Good morning, welcome to Agios fourth quarter and year-end 2022 conference call. At this time, all participants are in a 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 Jessy Rennekamp, Senior Director of Corporate Communications. Please go ahead. Thank you, operator. Good morning, everyone, welcome to Agios fourth quarter and year-end 2022 conference call. You can access slides for today's call by going to the investors section of our website, agios.com. With me on the call today with prepared remarks are Brian Goff, our Chief Executive Officer, Dr. Sarah Gheuens, our Chief Medical Officer and Head of Research and Development, Tsveta Milanova, our Chief Commercial Officer, and Cecilia Jones, our Chief Financial Officer. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of 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. With that, I will turn the call over to Brian. Good morning, everyone, and thank you for joining us. Agios is the pioneering leader in PK activation and is dedicated to developing and delivering transformative therapies for patients living with rare diseases. Driven by the cross-functional commitment of the Agios team, we made tremendous progress over the past year toward our goal of building a PK activation franchise focused on hematologic diseases that share a common underlying pathophysiology, limited treatment options, and profound unmet need. In particular, I'd like to highlight the excellence in execution displayed across our research and development team to bring forward PYRUKYND, our first-in-class PK activator, as the first and only approved disease-modifying therapy for adults living with PK deficiency. PYRUKYND was approved in the U.S., EU, and Great Britain in 2022 and represents the cornerstone of our growing PK activation franchise with the potential for two additional indications by 2026. In parallel with these approvals, we made significant advances across our broader clinical-stage pipeline, including our five ongoing pivotal studies, and met the ambitious clinical development targets we outlined at the beginning of last year. Notably, we continue to generate consistent and compelling data with our PK activators across multiple disease areas, highlighting the potential of this differentiated mechanism of action to transform patient function, quality of life, and long-term outcomes in not only PK deficiency, but also thalassemia, sickle cell disease, and lower risk MDS. In 2022, data across our clinical portfolio were presented at major medical meetings, including the annual meetings of the European Hematology Association and the American Society of Hematology, and were published in top-tier medical journals, including The Lancet and The New England Journal of Medicine. Following the third full quarter of the launch of PYRUKYND in PK deficiency, we continue to be encouraged by the positive reception from patients, physicians, and payers and the impact PYRUKYND is having for a community that previously had no treatment options. As we've said in the past, we continue to believe that this launch will be slow and steady and will provide a capability-building platform to support potential expansion in meaningfully larger patient populations. That said, our ambition is to improve the launch trajectory and realize the full potential of the opportunity we have in front of us. To that end, in December of last year, we appointed Tsveta Milanova as Chief Commercial Officer. Tsveta is a seasoned commercial leader who brings deep expertise in launching and commercializing medicines in rare diseases and hematology, with a particular focus on global market access and operations. Her experience and leadership will be critical as we continue to strengthen our commercial capabilities in order to both maximize the potential of the current launch in PK deficiency and prepare for potential future launches in thalassemia and sickle cell disease over the next few years. We ended 2022 in an enviable cash position with approximately $1.1 billion on the balance sheet. This includes the one-time payment we received in the fourth quarter of 2022 following the sale of our royalty rights on U.S. net sales of TIBSOVO to Sagard. We expect our cash position to support the completion of our ongoing programs, as well as enable us to expand our portfolio beyond PK activation through disciplined business development and the advancement of our earlier stage pipeline. We anticipate significant progress on each of these objectives in 2023. Specifically, in the middle of this year, we expect to complete enrollment of the phase III ENERGIZE and ENERGIZE-T studies of PYRUKYND in thalassemia and announce the data readout of the phase II RISE UP study of PYRUKYND in sickle cell disease and the go, no-go decision to phase III. By the end of the year, we expect to enroll more than half of the patients in the phase III ACTIVATE-Kids and ACTIVATE-KidsT studies of PYRUKYND in pediatric PK deficiency, complete enrollment of phase II-A study of our novel PK activator, AG-946, in lower risk MDS, and file the IND for our PAH stabilizer for the treatment of PKU. Throughout the year, we aim to continue to strengthen our commercial capabilities through our ongoing launch in PK deficiency and continue to evaluate BD opportunities to expand the pipeline. Looking forward to 2024- 2026, we anticipate a catalyst-rich period with the potential for two additional PYRUKYND