Good day and welcome to Agios Pharmaceuticals' Investor Conference Call and Webcast. At this time, all participants are in listen-only mode. There will be a question-and-answer session at the end. Please be advised that this call is being recorded at Agios' request. I would now like to turn the call over to Morgan Sanford, Head of Investor Relations at Agios. Thank you, Operator. Good morning, everyone. Thank you for joining us to discuss the FDA approval of mitapivat for the treatment of anemia in adults with alpha or beta thalassemia, which will be marketed under the brand name Aqneusai in the United States. You can access the slides for today's call by going to the Investor section of our website, agios.com. Next slide, please. Please note we'll be making certain forward-looking statements today. Actual events and results could differ materially from those expressed or implied by any forward-looking statements due to various risks, uncertainties, and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. On the next slide, you'll find the agenda for today's call. On the call with me today from Agios, we have Brian Goff, Chief Executive Officer; Dr. Sarah Gheuens, Chief Medical Officer and Head of Research and Development, and Tsveta Milanova, Chief Commercial Officer. Following prepared remarks, we will open the call for questions, for which we will be joined by Cecilia Jones, Chief Financial Officer. With that, please advance to the next slide, and I am pleased to turn the call over to Brian. Thank you, Morgan. Good morning, everyone, and thank you for joining us on this historic day. Next slide, please. I am very excited to announce the FDA approval of Aqneusa as the first and only medicine for the treatment of anemia in both non-transfusion-dependent and transfusion-dependent alpha or beta thalassemia, regardless of transfusion burden. Importantly, maintaining a separate brand name enables us to isolate the Aqneusa REMS to thalassemia, ensuring regulatory clarity and confirming it does not apply to Pyrukynd for PK deficiency. This landmark approval represents a significant advancement for the thalassemia community and a proud moment for Agios. This achievement would not have been possible without the collaboration and trust of the thalassemia community: patients, caregivers, investigators, and advocates, and we are deeply grateful for their partnership. I also want to recognize the Agios team for their significant efforts in bringing this important medicine to patients. Next slide, please. This approval delivers a series of firsts for the treatment of thalassemia, establishing a clear and differentiated value proposition for patients and physicians. Aqneusa is the first therapy indicated for both alpha or beta thalassemia, regardless of transfusion burden. As Sarah will outline, its oral twice-daily dosing offers a far less burdensome alternative to frequent transfusions or subcutaneous therapies. Importantly, Aqneusa is the first disease-modifying treatment for non-transfusion-dependent thalassemia and the first medicine to show quality-of-life improvements in non-transfusion-dependent patients, which we understand to be of critical importance. For transfusion-dependent patients, Aqneusa delivered durable reductions in transfusion burden, as demonstrated for up to 36 weeks in the ENERGIZE-T pivotal trial, a meaningful benefit for patients who may require transfusions as often as every two weeks. This compelling profile underscores both the significant commercial opportunity ahead, which Tsveta will provide more detail on shortly, as well as the transformative potential of Aqneusa. And with that, please advance to the next slide, and I'll hand the call over to Sarah to review the unmet need in thalassemia, summarize the ENERGIZE and ENERGIZE-T pivotal trial supporting approval, and walk through the Aqneusa label. Sarah? Thank you, Brian. We're thrilled about the opportunity to bring a first-in-class pyruvate kinase activator to adult patients with thalassemia, regardless of genotype or transfusion requirements. Before we dive into the Aqneusa label, I'd like to take a moment to highlight the significant disease burden these patients face and the clinical evidence that underpins our regulatory approval. Next slide, please. Thalassemia is an inherited blood disorder characterized by an imbalance in alpha and beta globin chain production, leading to defective hemoglobin synthesis. This imbalance drives ineffective erythropoiesis and chronic hemolysis, resulting in severe anemia and systemic complications. Patients often face significant life-threatening complications, including thrombosis, heart failure, liver injury, and cardiopulmonary disease, which contribute to substantial disease burden and reduced quality of life. Next slide, please. Until now, there were no approved disease-modifying therapies for the broad thalassemia population. Transfusion-dependent patients with beta thalassemia were heavily reliant on chronic transfusions and oral chelators, both associated with significant challenges, including secondary iron overload, compliance, and tolerability concerns. Additionally, treatment with luspatercept requires in-office injections, while gene therapy involves intensive conditioning, limiting access for most patients. For non-transfusion-dependent beta thalassemia, treatment was largely restricted to occasional transfusions and chelations with no