Good day and thank you for standing by. Welcome to the Modeyso Investor Webcast. At this time, all participants are in a listen-only mode. Please be advised that today's conference is being recorded. After the speaker's presentation, there will be a question and answer session. To ask a question, please press Star 1 1 on your telephone and wait for your name to be announced. To withdraw your question, please press Star 1 1 again. I would now like to hand the conference over to your speaker today, Jack Spinks, Executive Director, Investor Relations. Thank you, Operator. Good afternoon, everyone. Thank you for joining us today for a discussion on the FDA approval and U.S. commercial launch of Modeyso, formerly known as dordaviprone. The slide presentation accompanying this webcast and call is available on the Investors section of our website. Investors may also reference the press release we issued on August 6th, 2025, regarding the FDA approval of Modeyso. On the webcast today are Renee Gala, President and Chief Executive Officer, Dr. Robert Iannone, Global Head of Research and Development and Chief Medical Officer, Sam Pearce, Chief Commercial Officer, and Joshua Allen, Ph.D., Chief Scientific Officer, Chimerix, a Jazz Pharmaceuticals company. We are also pleased to have Dr. Timothy Cloughesy from UCLA, Distinguished Professor of Neurology, Director of the UCLA Neuro-Oncology Program, joining us today. On slide 2, I'd like to remind you that today's webcast includes forward-looking statements, which involve risks and uncertainties that could cause actual events, performance, and results to differ materially. We encourage you to review the statements contained in our latest SEC disclosure document, which identifies certain risk factors that may cause the company's actual results to differ materially from those projected. We undertake no duty or obligation to update our forward-looking statement. I'll now turn the call over to Renee. Thanks, Jack. Starting on slide 4, we are thrilled that the FDA approved Modeyso under an accelerated approval on August 6th. This approval is for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3K27M mutation with progressive disease following prior therapy. Modeyso will be marketed under the brand name Modeyso and is the first and only treatment option approved by the FDA for this ultra rare and aggressive brain tumor that mainly affects children and young adults. Following the close of the Chimerix acquisition on April 21st, 2025, the combined Jazz Pharmaceuticals and Chimerix teams have been focused on preparing for a rapid launch of Modeyso, and we are excited to report that as of August 15th, Modeyso is now available to patients with this disease. Which has a devastating outlook and for which there is a critical unmet medical need. The availability of Modeyso gives patients who previously had no other approved drug therapy the opportunity to benefit from a targeted therapy and offer them hope for more meaningful days ahead on slide 5. The addition of Modeyso to our portfolio strengthens our presence in rare oncology and diversifies our commercial portfolio. Given its patent protection into 2037, with potential to receive patent term extension and the opportunity for expanded use in the frontline setting, we view Modeyso as a meaningful and durable revenue opportunity for Jazz. We have the right capabilities in place to deliver a successful commercial launch and are thrilled to bring this first in class therapy to patients with H3K27M-mutant diffuse midline glioma who currently have very limited treatment options. I'll review our agenda for today's call on slide 6. First, Joshua Allen, Chief Scientific Officer of Chimerix and co-inventor of Modeyso, will share an overview of H3K27M-mutant diffuse midline glioma, including Modeyso's unique mechanism of action. We have the privilege of being joined today by leading expert and neuro-oncologist Dr. Timothy Cloughesy who will provide clinical perspectives on Modeyso, highlights of the clinical data supporting the approval of Modeyso, and the opportunity that Modeyso provides to patients and their families. Our Global Head of Research and Development and Chief Medical Officer Dr. Robert Iannone will review the U.S. prescribing information and labeling approved by the FDA. Our Chief Commercial Officer Samantha Pearce will follow with an overview of our U.S. commercial strategy for Modeyso. We'll open the call for Q& A. I'll now turn it over to Josh. Thank you, Renee. On behalf of the exceptional disease community that has collaborated tirelessly and selflessly to make this milestone possible, words cannot capture how proud I am to say that Modeyso has received accelerated approval from FDA as the first and only approved treatment for H3K27M-mutant diffuse midline glioma. After years of extraordinary collaborative efforts by patients, their families, advocacy groups, physicians, and scientists, I'll start on slide 8 to provide an overview of the unmet need. H3K27M-mutant diffuse midline glioma, or DMG for short, is a devastating form of high-grade glioma that predominantly affects children and young adults. This disease occurs in approximately 2,000 patients annually in the United States. Based on estimates derived from available literature, DMGs are tumors that occur in the midline structures of the central nervous system ranging from the spinal cord up to the thalamus. The H3K27M mutation is found in 40%- 90% of DMGs, with the incidence varying by the exact location within the midline. Patients with DMGs that harbor an H3K27M mutation are designated as WHO grade 4 given their dismal prognosis, and the disease entity has been part of the WHO classification system of CNS tumors since 2016. Advances in neurosurgical techniques have enabled stereotactic biopsy to become possible for many patients with DMGs. However, surgical resection of these tumors is often limited due to their sensitive location and their diffuse infiltrative nature. Standard frontline therapy consists of six weeks of radiation, with disease recurrence inevitably following. Systemic therapies used to treat other forms of brain cancer have not proven effective for this specific disease. Historically, available therapy in the recurrent setting has been considered palliative. Modeyso, now approved by FDA for H3K27M-mutant DMGs in the recurrent setting, represents an important step forward for the patients, their families, their loved ones, their caregivers, and so many others in the disease community who have worked relentlessly to improve options and outcomes. This also represents exactly the kind of transformative innovation that Jazz Pharmaceuticals strives to deliver for patients. On slide 9, I'll discuss the mechanism of the disease as well as dordaviprone that we now call Modeyso, starting with the mechanism of the disease. H3K27M-mutant DMG is a cancer that is defined