indications in this time frame. Specifically, in 2024, we're expecting the readouts of the phase III studies of PYRUKYND in thalassemia, as well as the readout of phase II-A study of AG-946 in lower risk MDS. In 2025, we're expecting the potential approval of PYRUKYND in thalassemia, as well as the phase III readouts of PYRUKYND in sickle cell disease and pediatric PK deficiency. In 2026, we're expecting the potential approvals of PYRUKYND in sickle cell disease and in pediatric PK deficiency. With this slate of potential near-term catalyst, I look forward to a productive year as we work toward our 2026 vision of Agios, an established hematology franchise with approval spanning three hemolytic anemias, an expanded portfolio fueled by business development, and advancement of our internal pipeline that is aligned with our core expertise in rare disease and cash flow positivity. With that, I'll now turn the call over to Sarah. Thanks, Brian. In 2022, our research and development organization made significant progress advancing our PK activator development programs across multiple disease areas, united by the shared underlying pathophysiology of red blood cell metabolic stress. Representing the largest data set generated for any PK activator, the consistent and compelling data we have generated to date with PYRUKYND in PK deficiency, thalassemia, and sickle cell disease highlight the potential for PK activation to correct red blood cell metabolism and transform patients' function, quality of life, and long-term outcomes in each of these disease areas. The most recent data updates across our clinical portfolio were presented at ASH in December, where Agios and our external collaborators were pleased to present a total of 22 abstracts. These included long-term data from the phase II study of PYRUKYND in thalassemia, demonstrating durable improvements in hemoglobin and hemolysis, and stabilized or improved erythropoiesis and iron homeostasis over 72 weeks in patients with alpha or beta non-transfusion dependent thalassemia. In PK deficiency, we presented updated long-term extension data demonstrating that adults treated with PYRUKYND exhibited sustained improvements in hemoglobin, iron overload, transfusion burden, and patient-reported outcomes regardless of transfusion status. We presented new data from the phase I study of our novel PK activator, AG-946 in healthy volunteers, which showed a favorable safety profile at pharmacologically active doses and a PK profile supportive of once-a-day dosing. Taken together, the clinical data we have generated to date suggests that PYRUKYND's differentiated mechanism of action is correcting red blood cell metabolism and leading to consistent improvements in hemoglobin, hemolysis, and erythropoiesis. With that context, let me now provide a brief update on the PYRUKYND development programs, beginning with thalassemia. As a reminder, the phase III program of PYRUKYND in thalassemia comprises two randomized placebo-controlled trials, each of which are enrolling patients with both alpha and beta thalassemia. ENERGIZE is enrolling patients who are not regularly transfused with a primary endpoint of hemoglobin response, and ENERGIZE-T is enrolling patients who are regularly transfused with a primary endpoint of transfusion reduction response. More than half of patients in each of these studies have now been enrolled, and we aim to complete enrollment of both studies in the middle of this year. Based on the data we have generated in this program to date, we believe strongly in the potential for PYRUKYND to become the first therapy to improve hemolytic anemia and ineffective erythropoiesis in all subtypes of thalassemia and become a foundational therapy in the treatment of this devastating disease. We look forward to the readouts from these phase III studies next year. I'll now turn to sickle cell disease, where we aim to deliver a novel oral therapy that both improves anemia and reduces vaso-occlusive crises or VOCs. To this end, we are advancing the operationally seamless phase II/3 RISE UP study of PYRUKYND in adults with sickle cell disease, and I am pleased to announce that the phase II portion of this study is now fully enrolled. The primary endpoints of the phase II portion of the study are hemoglobin response and safety, and we expect to announce the phase II data readout and the go, no-go decision to phase III in the middle of this year. This decision will be informed by the protocol-defined go, no-go criteria in the phase II portion of RISE UP, as well as any additional data from the phase II secondary endpoints and longer-term data from the ongoing extension studies of the investigator-sponsored trials at the NIH and the Utrecht University. To date, these investigator-sponsored trials have generated compelling data suggesting that in adults with sickle cell disease, PYRUKYND reduces red blood cell sickling and similar to what we have observed in PK deficiency and thalassemia, also resulting consistent improvements in hemoglobin, hemolysis, and erythropoiesis. We continue to advance the phase III ACTIVATE-KIDS and ACTIVATE-KIDS-T studies of PYRUKYND in pediatric PK deficiency as we aim to deliver the first approved therapy for children living with this disease. We aim to enroll at least half of the patients in each of these studies by the end of the year. In parallel with the PYRUKYND development program, we continue to