meaningful disease modification. Importantly, until the approval of Aqneusa, there were no approved therapies for alpha thalassemia. Therefore, when you consider the historical treatment landscape, there is clear opportunity for Aqneusa to transform care across the entire thalassemia spectrum. As you can see on the next slide, we conducted two global placebo-controlled phase 3 trials, ENERGIZE and ENERGIZE-T, investigating Aqneusa in non-transfusion and transfusion-dependent alpha or beta thalassemia patients, which supported our sNDA filing in the U.S. ENERGIZE, our first trial, enrolled 194 non-transfusion-dependent alpha or beta thalassemia patients. The primary endpoint evaluated the proportion of patients who achieved a hemoglobin response defined as an increase of at least one gram per deciliter or more in average hemoglobin concentrations from week 12 through 24, compared with baseline. Key secondary endpoints measured FACIT -Fatigue scores, average hemoglobin concentrations from week 12 through 24, safety, and tolerability. Our second trial, ENERGIZE-T, enrolled 258 transfusion-dependent alpha or beta thalassemia patients. As reduction in transfusion burden remains the primary treatment goal for patients, we designed our primary endpoint to evaluate a transfusion reduction response, or TRR, defined as at least a 50% reduction in transfused red blood cell units, with a reduction of at least two units over any consecutive 12-week period through week 48. The trial additionally evaluated other transfusion reduction measures in its key secondary endpoints and achievement of transfusion-independent as a secondary endpoint, which was defined by at least eight consecutive weeks without transfusion through week 48. These trials allowed us to assess the benefits of Aqneusa across multiple aspects of thalassemia for both non-transfusion-dependent and transfusion-dependent patients. Next slide, please. In the ENERGIZE pivotal trial, Aqneusa met the primary and key secondary endpoints. 42.3% of patients in the Aqneusa arm achieved the primary endpoint of hemoglobin response, and in these responders, the average increase in hemoglobin concentration from baseline was 1.56 grams per deciliter. This is a highly clinically meaningful result, as an increase in hemoglobin by one gram per deciliter was shown to significantly reduce the risk of adverse morbidity outcomes, as was seen in multiple observational studies that followed patients with thalassemia over multiple years. ENERGIZE also showed a statistically significant improvement in FACIT-Fatigue scores in non-transfusion-dependent patients, where there was a change of 4.85 points in the Aqneusa arm compared with 1.46 points in placebo. This was the first trial to show improvement in quality-of-life measures for non-transfusion-dependent patients. Aqneusa demonstrated improvement in hemolysis indicators, such as indirect bilirubin and LDH, addressing a key contributor to organ damage. Next slide, please. In our second trial, ENERGIZE-T, treatment with Aqneusa reduced transfusion burden across transfusion-dependent alpha or beta thalassemia patients. Specifically, 30.4% of patients in the Aqneusa arm met the primary endpoint of transfusion reduction response. Aqneusa demonstrated statistical significance across all three key secondary endpoints, which further evaluated transfusion reduction. Lastly, we were pleased to see that 9.9% of patients in the Aqneusa arm achieved transfusion-independence, meaning these patients were transfusion-free for eight or more consecutive weeks. In addition, as seen on the next slide, adverse reactions that occurred at a higher incidence in the Aqneusa arm compared to placebo included headache and insomnia. Next slide, please. We're very pleased with the final label for Aqneusa, supporting broad use across all adult thalassemia patients, regardless of genotype or transfusion burden. The label describes Aqneusa's novel mechanism of action as a pyruvate kinase activator, as well as its oral administration, representing two of the novel attributes of this medicine for the treatment of thalassemia. Next slide, please. Aqneusa's label has an associated risk evaluation and mitigation system to mitigate for adverse reactions suggestive of hepatocellular injury following observation in five patients across the ENERGIZE and ENERGIZE-T pivotal trials. On the left-hand side of the slide, you see an excerpt of the warnings and precautions language detailing the adverse reactions observed in the five patients. Each of these adverse reactions occurred within the first six months of exposure, and liver tests improved upon discontinuation of Aqneusa. To date, there have been no HCI cases in other indications following the same pattern as was seen in the thalassemia pivotal trials. The final label details requirements of the REMS program, including physician, patient, and pharmacist education and certification, a common element of many REMS programs, as well as liver testing at baseline and every four weeks for the first 24 weeks of treatment and as clinically indicated thereafter. This liver monitoring requirement is consistent with current language in Pyrukynd's PK deficiency label. This proposed REMS is unique and distinctive, requiring liver monitoring only for the first six months and then as clinically indicated, adding complexity and time to the regulatory review process. Additionally, as is common when