by alterations in genes that encode for proteins called histones that DNA within cells wrap around. H3K27M mutations cause a modification to these histones called trimethylation to be lost at a specific spot on the histone proteins. As a consequence, regions of the DNA are less tightly wrapped around the histones, leading to an increased expression of many genes that can fuel tumor growth. Modeyso, formerly called dordaviprone, is a first-in-class small molecule that at a downstream level reverses the loss of H3K27 trimethylation that is the central hallmark of H3K27M-mutant DMG. The compound selectively binds to two targets. One is dopamine receptor D2 and the other is a mitochondrial protease called CLIP P. Modeyso binds to CLIP P and it causes activation of that protease, leading to degradation of several proteins involved in energy production and metabolism. Some of the metabolites that are produced following CLIP P activation directly affect enzymes that regulate histone alterations, including H3K27 trimethylation. Ultimately, the effects of Modeyso lead to decreased tumor cell proliferation and tumor cell death. Slide 10 represents some of the key features of our collaboration with FDA, patient advocates, and key opinion leaders to bring Modeyso to patients with H3K27M-mutant DMG on an expedited basis in view of the high unmet need and observations in early stage clinical studies. Through serial dialogue with FDA, an approach was aligned to evaluate the monotherapy efficacy and safety of this therapy in patients enrolled across multiple early stage clinical studies that were inclusive of H3K27M-mutant DMG. Patient selection criteria were designed with the goals of isolating monotherapy treatment effect and ensuring homogeneity in addition to rigorous response evaluation methodology. To be valuable for the integrated efficacy analysis, patients needed to have H3K27M-mutant DMG that had progressed following prior therapy that included at least radiation. Patients also needed to have measurable disease according to standardized central response criteria for high grade gliomas and needed to have initiated Modeyso as a monotherapy after adequate washout periods from prior therapy, including at least 90 days from prior radiation. While the integrated efficacy analysis narrowed the number of patients in an effort to ensure rigorous attribution of monotherapy treatment effect, the broader population of glioma patients who received orgabaprone was represented in the new drug application for Modeyso, including the integrated safety experience. It is my pleasure to turn the call over to Dr. Timothy Cloughesy from UCLA, Distinguished Professor of Neurology and Director of the UCLA Neuro-Oncology Program, so that he can walk you through the results of these analyses. Thanks, Josh. I have the pleasure of being able to describe some of the data and provide some of my perspectives on that. I'm Dr. Tim Cloughesy, I'm the Director of Neuro-Oncology at UCLA. I'm going to start on slide 12, and this outlines the population that we're evaluating for determining the response rates. This involved a clinical study, a set of clinical studies, ONC13, ONC14, ONC16, and ONC18. These are all open-label, they're non-randomized trials. It involved adult and pediatric patients with gliomas, and the other pre-specified criteria for enrollment included patients having received single-agent Modeyso, diffuse midline glioma H3K27M-mutant with progressive and measurable disease. This means measurable contrast-enhancing disease based on the RANO assessment for high-grade glioma criteria. Patients needed to be greater than 90 days post-radiation with adequate washout from other anti-cancer therapies to help mitigate the risk for pseudoprogression. The Karnofsky performance status or Lansky performance status for the pediatric population required a score of 60 or greater. Patients need to be on stable or decreasing corticosteroids, and this excluded patients who had a DIPG or diffuse intrinsic pontine glioma, primary spinal tumors, other atypical histologies, or CSF dissemination. The dosing was weight-based for the pediatric population but otherwise with a stable dose of 625 mg once a week. On slide 13, this is the demographic and disease characteristics. I think it's interesting to note that the majority of the patients are between 18 and 40, but 8% of the patients are under 18, that's the pediatric population, and roughly 28% are over 40, and the range went up to 70. The male-female ratio was similar. The race determinations were in line with what we see with primary brain tumors. I think it is important to point out for the performance status that it's a pretty high percentage of performance status that are performing between 60 and 70. This is 28% of the patients, and only 32% of the patients are in the 90 to 100. I'm going to have us just move our eyes over to the other column to the tumor size for a second because I want to put this into context that a 10 cm sq lesion is about the size of maybe a ping pong ball, and then the 40, which is one of the upper range, would be like the size of a lemon. These tumors are located in the middle of the brain. These are critical structures in the middle of the brain. It's not surprising that even though these tumors may not be super large compared to hemispheric tumors, they still have a significant impact on their performance status. The location is predominantly thalamic, but there are other midline areas, and again the thalamic region is very sensitive to increased size and has an impact on clinical outcome and function. There was multifocal disease in 46%, but those that were target lesions were for the most part, about 80% of those with a single target. Most of the determination of the H3K27M mutation was through immunohistochemistry, and the majority of patients were first recurrence. Many had received temozolomide. The time from recurrence to initiating therapy is about 20 days. The time from prior radiation therapy was about 7.5 months. The time from initial diagnosis was about 11 months. The average or median daily steroid dose was about 1.1 mg. On slide 14, we're looking at the numbers for the response rates, and this is really where some of the exciting data exists. Here we could see that the percentage of patients who had a response is 28%. There were 14 patients. The partial response was seen in 10, minor response in four. There was also some stable disease, and many of the others going on and having progressive disease. The time to response was about 5 months, and the median duration of response was between 10 and 11 months. These are considered to be durable responses, especially with regard to what we see typically in the setting of high grade gliomas and such an aggressive disease. Out of this, it's interesting to note that in some of the other publications, there were some patients who