advance the development of AG-946, a novel PK activator, which provides the opportunity to further strengthen our PK activator franchise and pursue multiple therapeutic paths, including lower risk MDS. As we presented at ASH, pharmacokinetic data from the healthy volunteer cohorts of the phase I single and multiple ascending dose study were supportive of a once-daily dosing regimen, and pharmacodynamic data suggested sustained activation of the glycolytic pathway, including dose-dependent increases in ATP and dose-dependent decreases in 2,3-DPG. Taken together with a favorable safety profile, we look forward to progressing the ongoing phase II study of AG-946 in lower-risk MDS and expect to complete enrollment of phase II-A portion of this study by the end of this year. As Brian mentioned, we aim to expand our pipeline beyond PK activation through both disciplined business development and the advancement of our earlier-stage pipeline. Within our earlier-stage pipeline, we continue to progress our lead research program aimed to address phenylketonuria, or PKU. PKU is a rare genetic disease with limited treatment options that impact a total of approximately 35,000-40,000 patients in the U.S. and EU5, and it's caused by a deficiency of the phenylalanine hydroxylase, or PAH enzyme. Lack of PAH activity leads to the accumulation of phenylalanine and downstream sequelae, patients with PKU are therefore often advised to consume a highly restricted diet in order to minimize phenylalanine intake, which can further reduce patient quality of life. To directly address the underlying cause of PKU, we are developing an oral PAH stabilizer with the goal of reducing phenylalanine levels, we are targeting an IND filing for this program by the end of this year. Overall, I'm very pleased with the significant progress the team made executing across our portfolio in 2022 and look forward to the continued maturation of our five ongoing pivotal studies over the course of 2023. With that, I will now turn the call over to Tsveta. Thank you, Sarah. Since joining Agios last month, I've been impressed and energized by the rigor of the commercial team, the compelling data generated across our clinical programs, and the potential of our portfolio to transform the treatment paradigm of multiple rare hematologic diseases. It is truly a privilege to have the opportunity to join a company so clearly poised for near and long-term growth. For the last 20 years, I've led global rare disease launches at leading biopharmaceutical companies. While each of those launches presented unique challenges, my core focus has remained the same, to reduce the length of the patient journey and improve patient health outcomes as efficiently as possible. To achieve that goal, particularly for an ultra-rare disease, it is critical to implement and deploy a comprehensive commercial strategy that addresses each phase of the patient journey, from disease awareness to reimbursement. Specifically, that strategy must be underpinned by a focus on three key areas. Increasing awareness of the disease and educating on available treatment options, accelerating access by reducing the time between diagnosis and treatment initiation, and supporting adherence and maintaining reimbursement over the long term. Leveraging this strategy, my top priority is to drive operational excellence in the current launch in PK deficiency and build the capabilities we need to fully realize the commercial potential of PYRUKYND in anticipated future launches in thalassemia and sickle cell disease. In reviewing the launch to date, I've been particularly encouraged by the progress the team has made on market access. Payer policies are aligned to the label or clinical trial inclusion criteria, and prior authorization criteria are in line with expectations, with the majority of patients initiating therapy four to six weeks after completion of the Prescription Enrollment Form or PEF. Launched to date, discontinuations continue to remain low overall, reauthorizations have not been a barrier. This progress highlights both the positive impact of PYRUKYND and the strength of our market access and patient services capabilities. In the fourth quarter of 2022, which represented the third full quarter of launch, we generated $4.3 million in net PYRUKYND revenue. A total of 105 patients have now completed a PEF, including 21 in the fourth quarter of 2022, a 25% increase versus the third quarter. Given our strong conversion rate, this has translated to a net of 78 patients on therapy, a 39% increase over Q3. Patients on therapy stem from a growing and diverse prescriber base of 96 physicians and represent a broad demographic and disease manifestation range that is consistent with the adult PK deficiency population. Despite this progress, we have identified multiple opportunities for improvement. As is common in ultra-rare disease launches, we have observed a general lack of disease awareness and a corresponding lack of urgency to diagnose, monitor, and treat. This presents a clear opportunity to focus greater attention on the earliest stages of the patient journey and thereby increase disease awareness and diagnostic efficiency. Specifically, as the ICD-10 code for diagnosing PK deficiency was established less than two years ago, we plan to bolster our disease awareness efforts by augmenting our AI and machine learning capabilities to identify high-potential