a REMS is implemented, the label includes a black box warning for potential serious hepatocellular injury, advising against using patients with cirrhosis and recommending discontinuation if hepatic injury is suspected. In our discussions with KOLs and treating physicians, this type of black box warning is consistent with expectations for medicines requiring a REMS and does not present additional hurdles for prescribing. We believe the label appropriately reflects the clinical data we have demonstrated to support Aqneusa approval, as well as adequate monitoring for safety concerns. We are thrilled to deliver a first-in-class medicine to address critical care gaps in the treatment of thalassemia. Please move to the next slide, and I'll turn the call to Tsveta to review the commercial launch strategy. Thank you, Sarah. Next slide, please. As demonstrated by the ENERGIZE and ENERGIZE-T pivotal trials, Aqneusa's value proposition is firmly grounded in robust clinical evidence. In market research with treating physicians on the clinical profile, Aqneusa was consistently rated highly across key attributes valued in a novel thalassemia therapy. Notably, 86% of surveyed physicians indicated they plan to prescribe Aqneusa within six months of availability based on clinical profile. Following the PDUFA goal date extension, we engaged with both KOLs and targeted HCPs with actively managed patients to gather insights on prior REMS experience. KOLs have strong familiarity with REMS programs and therefore did not view REMS for Aqneusa as a prescribing barrier. Among community physicians where most thalassemia patients are treated, 94% of hematology oncologists reported prior REMS experience. Additionally, about two-thirds of HCPs anticipated no to minimal impact from REMS at launch. Next slide, please. We have executed a capital-efficient global commercial model, maintaining full economics and strategic focus in the U.S., which represents the largest commercial opportunity. In the U.S., there are 6,000 diagnosed, actively managed adult thalassemia patients. We have been able to verify this number through claims data and a comprehensive account profiling by our field teams. At launch, our initial addressable population is roughly 4,000 patients. This segment includes patients receiving transfusions and chelation therapy, older patients with comorbidities, and individuals with hemoglobin levels at or below 10 grams per deciliter who experience anemia-related complications and fatigue. Next slide, please. We remain sharply focused on executing a successful launch of Aqneusa for thalassemia. This work is already well underway, driven by initiatives to raise disease awareness and understand more deeply the thalassemia treatment landscape. Through these efforts, we have developed a refined national target list of HCPs who are eagerly awaiting novel treatment options. The additional time from our previous PDUFA goal date in September has allowed us to deepen engagement with physicians, building familiarity with REMS requirements, and strengthening patient and provider support services to streamline access. We are confident that we have the right infrastructure in place to ensure appropriate patients can start and stay on treatment with ease. Our ambition is clear: to establish Aqneusa as the standard of care for thalassemia, anchored by its unique value proposition and ability to address clinically critical treatment gaps. Please move to the next slide, where I will provide more detail on how to think about the initial Aqneusa launch curve. With the final label in hand, we can implement the final administrative processes of the REMS program, with the aim of making the REMS fully operational in late January. Until then, no Aqneusa prescriptions can be fulfilled. Between now and late January, our field teams will work towards educating physicians and patients on the REMS, as well as generating prescription demands. From late January, the initial phase of adoption will be gated both by HCP REMS enrollment and the frequency of patient visits, which will likely determine completion of baseline liver testing required for REMS certification. In the initial quarters of launch, we expect the time between prescription and treatment initiation will be roughly 10-12 weeks. As prescriber enrollment accelerates and patient onboarding gets to a steady state, we expect prescription volume to more closely track end patient revenue. Finally, we anticipate early skew toward transfusion-dependent patients, given their higher frequency of provider interactions. Over time, we expect the mix to shift toward non-transfusion-dependent patients who represent over two-thirds of the total thalassemia population. Next slide, please. Given the significant unmet need and Aqneusa's compelling value proposition, we see potential for it to become the standard of care for thalassemia. As Brian mentioned, this launch represents a series of firsts for the treatment of thalassemia, addressing broad patient population for the first time in the treatment of this rare disease. The market opportunity is meaningful, with approximately 4,000 addressable patients at launch: diagnosed, managed adults living with both non-transfusion-dependent and transfusion-dependent alpha or beta thalassemia. To capture this opportunity, we have approximately 40 dedicated sales representatives ready to go and have identified and refined a