did not have midline lesions that also responded to Modeyso. On slide 15, this is a waterfall plot. You can see on the left hand side this has to do with the enhancing disease and the changes that we're seeing. On the right hand side, this has to do with the non-enhancing disease. You could see those that have this green coloring that is showing those that had a partial response and those that had a minor response with kind of a lighter green that we see. The percentage of patients who did not have a response and some of them having significant tumor growth. These just indicate that there was significant shrinkage that was associated with the treatment of Modeyso in this patient population. On slide 16 we get to look at some of the other features that could be associated with tumor shrinkage, such as corticosteroid response or improvement in performance status or performance status response. On the corticosteroid side, we have these numbers that there were 15 patients that were evaluable and about 7 of those ended up having a greater than 50% decrease in their corticosteroid dose. This is for patients who are at 4 mg or higher. The time to response was about four months. You can see on the right-hand side, this is a spider plot showing where the corticosteroid doses are decreasing and how long that decrease lasted for. There was also an impact on the performance status that I think is interesting. This includes only patients who have a Karnofsky or Lansky score that is 80 or less. In that setting, we see response rates of about 21% of these 34 patients that were involved for the evaluation. The time to the response was about 3.5 months. On slide 17, we get some insight into overall survival of the totality of the population. This is the full 50 patients that are being evaluated. The median overall survival is 14 months. I think that's interesting because most of the time when you do recurrent evaluations, it's usually less than the newly diagnosed setting. This is around the level of what we would expect, a median survival or even lower in patients who are going to be newly diagnosed. Seeing these numbers is impressive. We get an idea of the percentage of patients, in particular the percentage of patients at 24 months who are still alive. That's 35%. That's an interesting tail on the curve that we're identifying on slide 18. This gives us this heat map. There's a box that exists here. In the box goes through the first 14 patients. Those are the patients who had either a partial response or minor response. What you see is this green clustering occurring because we're looking at not just tumor shrinkage. With Modeyso, we're looking at progression free survival at 6 months and 12 months. We're looking at the performance response, we're looking at the steroid response, and overall survival. You could see how clustered together all the green is in there, showing that it's just not tumor shrinkage, but it's progression free survival, the responses for performance status as well as steroid response and overall survival. On the next slide we get a chance to understand about the safety and tolerability of Modeyso. First we're taking a look at the treatment-related emergent effects. This is in those that are adverse events. These are for those that are occurring in greater than 5% of the patient population. What I usually do is I go over to the right-hand side where it says all grade and I look at patients with at least one treatment-related AE. In every study that I've been involved with, it's almost always close to around 90%. As we go down, we see that these numbers begin to get smaller and smaller. Focusing on grade three, we only have 10 patients who have a treatment-related adverse event. These are really relatively small numbers. We see fatigue, probably something that stands out a little bit. With the grade two and the grade one, the same thing. These are all pretty small numbers that we're seeing. Relatively small percentages of patients are having these treatment-related adverse events. There were no grade 4 and no treatment-related deaths that were reported. On slide 20, we get a more broad look. This is for the serious adverse events occurring in greater than 5% of patients. I think when you have these serious adverse events, there's an evaluation of relatedness. The first thing is that all these serious adverse events were considered by the sponsor to be not related. The investigator thought that there were two patients where they could have been related. One of them was seizure and one of them was pulmonary embolism. You take those out and you look at the rest of these that exist here and you can see that it's a really small percentage of patients that have any kind of treatment-related adverse event. These are brain tumor patients. These are brain tumor patients who are progressing. They're going to have these types of side effects: hydrocephalus, nausea, brain edema, encephalopathy, headache, and those patients who are not seeing a partial response. It's not uncommon to see these kinds of effects occurring. On slide 21, this is where we're looking at all treatment-emergent adverse events that led to discontinuations, reductions, or interruptions. This really is getting at tolerability. How long can patients be on this and not have to stop, pause for some period of time to reduce the dose, or completely stop the dose? What we see is that there's only four patients out of 50, which is a very small number. When you look at all of these different adverse events, if these are happening in four patients, many of these are happening in the same patient. These are the types of effects that might be more related if these are not treatment related. The evaluation that took place said that there was basically only one dose reduction or interruption that was treatment related, and that was related to the pulmonary embolism. Otherwise, there was no discontinuations that were treatment related in any way. The rest of these are probably more related to what we typically see in patients who have primary brain tumors who are in these settings progressing while on therapy. These are the totality of the data that we have at this time that help us understand the benefit of Modeyso in this patient population. Thanks for the opportunity to share this. I'd be happy to answer questions later. At this time, I'd like to turn the call over to Rob. Thanks, Dr. Cloughesy. That was a great overview of the value we believe Modeyso will bring to H3K27M-mutant diffuse midline glioma patients and their families. On slide 23, I will review the data from the new drug application that the FDA based its decision on. An integrated efficacy analysis of 50 patients with recurrent H3K27M-mutant diffuse midline glioma was selected from open-label clinical studies based on prespecified eligibility criteria. These studies were ONC 006, 013, 016, and 018. The