgram per ml for some reason?

Derek, I'm actually going to turn that one over to Shep.

Yes. Thanks very much for the question, Derek. It is exactly related to having enough exposure to maintain target engagement. And as we clearly showed in our Q2 dosing, we do maintain a Cmin of around 3.6. And we know that this is really critical to continuously engage the target and maintain the improvement on proptosis in patients as demonstrated on the monthly dosing, we showed very nicely that at the beginning of study with a 50-milligram dose, you seem to see a comparable magnitude of proptosis response. But just before redosing every 4 weeks, you lose the opportunity to maintain the Cmin and you lose your proptosis response. So we believe everything is really tracking around our optimization of maintaining a Cmin with the proposed dose we are taking forward of every 50 milligrams every 2 weeks in Phase III.

Got it. And just a follow-up to that. Just as you think about that Phase III dose regimen, I guess, what minimum concentration are you modeling? I mean I kind of can infer some things from the slide, but ultimately, it looks like it's going to be decently higher than maybe that 3 microgram per ml. So just want to know how you think that might impact efficacy but also safety?

Thanks, Derek. Yes, we expect it to be very comparable, right, to that weekly cohort, which is why we felt comfortable there. And it does maintain that Cmin, that concentration above 3.

So our next question comes from Yasmeen Rahimi at Piper.

I guess could you maybe help us understand given the modeling of moving forward with 100 mg loading dose and the 50 mg every other week. What do you expect efficacy to look like? Like are you -- is your powering assumption in LONGITUDE-1 and 2 similar to the Cohort 2 data that you showed would love a view to the extent you can elaborate on. What do you hope to see in your primary endpoint? And what do you consider to be really -- obviously, phenomenal safety aspect and differentiation from low volume and auto-injector, but how could we model what the efficacy could look like across these two studies? And should we be expecting also top line data from both LONGITUDE-1 and LONGITUDE-2 to the 24 weeks sort of sequentially or potentially at the same time? I know you're starting 1 ahead of 2, and I'll jump back in the queue.

Thanks, Yasmeen. Let me start with the second one first. So for the top line data, we would expect to see 24-week top line data from the first trial in the back half of '26. And we don't think that LONGITUDE-2 is going to be far behind, right? So we are hoping to start those very quickly, one after the other, right? And we'll obviously provide updates on timing. On your question around efficacy, right? As we have done this dosing work, I think as we noted in the script, we are really pushing towards a Cmin above 3. And we think that we're confident that we're going to have that with every other week dose in the same way that we did with that weekly dose, right? And we are trying to get to the right benefit/risk, right, as we think about that dose. But we're confident that based on the clinical data that we are going to drive towards sort of similar efficacy. Maybe I'll just ask Shep if he has anything to add there.

Yes. No, absolutely on point, Mina. I think what's really critical in our observation and if you look in the literature for tepro is that Cmin is a very good proxy for proptosis improvement. You need to have a respectable number of patients across their disease baseline characteristics, including weight to maintain that Cmin to be able to have proptosis improvement. But we have also seen in our data that most of the other manifestations do very well, sometimes irrespective of that Cmin, as I mentioned, in some of our data that we had improvement in CAS and GO-QoL, even though we had not maintained the Cmin that is required for proptosis. So overall, we believe with our current proposal dose regimen for Phase III, we have very good competitive profile across manifestation, and we'll be able to show durable and depth of response over time given that we are giving these patients treatment that's not fixed dosing.

Yes. And maybe just I'll ask Dr. Kossler and Dr. Subramanian if they have any comments actually on that question.

I would just add to that, that the idea of having an appropriate Cmin probably fits with what we are seeing with the current fixed dosing scheme that is being done with teprotumumab and may explain what the time course in which we are seeing a regression of treatment effect. And so I think, again, the design and the careful delineation of where that Cmin needs to be makes me somewhat optimistic that this trial design will show us a good response and a persistent response and allow us to be able to judge exactly what is happening here and how durable the effect of this treatment is over time.

Our next question comes from Tyler Van Buren at TD Securities.

But so the PK with the proposed Phase III dose regimen looks great, bouncing off the Cmin that we've been talking about or the Cmin proposed threshold. The efficacy data are promising. But it would be helpful if you could just again reiterate the evidence that suggests that Cmin of 3 micrograms per ml is sufficient for maximum efficacy considering that the exposure of Tepezza and Viridian drugs are so much higher. And my second question is for the Phase III, do you expect the broader inclusion criteria to impact response rate or proptosis response as we inevitably look to compare the data to the IV product data?

Yes. Thanks for the question. So maybe to start with just the second question first again. Just keep in mind, in that first trial, we will be doing a sort of an apples-to-apples cut, right, with the 81 active patients with similar baseline characteristics, right? And so I think we'll offer sort of the comparison, I think that you're referencing. And then maybe, Shep, I'll turn it over to you to answer the first question.