validated list of target prescribers. Engagement with HCPs will begin now to ensure smooth onboarding where possible ahead of Aqneusa availability in late January. Aqneusa will be introduced at approximately $425,000 per patient per year on a WAC basis, reflecting its differentiated benefit and value to the healthcare system in addressing critical gaps in thalassemia care. Our marketing and medical affairs teams have executed best-in-class disease awareness campaigns, driving strong engagement from both treating physicians and patients across transfusion and non-transfusion segments. Complementing this, our myAgios Patient Support Program is designed to facilitate access and provide comprehensive support throughout the patient journey. With that, I'll turn back to Brian for closing remarks. Next slide, please. Thank you, Tsveta. Next slide, please. In closing, the achievement of this historic approval reinforces our corporate priorities. First, we're focused on maximizing the value of mitapivat. With the thalassemia label now in hand, we'll work to implement final administrative elements of the REMS program with the aim of making Aqneusa available in late January. In the meantime, the field team will work to educate physicians and patients on the REMS and focus on generating prescription demand. Additionally, we look forward to engaging with the FDA in the first quarter of next year to review the phase three RISE UP data of mitapivat in sickle cell disease and determine the regulatory path forward. Second, we'll continue to advance our mid and early-stage pipeline, creating additional optionality within and beyond our foundation in non-malignant hematology. Critical steps towards achieving our goal of building a sustainable rare disease company. Finally, we remain committed to disciplined financial management. Early next year, we'll provide an update on proactive measures to reduce operating expenses and extend our cash runway while still ensuring appropriate investment behind the U.S. thalassemia launch. Our goal is clear: to become a sustainable rare disease company. This starts with delivering first on our core foundation in hematology, and we are executing with that objective in mind. With that, I'd like to now open the call for questions. Operator, please open the line. Thank you. At this time, we will conduct a question-and-answer session. As a reminder, to ask a question, you will need to press star 11 on your telephone and wait for your name and company name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. And our first question comes from Samantha Semenkow from Citi. Your line is now open. Hi, good morning and happy holidays. Congratulations to the team for the approval. I just wanted to follow up a little bit. Can you speak a little bit more about the physician target list that you've generated? I'm wondering how many physicians are in that list and what proportion of those 4,000 addressable patients are managed by these physicians? Thanks very much. Yeah, thanks a lot, Sam. I'm going to have Tsveta take that question, and we won't do so much quantification, but I think we can answer your question with a good qualification about the work we've done and generally the types of physicians that we'll be targeting first. Tsveta, you want to take that? Absolutely. Thanks, Brian and Sam, for the question. As Brian mentioned, we're not going to be giving specific numbers of physicians, but what I want you to keep in mind is that the team has done a very comprehensive launch preparation and physician targeting for us to get ready and execute on a successful launch. The initial target physician will focus on two groups of physicians. These are the KOLs who are experts and manage thalassemia patients, as well as HCPs who have thalassemia patients and have indicated their patients are likely to benefit from a novel therapy. So now, when we have the approval, the team will be trained, and they'll be able to engage with those physicians immediately to educate on the product profile and educate on the REMS. When we think about the initial launch trajectory, I want to stress that we don't expect dollars at the beginning of the launch, and that's driven by two things. The first, as we've mentioned in the past, thalassemia is not an imminently life-threatening disease, but also, as we mentioned on the call today, Aqneusa, due to the REMS implementation, will not be available until late January, so initially, at the beginning of the launch, we'll see the prescriptions and the demand generation, but there'll be lag between the prescriptions and the actual revenues at the initial quarters of the launch, and over time, as the processes get smoother and more physicians get certified, we will expect the revenues and the demand to align closer with one another. One final thing is, as you would expect, initially, we would expect out of the 4,000 patients, the transfusion-dependent patients, which are about half of them, to initiate therapy first. And this is because these patients are actually more engaged and have more frequent interactions with the healthcare system. But over the course of the launch, we would expect the proportion of non-transfusion-dependent patients to increase, given that two-thirds of the 6,000 patients are actually non-transfusion-dependent. Very helpful. Thank you. Thank you. Thank you. And our next question comes from analyst Gregory Renza, of Truist