clinicians likely to treat patients with PK deficiency. Additionally, given the breadth and diversity of the prescriber base, we aim to strengthen our capacity to engage and educate treating physicians, including on the availability of the Anemia ID program, which provides no-cost genetic testing to identify a range of hemolytic anemias, including PK deficiency. I'm confident that further strengthening these rare disease capabilities will help us maximize the potential of the current launch. PK deficiency is only the beginning. Building our capabilities to support diagnosis, education, access, and adherence will directly translate to future potential launches in meaningfully larger patient populations and will help us unlock the full commercial potential of our PK activator franchise. With that, I will now turn the call over to Cecilia. Thanks, Veta. Our fourth quarter and full year 2022 financial results can be found in the press release we issued this morning, which I will summarize. More detail will be included in our 10-K, which will be filed later today. Full year 2022 net PYRUKYND revenue was $11.7 million, including $4.3 million in the fourth quarter, an increase of $0.8 million compared to Q3. PYRUKYND is the first therapy for this ultra-rare patient population, we continue to gather data and insights on the launch trajectory and will not be providing guidance at this time. Consistent with other rare disease launches, gross-to-net continues to be in the 10%-20% range. Cost of sales for the quarter was $3.4 million. Moving to expenses on the balance sheet. R&D expenses were $70.3 million for the fourth quarter and $279.9 million for the full year 2022, an increase of $22.9 million compared to the full year 2021. This year-over-year increase was primarily driven by increased costs for our five ongoing PYRUKYND pivotal studies and for the AG-946 studies and increased workforce spend across R&D. SG&A expenses were $32.8 million for the fourth quarter and $121.7 million for the full year 2022, an increase of $0.3 million compared to full year 2021. Full year TIBSOVO royalty revenue, which is recorded under royalty income from gain on sale of oncology business on our income statement, was $9.9 million. As a reminder, TIBSOVO royalty income ceased after Q3 2022, given the sale of our right to 5% royalties on U.S. net sales of TIBSOVO to Sagard for a one-time payment of $131.8 million in October, of which we recorded $127.9 million under other income in Q4. As part of the divestiture of our oncology business to Servier, we retain rights to a potential $200 million milestone upon approval and 15% royalties on potential U.S. net sales of vorasidenib, a clinical-stage dual inhibitor of mutant IDH1 and IDH2. We ended the year with cash equivalents, and marketable securities of approximately $1.1 billion. We expect our cash equivalents, and marketable securities, together with anticipated product revenue and interest income, will enable us to execute our operating plan, including funding the currently planned development programs for mitapivat, AG-946, and PAH, and commercializing mitapivat outside of the U.S. through one or more partnerships to cash flow positivity without the need to raise additional equity. To maintain our strong cash position, we will remain focused on proactively managing our cost base and deploying a disciplined capital allocation approach to ensure the full development of our ongoing pivotal studies and flexibility to expand our pipelines through business development. I'll now turn the call back over to Brian for his closing remarks. Thanks, Cecilia. 2022 was a year of tremendous progress at Agios. With the approval of PYRUKYND in adults with PK deficiency, we've taken an important first step toward our 2026 vision, and we remain focused on advancing our industry-leading pipeline of PK activators to address the profound unmet needs of patients suffering from rare hematologic diseases. In 2023, we're anticipating a number of key clinical and regulatory milestones that will lay the foundation for potential phase III data readouts in thalassemia, sickle cell disease, and pediatric PK deficiency over the next few years. As always, we'll strive to be responsible stewards of our balance sheet, and we'll continue to evaluate meaningful opportunities for value creation. Finally, I'd like to thank all of our employees for their hard work and dedication to our mission of transforming the lives of patients living with rare diseases and all of our partners, including physicians, caregivers, patients, and participants in our clinical development programs. We'll now open the call for questions. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from Chris Raymond with Piper Sandler. Your line is now open. Hey, thanks guys for taking the question. Just, I guess, a couple questions. First on the phase II sickle cell, the phase II portion of your trial reading out mid-year. I know you guys have talked about the primary endpoint being hemoglobin response, but is there an option to show a VOC signal, at least in this portion of the trial? Can you just clarify that? I have a follow-up. Sure. Hi, this is Sarah. For the phase II portion of the trial, indeed we have a primary endpoint of hemoglobin response and safety as the first path. In our secondary endpoints, we are indeed capturing the rates of VOCs as well. That being said, it is indeed a 12-week period for the randomized controlled trial. The data coming from that is gonna be limited by the time that patients have been exposed to the drug. As always, we've always been saying this as well, that we will be looking at the totality of the data generated in that trial, specifically in the RISE-UP trial, and we will also be looking at our investigator-sponsored trials in which patients have been exposed for a longer duration. Okay, great. Thanks. Just on PYRUKYND in Europe. I know you have marketing authorization in Europe and the U.K. in hand, and you've talked about not wanting to build really an infrastructure there, Brian, I guess, until you get a larger indication. Maybe any update on that strategy for launch there especially, you know, given that you now have, you know, marketing authorization? Yeah. Good morning, Chris. Great question. As you noted, we have mentioned that we have interest in a partner or partners as we think about commercialization outside the U.S. PKD, as you know, is an ultra-rare indication, and just to have commercialization on its own for PKD would be quite a challenge. What we're looking towards is as we make progress, as Sarah just mentioned with the sickle cell data, and particularly thalassemia, where we stated that we expect to be fully enrolled by mid-year, that puts us on a path to really, you know, methodically look for partners that we believe will represent very well the footprint we anticipate globally for those launches to come. PKD, of course, as I mentioned, is very rare. Thalassemia is meaningfully larger as an opportunity. It does, just like sickle cell disease, have a unique global footprint. Those are the factors that'll go into our partnership. Great. Thank you. You bet. Please stand by for our next question. Our next question comes from Marc Frahm with Cowen. Your line is now open. Hi. Thanks for taking my questions. Maybe just to follow up on Chris's question just on thinking about the phase II data as we get it. In terms of making the go/no-go decision for phase III, are you just needing to see kind of more robust but very similar data to what you've already seen in terms of hemoglobin, things like that? Or are there really new endpoints that need to be revealed in this data to make you wanna go forward into phase III? The endpoints indeed are, you know, relatively similar to what we have in our other trials. However, this is the first placebo-controlled data set in our phase II, so we're actually very excited about that. Yeah, we are very eagerly looking forward to this year. I think, Mark, I would just add too, I mean, you know, one of the themes that we've been talking about that's so appealing of PYRUKYND is the consistency of the data that we've seen across hemolytic anemias PKD, all the way through launch of course, and then thalassemia, which is already through phase II, and we have the phase III underway. As you know, RISE UP, where we're waiting the phase II data, we're not expecting per se surprises, but it'll be confirmatory if we see compelling data coming out of the phase II RISE UP study. We have the endpoints of course identified, and then we will look at the totality of data, as Sarah just noted. Okay. Thanks. Maybe just to the, to the launch in PKD. You know, Q4 is kind of the first full quarter of, you know, some patients flowing through reauthorizations and things like that. You know, you've continued to have that experience this quarter. Just what are you seeing in terms of the reauthorization standards that are being applied? You know, what kind of% of patients do you think should we expect to continue on therapy for the long term? Thanks a lot for the question. It's Tsveta here. As we said, we have 78 net patients on therapy, at the end of fourth quarter of 2022. This really, net patient number is inclusive of all the patients who have started on therapy and all of the patients who have discontinued. We have not reported any specific numbers on discontinuations, but as we noted, the reauthorization rate for patients that are reaching the six-month Assessment has not been a barrier so far, at all. The discontinuations continue to remain low overall, for the product. For me, that truly reinforces the positive reception that we get from patients, physicians, and payers, on the profile of PYRUKYND, in the U.S. Okay. Thank you. Please stand by for our next question. Our next question comes from Greg Harrison with Bank of America. Your line is now open. Good morning. This is Mary Kate for Greg. Thanks for taking our questions. I guess as we hit one year since the approval of PYRUKYND in PKD, you've mentioned that you have about 96 unique physicians prescribing. Maybe how do you expect usage and updates to change as physicians become more aware of and experienced with PYRUKYND? We are actually very pleased with the progress that we've made on breadth of prescribing. As you mentioned already, we have 96 unique physicians who have generated 105 Prescription Enrollment Forms. It is an ultra-rare disease. From that perspective, expanding the breadth of prescribing is going to be our core focus today and moving forward. We have to keep in mind that it does take time because each of the unique prescribers will need to basically go on their own journey of disease awareness, diagnosis, and prescription as well. This is one of the main reasons, actually we'll put a greater emphasis on this first part of the