Yes, thanks for that question. As we mentioned, we were fortunate to do an adaptive design, which enabled us to use our well-behaved characteristic of lonigutamab pertaining to the PK, the PD and we also were able to look at target engagement from our healthy volunteer studies with a range of 25-milligram subcu to 250 milligram. We were able to establish how much drug do we need on board to continuously have target engagement. And that led us to our 40-milligram subcu Q3 dosing. When you look at that data set, you see that even though we have a slightly low Cmin, we achieved some remarkable robust clinical activity with a rapid onset. And from the iterative knowledge around a data set and understanding of our PK-PD and target engagement, we then move forward to explore the cohort that we just presented here with 50-milligram load and 25 milligrams every week. That really characterized very nicely the continued target engagement that's needed. And I presented the waterfall charts on min proptosis for those respective patients, where we have a Cmin of around 3.6. And you saw 7 out of 8 patients maintained their proptosis improvement. We have seen in other cohorts like the 50-milligram monthly, where we are not maintaining this level of Cmin. We don't have the profound improvement and sustenance of response. So we are very confident that this does rationale that has calibrated a very pristine goldilocks Cmin will be useful for us without really overexposing patients focusing on Cmax, but on this Cmin and [ steady trough ] to really arrive at an optimal exposure concentration that will be useful for maintaining response.

So our next question comes from Vikram Purohit of Morgan Stanley.

We had two following up on the Phase III trial design. So I believe you mentioned first that you'll be enrolling prior Tepezza responders. We were just wondering if you could mention kind of what the washout period is going to be? Could you also speak a bit about what portion of patients would be Tepezza responders versus treatment-naive patients? And then on Slide 42, I think you mentioned that you're going to be capping the number of patients with hearing impairment. We were just wondering if you could provide some more detail on what portion of patients this would apply to and exactly how you might filter patients based on baseline hearing impairment.

Yes. So with respect to hearing impairment. So we will be opening up the criteria a little bit, right, to allow for age-appropriate hearing loss is really the way that I would think about that. And we will be capping the number of those patients in the trial at 50%. And then, Shep, I don't know if you want to comment on the first question.

Thanks for the question, Purohit. So for the Tepezza previously treated patients, we are only taking in patients that have had a previous response to teprotumumab, but are now regressing. There is obviously an important consideration of a 3-month washout, which really matches the 5x half lives before you include any patient with the previous biologic exposure in any study.

Understood. And are you able to tease out what portion of patients might be Tepezza responders versus treatment-naive at this point in either or both of the Phase III studies?

Yes. So we believe, given the fact that Tepezza is not yet approved worldwide, this will possibly be mostly a few patients from U.S. sites or Canadian sites.

Our next question comes from Emily Bodnar at H.C. Wainwright.

I'm curious if you have any plans to evaluate a cohort of patients with the Phase III regimen, I guess, before ordering the Phase III program to kind of get an idea of how it compares to the Q weekly dosing? And then my second question is since it seems like in competitor studies, there are a baseline patients and even placebo groups who have hearing impairment or hyperglycemia. Is there a rate that you're kind of expecting to see maybe a baseline?

Great. So maybe Shep, do you want to take those? I'll hand that over to you.

Okay. So maybe I'll start with the second one on hearing. So in terms of hearing, for sure, we will have patients because we're doing audiogram as screening at baseline. We'll be able to see the percentage of patients who have normal hearing. We are also capping the number of patients that have what we call age-appropriate hearing impairment. So you can imagine a patient who's maybe about 50 years old. They have a certain well-recognized decibel frequency threshold reduction at a particular frequency. And we are keeping that to less than 50% of patients coming in our study. So if you can repeat the first question on...

Yes. Just if there's any plans to evaluate a cohort of patients with the Phase III regimen prior to starting the Phase III program?

Yes, I can take that. No, Emily, we're going to be -- we are going to be going straight into the Phase III program. We're finishing up just that last cohort that's got the loading dose confirmation, right? So that 100 mg loading dose, right? And we're really using that cohort to confirm PK right, in safety. And as we reported today, we are confident that the PK for that loading dose matches our modeling, right, and it does bring patients to sort of that therapeutic concentration often within days. And so that will be the final sort of cohort of patients for the Phase II program, and we will be going straight into the Phase III program.

Our last question comes from Sam Semenkow at Citi.

A couple for me. The first one, for your design treating patients out to week 52, I guess, in your discussions with FDA, what is your understanding of what you need to show at that 52-week time point to demonstrate that longer treatment is first necessary for some patients? And then second, efficacious. Is there a bar you're looking to show at week 52? And would you expect this to need to be included in the label to have payer coverage? And I have a follow-up.

Yes. So maybe just start there. I mean we do have alignment with the FDA already to go out to 52 weeks, but we will be filing on the 24-week data, right? So just to make that clear, I'm not sure that there is a set bar necessarily for that 52-week data. But I think we do have alignment that there could be real value in that longer-term sort of more flexible dosing that we talked about on the call today.