Securities. Your line is now open. Great. Good morning, Brian and team. Happy holidays as well, and congrats on the great news. Brian, maybe just with respect to the outcome here on the label and also the details on the REMS program, in light of just the extra time that was utilized by the FDA and for you, your reference of being highly engaged with the agency over the last several weeks and, of course, over this filing, could you just comment a bit about how you're viewing where you all landed up on the label and the REMS program, how it sort of fits your expectations, and what maybe has evolved over the last several weeks to the last few months with the extension that brings you to where you are today? Thanks so much. Yeah, sure, Greg. I'm going to let Sarah tackle that question. I will say I am very proud of the Agios team for the constructive engagement that we've had throughout. This is, as I think folks know, it's been a journey to work through the two very well-controlled, very impressive studies that back up the label. We're pleased with the outcome, but I'm going to let Sarah speak about the journey to get here and her thoughts ahead. Thanks, Greg. So I think, well, as you know, the REMS request came relatively late in the original review. I think once that occurred, we were able to really work collaboratively with the agency to get to this finish line. And I'm actually very proud of the outcome of the label because it truly reflects the data, both for efficacy but also on the safety side. Again, on the efficacy side, very happy to be able to deliver Aqneusa to all thalassemia patients independent of their transfusion need and genotype. So I think this is really a reflection of the rigor of the trials, the patient population involved, and ultimately, that translates into a label for everyone. And then, as it relates to hepatocellular injury, I'm also actually very proud of that language. It completely reflects the data that we've observed with the cases occurring in the first six months, as we had highlighted before. It also highlights that the monitoring indeed can be restricted to the first six months, so once a month for the first six months, which we believe is also a perfect reflection of the data, and I think the REMS reflects that as well. So I think we've landed in a great spot altogether in a very collaborative way, and again, this highlights the goal both on the FDA side and on our side to deliver safe and effective therapies to patients. That's fantastic. Thank you, Sarah, and congrats again. Thank you. Our next question comes from the line of Eric Schmidt from Cantor. Your line is now open. Good morning and my congratulations as well. Quite the achievement, many firsts for patients. My first, once the REMS program is in place in late January, Tsveta, I was hoping you could just sort of walk us through what actually has to happen from the time a start form is in place to shipping the drug to patients, specifically with regard to the steps that the REMS provider and pharmacist and patient need to go through. And then the second question would be on pricing. I noticed there's a lot of price discrepancy relative to the price of mitapivat in PKD. How do you police that or ensure no contamination across price utilization? Thanks. Thanks, Eric. Tsveta, you want to get started with the REMS process? Absolutely. So the REMS encompasses three steps. The first one is that the pharmacy needs to be certified. In our case, we have a single specialty pharmacy, so that will require one certification for the pharmacy. So that will be one time and one pharmacy. The second step is the physician certification, which requires education on the REMS and then being certified. It is important to note that once the physician is certified, the physician does not have to be certified again. And the third aspect is going to be the patient certification. The patient certification will require the patient to complete a liver test before they become certified. Once the three steps of the process for the REMS are completed and the patient has gone through their prior authorization aspect with the payers and their insurance company, then the drug can be dispensed by the pharmacy at that moment in time. The team is very well positioned to handle all of the steps. As I mentioned, at the moment, we're just working through the administrative steps of the process to ensure that the drug is going to be available in late January. But we are in a great place to start executing on demand generation immediately. On the second aspect of the pricing, both Pyrukynd and Aqneusa are priced within the rare disease price band. Both of the products reflect rare diseases with diseases which are representing a high unmet need and a strong value proposition. When it comes to Aqneusa, as we mentioned, that price is reflective of the strong data and the fact that it is the first therapy to address the totality of the thalassemia patient population. Given that both products are distributed through a single pharmacy at two different brand names, and we'll be able to ensure that patients actually receive products on label, and from a payer perspective, these are rare diseases, and we don't expect either of the categories to be managed, so we have a very strong market access team, and I'm very confident we can execute on the Aqneusa's launch successfully and continue to support Pyrukynd for PK deficiency