overall response rate as assessed by blinded independent central review using Response Assessment in Neuro-Oncology, or RANO 2.0, criteria was 22%. There was one additional responder identified by integrated RANO 2.0. Among those with an overall response, the median duration of response was 10.3 months, with 73% maintaining their response for at least 6 months and 27% for at least 12 months. Among responders, the median time to response was 3.6 months. Turning to slide 24, I'll review the U.S. prescribing information and label. Modeyso is indicated for the treatment of adult and pediatric patients 1 year of age and older with diffuse midline glioma harboring an H3K27M mutation with progressive disease following initial therapy. As the label notes, continued approval may be contingent upon verification of clinical benefit in a confirmatory trial. The ACTION trial will serve as the confirmatory trial and is ongoing. The recommended dose in adult patients is 625 mg orally once weekly, and pediatric dosing is weight-based. For patients who weigh at least 10 kg, Modeyso is administered as an oral capsule. Next, on slide 25, I will review important safety information. The safety of Modeyso was evaluated in 376 adult and pediatric patients with glioma across four open-label clinical studies. Serious adverse reactions occurred in 33% of patients. Serious adverse reactions reported in more than 2% of patients included hydrocephalus 5%, vomiting 4.3%, headache 3.2%, seizure 2.4%, and muscular weakness 2.1%. The most common adverse reactions in patients who received Modeyso in more than 20% of patients were fatigue, headache, vomiting, nausea, and musculoskeletal pain. Overall, Modeyso has been very well tolerated, with only 2.1% of these 376 patients discontinuing Modeyso due to an adverse reaction. Moving now to slide 26, I'll review the next steps in the development program. Accelerated approval was received from FDA on August 6, 2025, which was granted based on the data packet submitted at the end of last year. At approval, Jazz was granted a rare pediatric disease priority review voucher by the FDA. We're thrilled that Modeyso was quickly approved for use in patients who previously had no approved drug options. As mentioned, we have an ongoing phase III ACTION trial to confirm the benefit of Modeyso. ACTION is a randomized, double-blind, placebo-controlled phase III clinical trial evaluating Modeyso in patients with newly diagnosed H3K27M-mutant diffuse midline glioma following radiotherapy. Given the significant need, we are evaluating next steps and potential submissions in markets outside of the U.S. provided the readout of the ACTION trial is supportive, which we expect will be the basis for most international submissions. As outlined on slide 27, the ACTION trial is currently enrolling at more than 95 international sites. An enrollment of approximately 450 patients remains on track with more than 50% of patients currently enrolled. Earlier this year, recruitment at U.S. sites was paused in order to mitigate the potential for confounding in the phase III ACTION study, specifically crossover of patients randomized to placebo which could affect the OS analysis. While recruitment at international sites is going well, we continue to assess timelines for the trial and statements previously made regarding top line data readout for the ACTION trial should no longer be referenced. We will provide an update on anticipated timing as appropriate. We are pleased that Modeyso has been granted Fast Track and Orphan designations in the U.S., Europe, and Australia, recognizing the clinical importance of this medication for this patient population. We believe Modeyso is a significant and much needed advance for patients and we're excited to bring this new therapy to those in critical need. I'd now like to turn the call over to Sam to discuss our commercial strategy. Sam? Thanks Rob. I'll start on slide 29. As previous speakers have highlighted, H3K27M-mutant diffuse midline glioma is a highly aggressive cancer most common in children and young adults, which is lethal and lacks effective systemic therapies. We're delighted to be able to provide a treatment option that confers meaningful clinical benefit to patients. In particular, since no systemic therapies have shown meaningful clinical benefit to date in the U.S., the estimated annual incidence is approximately 2,000 patients to this ultra-rare tumor type. The unfortunate reality for these patients, who are predominantly young children, is a poor outcome with median survival of approximately one year from diagnosis and less than six months after progression following frontline radiotherapy. We believe Modeyso is a significant advance for patients, providing a much-needed treatment option and renewed hope to patients and families facing such a devastating diagnosis. Moving to slide 30, our cross-functional team's depth of engagement with key stakeholders across the neuro-oncology community, including key opinion leaders, healthcare providers, payers, and patient advocacy organizations, has resulted in a highly informed and comprehensive commercial strategy and launch plan, which I'll briefly outline over the next few slides. Given the need to biopsy and test for the presence of the H3K27M mutation and the extremely challenging and difficult-to-reach location of the tumor, we expect Modeyso will be predominantly administered in academic centers of excellence. Our commercial launch strategy will be executed by a highly experienced and dedicated neuro-oncology focused sales team sized to provide appropriate reach and frequency with these key customers. I'm proud of the speed with which our commercial supply chain and regulatory teams have worked together to ensure Modeyso is commercially available to patients in need as quickly as possible following FDA approval. Turning to slide 31, I'll cover our disease education and awareness campaigns. We have a disease education campaign to elevate awareness of and drive urgency for testing in patients with midline glioma. To complement the disease education, we've launched a brand campaign for Modeyso called Head to Hope, for which our goal is to establish Modeyso as a new paradigm in treating H3K27M-mutant diffuse midline glioma. These efforts will be supported by both branded and unbranded campaigns focused on our key messaging, which will be delivered through a suite of both digital media and direct contact. I'm excited about what our teams can achieve and the resources that they have at hand to ensure that we meet our goal of ensuring that clinicians are aware of the availability of Modeyso and the importance of testing to the H3K27M mutation. In addition, we are targeting in person. Engagement with approximately 3,000 HCPs as well as a further 7,000 HCPs through non-personal promotion. This targeted cohort of HCPs can be effectively covered