Yes. Maybe just to add, we had from our experts that thyroid eye disease is like a chronic autoimmune disease. And the severity and duration of disease is very variable in patients. Current fixed dose treatment does not result in disease resolution or modification after 24 weeks of treatment. So to your question around our expectation, we believe that different patients might arrive at disease resolution at different time points. And therefore, the opportunity to have good exposure far beyond the fixed dosing who enabled this to happen for the respective individuals. So we expect the same IV-like efficacy to be maintained up to those time frames of treatment and maybe patients might not have to have the regression that is currently happening at all after that treatment duration.

Got it. Okay. That's helpful. And then maybe one for the physicians. I guess what would you like to see in the data that goes past 24 weeks? And how do you think about some of these patients that maybe don't need the extra 20 -- full extra 28 weeks? And yet in the study, they're receiving the full 28 extra weeks. How do you make the decision when you are potentially looking at the data down the road on when to stop treatment? Just any thoughts that you have around that dynamic would be helpful.

I think what's interesting about this study is that there's kind of 2 groups of patients. You're going to have 1 group that's going to receive all of the doses because they started off in the treatment group, so they'll receive about 26 doses. And then you're going to have that second group, that placebo group that they're going to automatically transition into the treatment group, so they're going to receive, I think, about 16 doses. So we'll get some information to know if the 16 doses alone was effective enough, if the 26 doses adds any benefit. And then just like any other post-study drug, there's lots of research that's going to need to be done to further understand who needs short term, who needs long-term treatment. As a provider, I don't expect to have those answers right away with this study. There are so many things that we're still looking, things in thyroid eye disease, the definitions and our understanding are continuing to evolve. But at least, I feel that I will have the ability to be able to treat my patients longer if I feel that it's indicated. So I may treat certain patients still for only 24 weeks. But if it seems like they're continuing to improve, I may want to continue to treat them longer. If it seems like they haven't had full improvement and they're tolerating well, I might keep treating them longer. There may be some patients that have full improvement, and there's no reason to continue them on drug, but I feel that if 3, 4, 6 months later, they have return of symptoms will then -- and most likely, we'll still be able to treat them with drug because it has hopefully been approved for a long duration of treatment. So I think it gives me flexibility, and then I think that this study alone is going to answer a bunch of questions that we don't yet have answered with current IGF-1 therapies.

And I'll just add to that, that what Dr. Kossler is getting at is our thinking about the disease may actually be a little bit flawed in the sense that it's been driven by this idea that drives from oncology really that you treat these patients for a fixed period of time, and you expect the majority of them to get better and stay better. Some of them may, but just like other autoimmune diseases, having that flexibility to then persist with treatment and withdraw and reinstitute treatment as necessary is hopefully something that a more extended treatment trial like this will demonstrate for us in terms of both the safety and efficacy to again help us to individualize treatments in a way that's going to be more effective.

Got it. That's very helpful. And if I could just squeeze in one last one. As you think about the flexibility that you potentially might have with [ Lani ] in treating versus, say, some of the other competitors, subcutaneous program that is out there that is -- maybe has a less frequent dosing regimen, and weighing how the efficacy lays out, let's say, hypothetically, [ Lani ] comes in, either equal or slightly under, but you have flexibility. I'm just trying to gauge how you think about each of these potential factors of the different therapeutic product profiles that we could see as these -- the field evolves?

Sure. I'll make a comparison to a multiple sclerosis, for example, the neuro-ophthalmologist take care of a lot of patients, so a lot of options there. And I think some of it comes down to the side effect profile tolerability. And so as you mentioned, if this drug is equal in its efficacy but has a safety profile that is more favorable, then that is something that's going to influence me as well. And then if there is some flexibility in terms of shortening or lengthening an interval, if you have a drug, it seems a little counterintuitive, but one that can begin given every 2 weeks compared to one where the dose interval is longer, then your ability to really play with that dosing interval is less if the dosing interval is longer as originally set. So I think that's a potential advantage there.

Yes, I agree with that. I think flexibility is nice, but safety is more important. And so I think what we're seeing with what's been presented here is that we might get both out of this drug. And again, safety is the most important thing. So even though patients have to be injected every 2 weeks, I think that -- for some reason, that doesn't bother me at all. I think that every 2 weeks is just fine as long as it's safe. And again, if it's easy to be injected. Nobody -- we were talking earlier about diabetes, right? So I have plenty of patients. Of course, this is an endocrinologic disease. We see tons of patients with diabetes that have to check their blood sugar daily or sometimes after every single meal or sometimes they have to wear pumps that injects them, and as long as it doesn't hurt, and it's very easy to do, patients don't mind doing injections and checking their blood sugars very frequently. And I think that the same will be true for this drug as long as it's effective and then we don't have to worry about major safety concerns, and I don't think that the frequency is going to matter. As far as the flexibility, currently, we have drugs that we can only treat for 24 weeks. And then after that, it's a constant struggle and fight with the insurance. And so as a provider, this flexibility is huge for me. I want to be able to treat my patients the way I think they need to be treated. So there's many aspects about this that seem favorable.

Great. Thank you for the questions, Sam. So with no more questions, this concludes today's investor event. Thank you, everyone, for joining, and have a great rest of your day.