patients as well. Thank you very much. Thanks, Eric. Next question comes from the line of Alec Stranahan of Bank of America. Your line is now open. Hey, guys. Thanks for taking our questions, and congrats from us on the approval. Really, really great to see. Maybe two quick questions on just the launch dynamic piece, and then I've got a follow-up. I guess, as we're modeling the launch, should we assume initial sales will likely happen in Q2 with little to none in Q1, just given the lead time on the prescription to dose? And I guess, would you say the normalization on the new start to dosing could happen this year, or is this more of a 2027 aspect for the launch? Yeah, thanks, Alec. I think this is a good opportunity for Tsveta to take a break, and Cecilia can comment on revenue expectations here. Yes, thanks, Alec. So in terms of the initial quarter, so as Tsveta mentioned, we have to finish implementing the last steps of REMS, and that would happen late January. What will happen probably in Q1 is you will see some initial orders coming in in order to stock as well because, as Tsveta mentioned, this is a different brand, different dose than we have. So we'll have some shipments going in, and we do expect some prescriptions to be fulfilled as well in Q1. And then on your second question, as Tsveta mentioned, at the beginning, there will be prescriptions go ahead of revenues in a way. And I think we'll see that probably towards the later part of the year or early next year start to be more aligned with revenues as well. Okay. That's helpful. And then maybe one quick one on sickle cell. I guess, given you haven't seen the similar levels of liver AEs in RISE UP, I'm curious how you think about potential labeling if you were to seek, say, a conditional approval here. Do you think there's a path to getting sickle cell added to the PYRUKYND label where there's no black box? Thank you. Sarah, you want to take that one? Sure. So thanks, Alec. So first of all, it's important for us to go engage with the FDA on this in our pre-SNDA meeting in Q1. Of course, as you highlighted yourself, the data has not shown any hepatocellular injury cases in sickle cell disease like what we've seen in thalassemia. So that is what we will be walking the agency through and highlight what we believe is the right path. But as always, it will be a matter of review. Again, our assessment is that we have not seen any HCI in sickle cell disease. And so therefore, we believe there may be a path following pyruvate kinase deficiency. All right. Thank you, and congrats again on the approval. Thank you. Thanks, Alec. Thank you. Our next question will come from the line of Marc Frahm from TD Cowen. Your line is now open. Hi. Thanks for taking my questions and congrats on the approval. Maybe just following up on a few of the other questions. Just given there's maybe a bit of a disconnect between prescription demand and the ability to book revenue, at least in the early stages, just will you be providing the TRX volumes as part of your kind of quarterly reporting? Are there other metrics kind of along the certification process that you think are particularly key for investors to be tracking the progress of the launch? And then related on the pricing question, just if you are successful in getting the FDA to ultimately agree to a sickle cell label based on the data, would this branding allow you, you think, also to keep a differentiated price for sickle cell that could potentially be even a bigger gap than the Pyrukynd pricing gap right now? Yeah. Thanks, Marc. Let's do two parts here. Cecilia can take the first one in terms of launch metrics. And then it's premature to say anything about pricing with sickle cell disease at this point, but Tsveta can comment on the approach. Cecilia, you want to start? Yes. Thanks, Marc. So our plan for next year, so with each quarter, we plan to share Aqneusa prescription volume. And then from a revenue perspective, we plan to show mitapivat aggregate revenues, and we will split between U.S. and ex-U.S. Great. And Tsveta? So we are excited about the opportunity and the potential to engage with the FDA on the sickle cell disease filing in early 2026. When it comes to pricing, as Brian mentioned, we'll look at the time of approval at the label. We'll look at the competitive space, and we'll make the right pricing decision at the time. It's a little bit premature for now to comment, but different brand names provide different optionalities. And again, I'll just reinforce, Marc, that we are pleased with the fact that this novel approach of having two different brands has really given us the opportunity to align the value that we see with thalassemia and the price. And of course, as we've already noted on this call, that's distinct now from PKD. So certainly pleased with the position that we're in. Okay. Thanks for the topic, and congrats again. Thanks a lot. Thank you. And our next question will come from the line of Emily Bodnar of H.C. Wainwright. Your line is now open. Hi. Good morning. Thanks for taking the questions, and congrats on the approval. I guess first one, if you could comment on how long that process for the REMS certification takes with the three elements that you discussed? And also curious on how common liver issues such as cirrhosis are in thalassemia patients? And then maybe if you can comment on ex-US launch process with some of your partners and how