by our specialized neuro-oncology customer-facing teams. On slide 32, I will discuss our high-touch support services for patients and caregivers. Our robust access and patient support services are in place to ensure that patients can readily access Modeyso, help patients navigate reimbursement approvals, and provide patient support through dedicated Jazz resources and the Chimerix Care Suite Observators. The strong cross-functional collaboration across the launch planning provided valuable insights into the needs of patients and caregivers, the support required by HCPs, and the role played by advocacy groups, enabling Jazz to deliver a patient-centric approach. With respect to the distribution of Modeyso, we have exclusive distribution by Onco360, a specialty oncology pharmacy. By working with an exclusive distributor, we believe we can provide a valuable and consistent high-touch patient support program that will provide meaningful benefit to patients treated with Modeyso. We are working with targeted payer accounts covering approximately 80% of commercial and Medicaid lives. Given the very significant unmet medical need and the fact that this disease primarily impacts pediatric and young adult patients, we anticipate strong payer coverage from launch. The Modeyso Wholesale Acquisition Price, or WAC, is $32,000 per bottle. We believe this price reflects the value and innovation this new therapy brings to patients. I'll conclude on slide 33 with some final comments on our launch confidence before handing the call back to Renee for closing remarks. Following FDA approval on August 6th, I'm delighted to confirm that product has been shipped and HCPs in the U.S. have already started to prescribe Modeyso for their patients. By leveraging the specialist expertise of our dedicated neuro-oncology team, backed by Jazz's established expertise in rare disease, we are confident in our ability to successfully commercialize Modeyso. We've hired and trained a dedicated team of approximately 50 full-time employees with sales representatives, field access navigators, thought leader liaisons, and medical science liaisons all working together to ensure we are well positioned to maximize the full potential and patient impact of Modeyso. Our Modeyso sales team will be calling directly on our target prescriber base, predominantly located at academic centers of excellence. Our account reimbursement managers will be working with pharmacy decision makers to ensure confidence in access and reimbursement, and our regional marketing and medical teams will be engaging with thought leaders to build and mobilize advocacy support. As Rob mentioned, our goal is for Modeyso to become the new standard of care, and I have confidence in our teams to deliver on that goal. I'll now turn the call over to Renee for closing comments. Renee? Thanks Sam. I'll close out our prepared remarks on slide 35. The approval and launch of Modeyso exemplifies Jazz's proven capabilities in driving near commercial assets to regulatory approval and commercial launch for rare diseases and oncology medicine more broadly. With the superb cultural fit between the Jazz and legacy Chimerix teams, the successful completion of our integration will only further enhance our ability to innovate and execute and bring novel treatment options to patients. We view Modeyso as a durable and long lived product with patent portfolio protection into 2037 with potential to receive patent term extension. We are excited to continue progressing the ACTION trial while evaluating next steps for markets outside the U.S. This opportunity also drives further momentum in our oncology portfolio and continues our focus of bringing new treatment options to patients and delivering long term value to shareholders. That concludes our prepared remarks. I'd now like to turn the call over to the operator to open the line for Q& A. Thank you. As a reminder to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please limit yourself to one question. Our first question comes from Jason Gerberry with Bank of America. You may proceed. Hey guys, thanks for taking my questions. Just thinking about phase III ACTION trial and how to extrapolate the data that we've seen in the recurrent setting. I guess for the KOL, I'm just curious how to think about maybe the response rate seen in the recurrent setting relative to what you may have expected with no therapy or chemotherapy to drive confidence and read through to the activity of the drug. For the company, as we think about phase 3 ACTION, I do wonder about how the age split is going to look different in ACTION versus the recurrent data set which only had, I think, what, 8% of patients were in the under 18. Just trying to think about the similarity and or the risks of different population dynamics. Thanks. Great. Thanks, Jason. Why don't I have Rob jump in on that first, and then can determine if he wants to have others chime in. Great. Thank you very much, Renee. When I think about ACTION versus the data set that supported approval, I'm actually quite optimistic about ACTION because it's an opportunity to preemptively treat the progression. Much like we rationalized in the IMforte trial, we know this is an active drug, we know it's a very aggressive disease, and ideally treating up front as soon as you can would provide patients with the greatest opportunity for benefit. That's exactly how ACTION is designed. I think while there may be some differences in the age group across ACTION versus what was in the pivotal cohort, we certainly see broad activity of Modeyso. Regardless of the age, provided that they fall within the indication, I don't think that would be a significant challenge. If I could just follow up because it has relevance to how we. Think about pricing what is probably the more representative split of age. When we think about the proportion that are adult versus the weight-based cohort? It's not data that we've provided for the ongoing trial yet, but I would say we're not expecting major differences there. Okay. I would like maybe for Dr. Cloughesy to comment on your question about ACTION upfront, et cetera. Yeah, you know, I very much feel the same way about what Rob said. This has been the case in every neuro-oncology setting where there's been a targeted therapy. The targeted therapy seems to be relatively less effective in the recurrent setting than the frontline setting. We've seen this with IDH mutant gliomas. We've seen this with the use of temozolomide in glioblastoma and tumor treating fields in glioblastoma. Not much effect in the recurrent setting, yet a very clear effect in the frontline setting. Here, it looks like we're doing even better. We have clear evidence of tumor shrinkage and efficacy. I would expect that to be a larger effect size in the ACTION trial than what we're seeing in the recurrent setting. Got it. Thank you. Thank you. Our