patient journey, from really shortening the time from diagnosis to treatment, and invest greater efforts in the data and analytics to help diagnostic efficiency, and very importantly, help us improve our targeting efforts with clinicians as well. I'll just add that the kinetics of an ultra-rare disease launch, as Tsveta noted, really will be about breadth of prescribing. We describe it often as inch deep, mile wide, because it would be unusual for PKD for a physician to have more than one or two or maybe three patients at the most. These efforts that Tsveta refers to about, first of all, education, which is critically important. Secondly, and she alluded to this in the prior comments, the machine learning capabilities that we're working on using claims database analysis is critically important. It's a modern state capability for rare disease launches that we will look to master because the more that we can be efficient in guiding our call plan targeting towards high potential providers who are likely to have a PKD patient, the more effective our breadth proliferation will be. That really is one of the key areas of focus. Great. Thanks. If I could, one more. For those on treatment are already prescribing PYRUKYND, what kind of feedback have you been receiving from patients and physicians who either use or prescribe the drug? Thank you. We're very pleased with the feedback that we are getting across the board from patients, physicians, and payers as well. I think the success of our market access efforts definitely speaks to the positive reception of payers, both for patients who are initiating therapy, but also the great success we see with reauthorization rate. We get a lot of positive anecdotal feedback from our patient services team, which is fantastic to hear. I actually had the opportunity to hear some of the direct feedback from our customers when I had actually went out on the field and met with some of them in my first month on the job. It really reinforces the positive, not only for reception of the product, but already experience that early in the launch with how PYRUKYND is performing for those patients. We are excited. As we said, it's gonna take some time, but I believe we're putting some of the right elements in place to continue to drive breadth of prescribing. That's for PKD, which is really encouraging. Tsveta, do you wanna comment on the clinical trial experience? Sure. It's, it's very similar in a way. The clinical trial continue to gather data in the long term for patients with PKD who have been on PYRUKYND for now a long time. What we see is our data is getting stronger as it matures, even because the hemoglobin effect is maintained, the impact on hemodialysis is maintained. Very importantly, we see patient-reported outcomes that are also maintained and really reach this clinical significant threshold for feeling better and functioning better. On top of that, what we are very excited about is our iron overload data as well, where we start seeing more and more an impact on iron overload as well. I think we're very excited about what PYRUKYND has already delivered and is continuing to deliver for patients with PKD. Great. Thank you. Please stand by for our next question. Our next question comes from Tessa Romero with JP Morgan. Your line is now open. Good morning, Brian and team. Thank you for taking our question. Just one from me on the sickle cell disease program, if I could. Thinking a little bit about the phase II RISE UP data and your go, no-go decision here. Specifically, is there a quantitative hemoglobin response rate that you view as differentiated here? I know in the past, we've talked a little bit about vaso-occlusive crises as also being important to monitor. Could you help us understand a little bit better what an encouraging trend might look like there for VOCs as well? For our primary endpoint, it's the hemoglobin response, right? We do have the bar set there as 1 g per deciliter to be qualified as a hemoglobin response between specific time points in the clinical trial. We have pre-specified in our protocol what we consider, you know, statistical significant results for our primary endpoints, and then how we move forward into our secondary endpoint testing. It's a very sort of classical setup for a phase II. Now, for a phase II, of course, what we're looking for in the secondary endpoint is trends. Our VOCs that we're capturing over time, you know, we will accrue that data, but we're not looking there for something hugely impactful or meaningful because that's ultimately what the phase III will deliver on. The phase III is set up to truly deliver towards our target product profile, in which we're hoping to be able to treat the totality of sickle cell disease by impacting both hemolytic anemia, sickle cell pain crisis, and then there is this, also the opportunity to then further hit on patient-reported outcomes. Really providing a drug that can be meaningful across the totality of sickle cell. Please stand by for our next question. Our next question comes from Greg Renza with RBC. Your line is now open. Great. Thanks. Good morning, Brian and team. Congrats on the progress, and thanks for taking my question. Brian, just maybe turning to 2026 and just the remarks on cash flow positivity. I just wanted to give you an opportunity to perhaps provide some color on some of those assumptions and how you're thinking about the inputs to