we should be thinking about that ramp-up? Thank you. All right. Thanks, Emily. So we'll batch together two of your questions, which are commercially oriented. And I'll ask Tsveta to comment first on the process for REMS certification. And maybe I'll expand the question a little bit, not so much for REMS itself, but the process from prescription all the way to treatment initiation, which Tsveta can comment on. And then Tsveta talk a little bit about ex-US and our partners, and then we'll turn it over to Sarah for thalassemia and incidence of cirrhosis. Absolutely, so as we mentioned on the call, we expect initially the time from prescription to treatment initiation to take about 10-12 weeks. As Brian mentioned, this is driven by two things. The first one is the time it takes for the patient to complete the prior authorization with the insurance company. That's a highly variable process and really depends on the patient insurance, but that could take a month or even longer for some of the patients, and the second gating factor from prescription to initiation is going to be completing the REMS process, which has three elements: the physician certification, as we mentioned, the pharmacy certification, which will happen once at the beginning, and the patient certification. From a patient certification perspective, they'll need to complete the liver test ahead of dispense. Our initial assessment initially that will take 10-12 weeks with the goal of shortening that time as more physicians get certified. I'll just remind you again, physicians need to get certified only once, and then they can prescribe the drug with the REMS. Of course, as the patient onboarding process gets to a steady state, we'll be looking to shorten the time as we progress with the launch. When it comes to the ex-US, we are very excited that we have an approval in KSA, which came in August of this year. Both Europe and the Gulf countries have a delay between actually initial approval and where we expect to see revenues. When it comes specifically to the Gulf countries and KSA, that's driven by the fact that after you have an approval, the initial prescriptions come on a nomination basis, and these prescriptions need to be approved by the individual hospital, and budgets need to be allocated to these prescriptions. As the prescribing volume increases, then the national procurement process can start, and that can open access significantly. That process can take about two years. So initially, in the Gulf countries and KSA specifically, we would expect a very slow demand generation and revenues then accelerating after the national procurement process is complete. When it comes to Europe, after we have the approval by the EMA, and as we said, we expect an EC decision on the label for thalassemia early 2026, then we'll need to go through the individual country pricing and reimbursement processes, which can take 12 to 18 months themselves, and after that, once the product is available in the individual markets, we'll see revenues, so in that case, we wouldn't expect revenues coming from Europe early in 2026, if not even 2027. Thanks, Tsveta. And then Sarah, over to you just for the second part of Emily's question about cirrhosis and how common that is in thalassemia. Sure. So the natural history data of thalassemia, I think there is one publication that just recently came out that highlights in a cohort that was followed over 38 years about 25% of patients ended up having cirrhosis in that untreated cohort. And this is where, of course, we have to remind ourselves that the cirrhosis typically comes because of iron overload in this condition in which patients get iron overload, secondary iron overload just because of transfusions, and of course, primary iron overload from dysregulated iron metabolism plus hemolysis. And this is where we're excited that now mitapivat actually has shown that it reduces hemolysis as shown by a positive impact on bilirubin and LDH, and we have the transfusion reduction. So hopefully, these are two of the main sources of iron overload that we can tackle with this drug for thalassemia patients. Hopefully, in the long run, that also leads to similar observations that we have seen in PKD with an improvement on iron overload. Thanks, Sarah. Great. Thank you. Thank you. And our next question will come from the line of Salveen Richter of Goldman Sachs. Your line is now open. Hi. This is Salveen Richter. Thanks for taking my question, and congratulations on the approval. Could you comment on the path of getting from this 4K addressable population at launch to the 6K target TAM in the longer term and the expected drivers of growth that you believe will contribute to this? Yeah. Sure. Tsveta had commented a little bit in her prepared comments, but maybe Tsveta would put a little more color on that bridge from the 4,000 target thalassemia patient population and longer term, the broader 6,000 adult patients in the U.S. Absolutely. So in the U.S., there are 6,000 diagnosed and actively managed patients with thalassemia. And we've been able to verify that number from the claims data and our extensive account profiling at launch. From these 6,000 patients, we have prioritized 4,000 patients for our initial launch focus. And these patients constitute the patients who are transfusion-dependent patients as well as non-transfusion-dependent patients who have already developed disease complications