next question comes from Jess Fye with JPMorgan. You may proceed. Hey, guys. Good afternoon. Thanks for taking our question. Curious about how you think about the average duration of therapy here. If I could just ask, tack on one kind of follow up. Just confirm that the patent here is to 2037 prior to any PTE. Now that we know the approval date, is it possible to calculate and share just like when PTE might take that coverage out to? Thank you. Thanks, Jess. Just to confirm, it does go out to 2037 and stay tuned. I'm sure we'll be updating information on that over time. Rob, do you want to jump in on Jess' other question? Yeah, I mean, maybe the place to start is for those patients who did have an objective response. The median duration of response was 10.3 months, and there was a fairly long ramp up to that effect. You know, three months or so on average to achieve that response. About, as we mentioned in the webcast, 3/4 of the patients continuing a response at 6 months, a little over 1/4 at 12 months. I don't know that we have a specific number on treatment duration in the broader population. That's in part because it's a little bit difficult to predict exactly what that treated population will look like relative to the 50 patients in the pivotal cohort. Great. Thank you. Thank you. Our next question comes from Leonid Timoshev with RBC. You may proceed. Hey, thanks for taking my question. I just want to ask on diagnosis and maybe the size of the funnel, maybe just one related question of that. I guess, given the challenges with diagnosis here, do you have a sense of what% of patients with midline glioma are accurately diagnosed? Are there alternative ways of diagnosis other than biopsies that you're exploring or working with partners on, like CSF testing or PCR testing? Just related to that, given that you said that patients often are treated in academic centers, do you have a sense of what% of patients actually end up in an academic center at some point in their treatment journey? Thanks. Yeah, why don't we have Sam take the first part of that question on the commercial front, and then welcome Josh to provide some input. Yeah, happy to. Thank you, Renee. Yeah, so the population that we're really talking about here is obviously ultra rare. The incident population in the U.S. is 2,000 patients annually. The testing rates are already high in this area, but we would expect to probably drive those even higher, especially now, given the availability of a treatment specifically targeted to this mutation. In relation to the other part of your question, which is around where these patients get treated, our expectation is that the majority of these patients will be referred into academic centers of excellence. Of course, they may well first present in the community, but we would expect the treatment be initiated in academic centers. Yeah, it's Josh, I'll just add to that. I think those two topics Sam just got into there are related. The increasing testing rates are related to advances in neurosurgical techniques that allow for those biopsies that predominantly have expertise housed at academic centers of excellence. There is sort of a natural clustering of these patients due to that phenomenon. What we've seen over time, given that this diagnosis has been part of the WHO diagnostics team since 2016, we've seen an increase in the biopsy rates over time and would expect that to only increase with the educational campaigns that Sam has mentioned. That, of course, with this becoming actionable information in addition to just prognostic information, now that Modeyso was approved. With regards to additional detection techniques that I think you were getting at for CSF and blood, historically, for our clinical trials that fed into this new drug application, all of those required known presence of the mutation to be detected by IHC or NGS testing. We have done some work and have published at the research level on digital droplet PCR, looking at investigations of plasma specimens as well as CSF. At the moment, that is at a research level. Standard of care diagnostics are taking care of the vast majority of patients by a conventional method. I do expect research would continue along the lines of liquid biopsies. Thank you. Our next question comes from Annabel Samimy with Stifel. You may proceed. Hi. Thanks for taking my question. Given this is an underserved and rare aggressive condition and the relative, I guess, ease of administration, how are you thinking about the launch trajectory, and are there current hurdles to adoption other than awareness? Maybe you can just talk about the level of awareness among the neuro-oncologists for this drug. What has been done ahead of the actual launch? Thanks. Annabel, I'll ask Sam to chime in in just a moment here, but I would say there's quite strong awareness of Modeyso's approval just given the significant unmet need and the broad reaching collaboration that took place as part of this program to reach the point we're at now. Sam, do you want to provide more detail? Yeah, I would agree with that, Renee. I think there's been a lot of excitement and anticipation in the prescribing community. This is a really significant advance after, you know, 60 years really of nothing really new, no innovations in this area. The launch of Modeyso has been highly anticipated. We believe awareness is high at this moment. Of course, we'll be working closely with the whole prescribing community to ensure that there is a good understanding about how to get the optimal benefit from Modeyso. As we spoke about just a moment ago, just to make sure that those patients are getting tested so that those with a positive mutation can have the benefit of this treatment. Okay. When you're thinking about the ACTION trial moving into frontline, this isn't really an expansion of the population given that most patients recur. It's really about enhancing the effect. Yes. Rob, you want to jump in and maybe we can also have Dr. Cloughesy weigh in on the prior question in terms of awareness of the drug. Yeah, I certainly think, you know, there are analogies to the IMforte trial. Given such a poor prognosis, it is an opportunity to treat patients for a longer period of time so that they derive a more long lasting benefit. There may well be some patients who, because of the aggressive nature of the disease, don't make it from frontline to second line. I think of it similarly in terms of an expansion in size as well as duration of therapy, going from the current label indication to indication we might have after the ACTION trial. I'd certainly welcome Dr. Cloughesy's view on that as well. Sorry about that. I'll just start with the perceived awareness. Anytime there's an FDA approval in the setting of neuro-oncology, I would say probably 95%- 98% of the neuro-oncologists at least are aware of that approval. We don't have a lot to offer