get there, certainly keeping in mind the launch, the many programs in development, and of course, your mention on looking at external assets in the pipeline. Thank you very much. Sure. Thanks. Good morning, Greg. I'm gonna have Cecilia start. Yes. Thanks, Greg, for the question. As we mentioned, our cash equivalents and marketable securities will, in addition to anticipating the product revenue and interest income will enable us to execute the plan. Our current plan obviously includes all the pivotal trials that Sarah described for mitapivat in PKD pediatric thalassemia and sickle cell, also AG-946 and the earlier program in PAH. Part of the plan, as Brian described earlier, about commercializing mitapivat outside the U.S. Got it. Just any color on even on top line. I know we're not asking for guidance. As you, as you think about PYRUKYND, certainly as a backbone therapy and the potential across all these indications, how do you see sort of the velocity of that potential layering as you march through this development and potential approvals in the mid-twenties? Thank you so much. Greg. With PKD, we certainly have an ambition to maximize the PKD launch opportunity. The bigger picture, of course, for us is to strengthen our commercial capabilities for these meaningfully larger sequential launches potentially to come, you know, namely thalassemia and sickle cell disease. In the case of PKD, it's ultra-rare by name and by nature. It will take some time for us to refine the prevalence as well as the peak sales estimates as we learn more. I would say peak sales depends on a whole lot of factors, including the time to peak sales, the approval timelines, the distribution and partnerships as we talked about outside the U.S. Where we are today, you know, this discussion reflects only the third full quarter of launch. So far, it's clear to us that the PKD launch will be slow and steady. I think that's reflected in the numbers that we continue to report out. I will say, I'm just gonna take the opportunity to reiterate that I am super pleased that Tsveta Milanova has joined us as CCO because Tsveta has deep expertise and experience in rare disease launches. I think that's not a moment too soon for us as we look at continuing the momentum of the PKD launch, and more importantly, getting ready for these bigger launches potentially to come. Great. Thanks again and congrats on the progress. Thanks, Greg. Please stand by for our next question. Our next question comes from Mark Breidenbach with Oppenheimer. Your line is now open. Hey, good morning. Most of my questions have been answered, but let me dip down into kind of the early-stage pipeline. Maybe you could just remind us how the PAH stabilizer for PKU is differentiated from sapropterin and related drugs that are already approved or in late development for PKU. Thanks. Sure. This is Sarah. Our program is really indeed that it has a different mechanism of action than the others that are currently in development or are being or have been approved and have been on the market for a while. It's indeed a pH stabilizer, which is different. Where we see an opportunity with this product is because the two that are currently available do have their own limitations in the treatment of PKU in the sense that either there's a lot of drug to take or it's you know, subcutaneous administration, so there is a lot that goes along with that. That's where we are looking to develop an oral therapy that would treat the majority of PKU. Of course, the hope is for us to provide something that can be meaningfully different in the sense that it is providing all of the benefits as measured on phenylalanine reductions, but also easier to use, easier to tolerate. We will disclose more details on our CDPs as we progress the program. Mark, I'll just add that the addressable market is significant. We're talking here about another step function change in prevalence from where we are today with PKD. This would be 35,000-40,000 patients across the U.S. and EU five. The other point about this one is this comes from Agios expertise in cellular metabolism. It's pretty early right now. We've talked about a potential pathway towards an IND at the end of this year, but we are excited to have this as a potential continued diversification of our pipeline. Got it. Thank you. You bet. Please stand by for our next question. Our next question comes from Danielle Brill with Raymond James. Your line is now open. Hi, guys. Good morning. Thanks so much for the questions. I have a couple. First on AG-946, just a clarification. Can you remind us plans for the phase I sickle cell cohort that you're enrolling? you know, how that's tracking and what your plans are for data. Then on PYRUKYND, I just wanted to clarify, does the 78 patients that are on drug factor in discontinuations, or is that the total number of patients that have received PYRUKYND? Then I have a follow-up to that. Sure. Sarah can start with the first one. Yes. Thanks for the question. 