or are living with very low hemoglobin levels at about 10 or below 10 and are experiencing severe fatigue and are looking for additional therapies to help them manage their disease. When we think about the initial launch trajectory, we would expect the transfusion-dependent patients to consider and initiate therapy first, and that is primarily driven by the fact that these patients are in regular frequent interactions with the healthcare system. So they are more likely to actually have the conversation with their physicians and initiate therapy first. Over the lifetime of the product and the launch, we would expect the proportion of non-transfusion-dependent patients to increase, starting with the more symptomatic non-transfusion-dependent patients who are currently actively looking to actually improve the management of their disease and are actively looking for new treatment options. And as the launch progresses, we will expand beyond the 4,000 addressable to the 6,000 patient population because ultimately all of the 6,000 patients are on label. As we mentioned in the call, we have a broad label for thalassemia, which includes patients who are transfusion-dependent, patients who are non-transfusion-dependent, and patients who are with alpha or beta thalassemia as well. Thanks, Tsvetaa. Thank you. And our final question comes from the line of Luca Issi of RBC Capital Markets. Your line is now open. Good morning, team. Hi. This is Kasia for Luca. Congratulations on the approval. We have a question for the launch as well. On luspatercept, it generated $117 million and $224 million in revenue in year one and year two post-launch in thalassemia alone, according to Evaluate Pharma. Is that the right comp for us to think about as we think about revenue for Aqneusa in 2026 and 2027, or would you advise us against that comp? And if you can also maybe speak to the alpha versus beta thalassemia breakdown in your 4,000 initial targeted population, that would be much appreciated. Thank you so much. Sure. So two-parter there, and we're keeping Tsveta joyfully busy today with all these commercial questions. Tsveta first, maybe a commentary on why luspatercept, we believe, is not a compelling analog, and then we can talk about alpha versus beta. Absolutely. I wouldn't use Reblozyl as a comparator here for two reasons. The first one is the company did not formally split the revenues between thalassemia and MDS. The only thing that they have commented on is that the majority of their revenues are coming from MDS. So I wouldn't know if the Evaluate Pharma estimate for the indication split is accurate or not. The second thing that we want to stress is the fact that Reblozyl actually has a very low penetration in thalassemia, and that's driven by two things. The first aspect is the fact that Reblozyl has a narrow label. They focus only on transfusion-dependent beta thalassemia patients in the U.S. and do not cover the rest of the patient population. The second, what we've heard from treating physicians is the fact that even though a lot of the patients were eager to try Reblozyl, a lot of the patients actually opted out of continuing to stay on therapy with Reblozyl for thalassemia, driven either by lack of efficacy or the fact that the product is administered in the physician office every three weeks, which significantly increases the treatment burden for the patients. They opted out not to stay on therapy. When you think about the 4,000 patient population that is our initial launch target, 50% of these 4,000 patients, they are transfusion-dependent patients. The majority of the transfusion-dependent patients are beta thalassemia patients. When you think about it, around 2,000 of those will be transfusion-dependent beta thalassemia patients. The non-transfusion-dependent patient population within the 4,000 is a mix between alpha and beta thalassemia. That mix varies actually by region. For example, you see more alpha thalassemia patients in areas where it's like New York or LA, where you have a lot of Asian patient population versus other parts of the country. It's a mix of symptomatic non-transfusion-dependent alpha and beta thalassemia patients. Thank you. I would now like to turn the call back over to Brian Goff for closing remarks. Thanks, Siobhan. And thank you all for your thoughtful questions and for joining us today, especially during the holiday season. I really love the fact that we had a lot of commercial questions, which I think speaks to recognition of the size of this opportunity in front of us. The FDA approval of Aqneusa is clearly a landmark moment for both the thalassemia community and for Agios, and it has been truly heartening for us to have heard from many thought leaders and thalassemia advocacy leaders just in the past few hours since they read the news. As noted, we expect the REMS program to be fully operational in late January. And as Tsveta has said a few times, our teams are already working diligently to ensure a seamless start for physicians and patients. Looking ahead, we're energized by the opportunity to deliver this first-in-class medicine to thalassemia patients in the U.S., and we look forward to keeping you updated on our progress, so on behalf of the entire Agios team, thank you very much for your continued interest and support, and we wish for you a wonderful holiday season. Thanks a lot. Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.