our patients in many different settings. Here we have essentially nothing other than radiation to offer them. These are really dedicated folks. I think there's a huge interest in this and that it's already well known by, as I said, close to 98%. I think it's probably not so much the issue of making sure the neuro-oncologists know about this, but also through the education program that's going to take place to hit the neurosurgeons and the neuropathologists, I'm sure, just to make sure everybody is providing the opportunity for treatment with this targeted therapy. Thank you. As a reminder, please limit yourself to one question. Our next question comes from Andrea Newkirk with Goldman Sachs. You may proceed. Hi, everyone, this is Tolani on for Andrea, thanks for taking our question. Just one quick one from us. To the extent possible, can you elaborate on some of the work you've done to understanding epidemiology and indication and the addressable population? For Modeyso, do you anticipate that all patients would be eligible for the drug every year we should be aware of? Thank you. Yeah, on that one, Josh, perhaps you'd like to make some comments. Yeah, if I heard the question right. It was with regards to EPI around this disease. I would say that this is a disease that was first codified in 2016 by WHO. There's a limited amount of available literature that leads you directly to an answer. Instead, we have to build from a number of diverse sources of data up until EPI estimates. We essentially do that through two different approaches. One is to look at the incidence of the H3K27M mutation based on a histologic basis. In other words, you kind of flip through the encyclopedia of all the histologies present in CNS tumors and then calculate an incidence rate and then add all those up. The second way we do that is really on a structured basis, you could take each structure of the brain essentially and do a similar exercise and add up the number and we get ultimately to a very similar number via either approach. That leads us to the 2,000 patient annual incidence that I mentioned in my prepared remarks for the United States. Unfortunately, in this disease, incidence is essentially synonymous with prevalence given the prognosis of the patients. Thank you. Our next question comes from David Anselm with Piper Sandler. You may proceed. Thanks. Just a quick one for me. Are there any other tumor types, related or otherwise, that you think would be worthy of further exploration of the drug? I know there's some other trials. Including ClinicalTrials.gov that have been kicking around, just wanted to get a sense of the potential for expansion around the beyond the core indication. Thanks. Definitely an active area of investigation. The H3K27M mutation is a marker for hypomethylation, and that ultimately is a tumor driver in this midline glioma population. We're very, very interested in understanding where there might be similar biology where this mechanism could be further exploited. That is a work in progress. We haven't said yet exactly where we would go with that, but we're certainly very interested. I know this is an area that Josh has been working on for a long time. Josh, I would welcome anything else you have to add. I'll just add a little bit of color. You know, there's a remarkable amount of information we've learned from Modeyso over the years. The two novel targets that the molecule sticks to, the number of downstream effects that involve activation of a stress response, effects on metabolites, and effects on the epigenome. We do think, to Rob's point, there could be broader potential here beyond just this one indication. It's an area we're very interested in doing further research on. Thank you. Our next question comes from Mark Goodman with Leerink Partners. You may proceed. Hi, good afternoon. This is Basma on for Mark. Thank you for taking our question. Do you have any plans for filling in OUS? I know you mentioned there's an EMEA plan to file in the EMA. Do you have any other, are you planning to file in any other territories or that's just of European territories for now? Thank you. That's it for us. Yeah, I'll step in on this one. I would say with respect to outside the U.S., we haven't disclosed specific plans. We do have global rights to Modeyso, outside of Japan and China. There is an unmet need more broadly, and as we solidify plans for areas outside the U.S., we'll be sure to keep all posted. Thank you. Our next question comes from David Huang with Deutsche Bank. You may proceed. Hi, thanks for taking my question. Can you just talk a little bit? About the work that you need to do in terms of communicating the value proposition to payers, do you expect any hurdles there, and how fast should we expect the payer coverage to come online? Thank you. Yeah, Sam, you want to jump in on that one? Yes, absolutely. Of course, this is always an important consideration. In developing the value proposition, what's important to note is, as has already been said on this call, that this is a really serious disease. It's a disease that has really, really high unmet need. I think that the value proposition that we're bringing, the innovation that we're bringing, has already been highly appreciated by prescribers and by payers. We're not anticipating any significant hurdles in terms of access. In fact, we know that since the product has been launched, patients are already benefiting from this treatment, which is just great to see. Yes, I think at the moment we're very confident that all patients that need to access the treatment will be able to access it. We've invested in ensuring that we have field teams, field access navigators to really support HCPs and patients to navigate and ensure that any hurdles they do. Experiences are overcome successfully. Thank you. Our next question comes from Joon Lee with Truist Securities. You may proceed. Thanks for the update and for taking our questions. There were several exclusion criteria in the trials. For example, you excluded patients with pontine glioma in the trial. In the real world, would you actually use what they saw in patients with pontine glioma, as long as they have that H3K27M mutation and as it l ooks like even works in patients with non-midline glioma. Thank you. Yeah, I'm happy to take that one. The indication includes all midline gliomas, including the pons using that nomenclature, the DIPG. They would be part of the indication, which of course is age one year and older. Certainly, even though there may be an exclusion for that specifically in the ACTION trial, the indication includes it. Thank you. Our next question comes from Ami Fadia with Needham and Company. You may proceed. Hi, this is Poorna on for Ami. Thank you for taking our question. Just based on your market research, what? What percentage of patients would need to receive surgery versus would be eligible to