946 in sickle cell disease, indeed, it's. We have completed and disclosed all of the results of our phase I in healthy volunteers. Within that trial, there is indeed a cohort that is ongoing for sickle cell disease, in which it's a multiple ascending dose scheme within the phase I for sickle cell disease specifically, in which we are looking to generate data in the context of hemolytic anemia. It's a short duration trial. We have not disclosed when we are going to release those results. The trial is ongoing and is on track right now. We are very excited, though, with AG-946. I know you didn't ask, but I just wanna say because we are very excited about our MDS program, which is currently in phase II-A portion of that specific trial. Tsveta, I think that's going to be an easy one on the patients, but I'm glad you asked, Danielle. It's good to clarify. Clarify. Yeah. 78 patients on therapy at the end of Q4 is really a net number of patients. That includes the patients who have started therapy. It deducts the patients who have discontinued. All the 78 patients were actually actively receiving PYRUKYND at the end of the quarter. The only thing I'll add is, again, the discontinuation rates launched to date have been low, which is super encouraging because it shows us that PYRUKYND is performing very well at the patient and provider level. As we look beyond PKD, that's a very important data point as we think about bigger launches to come. That's okay. Thanks. That's very helpful. I guess my follow-up was for the enrollment form. I'm just curious what proportion of those actually translate to patients on drug. When it comes to the PEF, we are very pleased with the progress we've made on market access as well as patient services because we do see the majority of the PEF to actually progress to treatment initiation. There is a time delay between the completion of a PEF and treatment initiation. At the moment, it's about four to six weeks. We do not expect for that timeframe to shorten significantly. That is really primarily driven by the fact that a lot of the payer policies and prior authorization criteria require genetic testing. If a patient has not completed a genetic test or they don't have the results, they will need to go through the process and the pure timing of genetic testing is the driving force of the four to six weeks. Yeah. The challenge really in an ultra-rare disease launch is the generation of the PEFs, the demand, because it's so rare and there's so much heavy lifting required in terms of educational components. I think the pull through PEF to patient on therapy will take time, but that's not per se the real challenge of the launch. Great. Thank you so much. You're welcome. Please stand by for our next question. Our next question comes from Salveen Richter with Goldman Sachs. Your line is now open. Good morning, this is Anupam Rama for Salveen Richter. First, I guess, into the mid-2023 sickle cell update. What should we be most focused on? In your opinion, what would be considered success in the phase II portion? Just conversely, what would lead you to make a no-go decision? Thank you. For the phase II, we have our, you know, pre-specified criteria for our primary endpoints, which the primary endpoints are the hemoglobin response and then safety. In the secondary endpoints, we have, you know, hemolytic markers, you know, patient-reported outcome and VOC as our secondary endpoints. We are, first of all, looking to pass our primary endpoint bars. It's two doses tested against placebo. We will be looking for both doses to see which one is the better dose to move forward into phase III. Those are all things that are pre-specified within the protocol. Of course, in the context of an overall go, no-go decision, for the program, there is other data that we will take into account, including our investigator-sponsored trials. We are, of course, as always, for any program that we have, when we take a step towards the next part of development, we make sure that we, that we truly believe that we're going to hit on our target product profile. That is the discipline we, you know, have for this program, for all of our programs. We are, like, very excited to reach mid-year, so we can actually talk about data. Thank you. I guess just to follow up on that, what would be the ideal target profile for PYRUKYND in sickle cell? Our ideal target product profile is truly like a product that can deliver benefit for the totality of sickle cell disease, meaning that our program is designed to end treat hemolytic anemia and have a reduction on sickle cell pain crisis, but then we are also hoping to be able to demonstrate a benefit on PROs. Sorry, just one more question. I guess if you don't see an improvement on the VOC rates, would that influence your decision to not go forward with the trial? The data that we have in our phase II on VOCs will be very limited just because of the duration of the trial. It's a 12-week randomized controlled trial portion. That's not how the trial is designed to show a huge benefit on VOC. We continue to collect data on VOCs in our open label extension in the phase II, and then we, of course, have much longer exposure via our investigator-sponsored trials. Thank you. Thank you. I am showing no further questions. I would now like to turn the conference back to Brian for closing remarks. All right. Well, thanks a lot, everybody, for participating in today's call and of course for your continued interest in Agios. As you heard this morning, we're generating significant momentum towards our long-term vision, and we are confident in our potential to deliver significant value for both patients and shareholders. Thanks again, and we'll look forward to speaking with all of you real soon. This concludes today's conference call. Thank you for participating. You may now disconnect.