receive Modeyso? And just another question on the post marketing commitment there is there was an in vitro diagnostic device development. Just curious to understand what is the significance of that development. Thank you. I can go ahead. Sam, do you want to handle the first one and then I'll come back to the in vitro diagnostic? I didn't actually quite catch that first part of that question. If you could repeat it. Just wondering what percentage of patients would be receiving surgery versus would be eligible to receive Modeyso. Surgery is very difficult in these patients because of the location of the tumor. The patients will receive radiotherapy as their first treatment, and then they'll be eligible to, providing they have the requisite mutation, they'll be eligible to receive Modeyso following radiation. Often the surgical procedure is for the purpose of a biopsy, where it's possible to get some debulking. There would be an attempt. Sam's right, this is often not a disease that can be addressed substantially with surgery. I certainly, after I address the in vitro diagnostic question, would love for Dr. Cloughesy to jump in there as well on the in vitro diagnostics. As you know, this is a fairly straightforward mutation to detect and there are a couple different ways to do it. As a part of a post marketing commitment, the FDA has asked for some additional validation work to be done, which will be straightforward and can be based on the ongoing trial that we're doing with ACTION. That's pretty par for the course in a situation like this. Certainly the current label indication and approval is not impacted by that in any way. Yeah. This is Dr. Timothy Cloughesy. Just to address the issues around obtaining tissue, I think in most cases, as has been discussed already, we are able to obtain tissue. It's not enough to debulk. We can't remove a substantial amount, but we could obtain tissue to get the diagnosis. That will occur, I would say, at least in academic practices at around 98%- 99% of the time. Thank you. Our next question comes from Joseph Thome with TD Cowen. You may proceed. Hi there, good afternoon. Thank you for taking my question. The ACTION study does allow for patients with both midline and non-midline diffuse glioma to enroll. I guess first for Dr. Cloughesy, with the refractory indication, would you treat patients that have non-midline tumors? For the company, does the inclusion of the non-midline diffuse glioma patients in ACTION limit any of the translatability between what we've seen so far for the approval and the phase III outcomes? Thank you. Rob, why don't you jump in on the second one and then you can hand it to Dr. Cloughesy. Sure. I think the way we think about this is the mutation and the biology are what predict response to the therapy. The epidemiology is such that it's much more common when these occur in the midline for that biology to be relevant. It doesn't mean that non-midline tumors where the mutation exists and there's a hypomethylation effect, that the biology wouldn't be similar. We think it really follows the biology more than the location, even though the epidemiology is such that it's more common in the midline. I would just say I completely agree with what Rob had said, and I think most physicians would follow the biology. I'm also going to say that patients are getting smarter and smarter in their ability to understand what's available. I don't think a patient would allow me not to suggest this and provide it for them in that setting. Thank you. Our next question comes from Gary Nachman with Raymond James. You may proceed. Hi, this is Steve Harman. I'm on for Gary Nachman. Thank you for taking my question and congrats on the approval from Modeyso. My question is, while Modeyso is a first in class, how is management assessing the competitive landscape and what is Jazz doing to ensure Modeyso maintains leadership both through life cycle management and potential combinations? Thank you for the question. Certainly we're incredibly excited about having closed the Chimerix transaction earlier this year to be able to bring Modeyso into the company and support the launch. This is certainly a product that we would like to build on over time. I think Rob referred to some of our thinking and I'll turn to him in a moment to jump in. When you think about this type of transaction and how it fits within our portfolio, it really strengthens our rare business, particularly Rare Oncology. It has a really meaningful impact for patients that, as we've said today, really have limited to no options. It's a long-lived, durable asset, as we've also talked about. It enables us to leverage the patient support curb assessment services that we've put in place across a number of our products. While we're very interested in continuing to build our capabilities in Rare Oncology and ideally in Neuro-Oncology, we also see a nice connection and leveraging of our current capabilities within the rest of our rare portfolio. Rob, you want to jump in? Yeah. Modeyso really has a unique mechanism of action. There really is no direct competition. It's also a drug that can be given pretty easily, once weekly orally, and has a remarkable safety profile. I don't think about the competition as much, but certainly we are thinking about ways to improve the benefit and to reach more patients. Some of that may involve combination therapies. Some of these patients with glioma may have multiple mutations that are actionable. Example of that would be BRAF. We are certainly thinking about not only moving it to the frontline as in the ACTION trial, but thinking about patient populations where combinations would be of value. Thank you. I would now like to turn the call back over to Renee Gala for any closing remarks. Great. Thank you, operator. To conclude, we are very excited to bring Modeyso to patients with H3K27M-mutant diffuse midline glioma who have been given now new hope with our innovative therapy and this approval. I'd like to thank Dr. Cloughesy for joining us today, sharing his perspective. I'd also like to thank our Jazz and legacy Chimerix colleagues for their unwavering commitment to the program and the laser focus on our launch readiness and being able to get us through these early stages of the launch where we're off to a great start. This is a great example of what we're capable of accomplishing on behalf of patients. I'd also like to recognize the numerous patients and their families who participated in our clinical development program, advocacy groups and scientists who collaborated, as well as the clinical investigators, physicians, nurse site coordinators, and countless support staff for their invaluable contributions to the Modeyso development program. Thank you all for all that you do. We will now close the call. Thank you. This concludes the conference. Thank you for your participation. You may now disconnect.