Agios Pharmaceuticals, Inc. (AGIO) Earnings Call Transcript & Summary

All right. Can everyone see my screen? Great. Well, now that George is safe and sound, we can kick things off. All right. Jackie, you ready, you want me to turn it over to you?

I am ready. George is back in the house. So here we are. Thank you, Holly. Hi, everybody. Thanks for being with us this afternoon. We do appreciate your time for an event that we're very pleased to participate in with you this afternoon. We think we've got some interesting things to talk about, and we hope that you're going to be excited about what we're seeing, that we're excited about. And I want to thank all my panelists in advance for joining us today. I think we've got a great agenda, and maybe Holly will just click to the next slide, please. Forward-looking statements that you're all very familiar with. Thank you. So here's our agenda today. I will be pretty brief with my opening remarks, and I'm going to turn it over to Charlie and before I do that a little bit later, I'll introduce her for those of you who don't know her, then we'll hear from Bruce regarding our research pipeline. We're very happy to have Hanny with us today. He's going to speak on 2 different topics. And so he'll follow Bruce. Sarah will come up and speak about the latest progress on our PK activator clinical programs and the things that she's excited about, and then Hanny will come back again and speak a bit about PK deficiency. And Darrin will wrap it up before Q&A with some, we think, interesting information about our commercial launch prep for mitapivat in PKD in the U.S. and how we're thinking about that whole arena, and we're very excited about that. So -- and we'll do Q&A for as long as you want to do Q&A for afterwards. Next slide, please, Holly. Thank you. So for those of you who don't know Agios that well, I'm not going to belabor too much our history, but we were founded in 2008. So we've been doing this for almost 14 years. One of the things that we have determined over time is something that makes us differentiated and successful or the connections that we have built with health care providers, with patients, with the partners that we work with, with ourselves. And so you'll hear the theme of connections across all of the presentations today, and you'll hear more about that from us as a company on a go-forward basis. We also have a very unique scientific platform and a number of years looking at the area of cellular metabolism and how we can bring the science of cellular metabolism to patients. We also think that makes us unique, but it's this combination of how we view connections as well as the depth and breadth of our science and cellular metabolism that make us who we are. That science allowed us to bring IDH inhibitors to patients in acute myeloid leukemia in the cancer space, and we brought 2 products to market in less than 10 years or in about 10 years since the time of our founding. And as many of you will remember from a year ago, we announced the divestiture of our oncology business so that we could focus on genetically defined diseases outside of oncology. And a big driver for that was the progress that we were making both with our clinical programs as well as our research programs and the potential we saw to impact even more patients outside of oncology on a go-forward basis and be even more differentiated with the same scientific platform. And so we think that focus is allowing us to develop even deeper connections with the communities in the patients that we are serving now and going to serve in the future. And that focus is going to allow us to advance our programs even faster and really fully exploit the impact that we think our science can have for patients. Next slide, please, Holly. We talk about patients all the time. We don't just talk about them though because that part of it is actually really easy. We connect with our patients. We work with our patients to make sure that their voices inform our work and help drive a sense of urgency for how we're moving things along. And we have become even more consultative with patients, I would say, over time and as we're focused on genetically defined diseases in terms of how we work alongside with them to partner to take our science into the diseases that are impacting them and figure out the best way to serve their needs over time. And from some of the presenters today, you'll hear about some of that work that we're doing with patients to collaborate even more closely on our programs with them as we move things forward. So look for more of that. Next slide, please. The 2021 has been a very interesting year for us. As you will remember, we announced the divestiture of our oncology business in December of 2020. And frankly, the first part of this year was an extremely active one for our teams because we not only closed on that oncology business divestiture, we also worked very hard to transition 200 employees in those programs in a seamless fashion to Servier so that we can ensure that those programs continue to move along on behalf of oncology patients. And while we were doing all of that, the remaining team at Agios was highly focused on advancing our clinical programs for both mitapivat as well as AG-946 in the PK activator arena, and then Bruce and his team, we're also very focused on executing on the promise that we see coming out of our areas of research and our research pipeline. And so it's been a tremendously busy year. We're looking forward as I completely focused genetically defined disease company now having successfully transitioned our oncology assets to Servier. And one of the reasons why we're here today is we're excited to update you on the latest with respect to our clinical programs as well as our research programs and our launch preparedness for PKD in the U.S. where we have a PDUFA date of February 17, 2022. Next slide, please. Our vision, our 5-year vision that we updated a little bit and spoke with you about earlier this year has not change. This vision largely hasn't changed since we first talked about it in January of 2020, except for we adapted it a bit following the divestiture of our oncology business. But these 4 areas where we have made commitments to you remain part of our vision, and we're on track to deliver 3 approvals from mitapivat across indications in hemolytic anemias. We expect to have 5 -- at least 5 molecules exploring at least 10 indications. Again, with this, so we're talking about the 2022 to 2026 time frame, a pipeline that's poised to deliver a new IND every 12 to 24 months, and we'll be cash flow positive by the time we get to 2026. So I just wanted to remind everybody of that vision that we are still anchored to and committed to delivering on behalf of patients and you, our shareholders, as well. Next slide, please. So I think you're going to hear 4 main themes today. The first one you're going to hear about from Charlie in a fairly brief presentation, but it's quite important. And in any point in the future, if you want more details from her about this, please don't hesitate to ask. But we think that we've got a unique way that we manage our portfolio and have Charlie and her team create the cross-functional connections and interactions and the oversight of our portfolio and our programs to make sure that we foster those connections, both internally and externally that are going to allow us to drive our programs very efficiently and very successfully with great impact. You're going to hear from Bruce about where we are with our research pipeline. Again, we've been doing this in cellular metabolism for a long time, and I think you're going to start to see some of the fruits of what are coming out from his team in that regard. And you're going to hear from Sarah about the progress that we made in the clinical areas, our clinical development portfolio continues to expand and how we're working with the patient community and other partners on these programs to execute them successfully and with what we think is a differentiated approach. And then lastly, you'll hear from Darrin before we go into Q&A as to how we are getting ready and we're already basically ready for success with our first commercial launch outside of oncology and a terrific commercial team that we have ready to bring PKD, mitapivat for PKD2 patients. So with that, I'm going to turn it over to Charlie. I'm going to introduce her just very quickly. I'm very happy to have Charlie and the team. She joined us at Agios in 2018. She's our Senior Vice President of genetically defined diseases and portfolio leadership. And Charlie has got 23 years or so of industry experience. She joined us from Biogen previously right before Agios and she's worked in research and clinical development and commercial operations and most of her industry experiences outside of oncology, including in immunology and neurology. And we brought her in Agios back in 2018 when we wanted to kind of up our game, so to speak, on rare diseases and as that has evolved into genetically defined diseases. So we brought her in as part of the talent recruitment to help us do that as we saw the potential for these indications developing for us. So very happy to have Charlie and the team, and I'm now going to turn it over to her. Thank you.

Thank you, Jackie, and good afternoon, everybody. And yes, I'm going to just speak for a few minutes picking up on some of the themes you've already heard there from Jackie and then move swiftly forward to Bruce and the rest of my colleagues here. You can move forward the slides, Holly. Thank you. So as Jackie was just discussing, our pipeline has been built on and will continue to be fed by our deep history and understanding of cellular metabolism. A history, as you've heard, that has seen Agios uncover very important biology and bring more than one innovative medicine to patients. The application of our expertise by focusing on genetically defined diseases, that is diseases with lifelong and compelling needs, allows us to be deliberately focused yet still open to the opportunities our scientific inquiry continue to uncover. On next slide, Holly. Okay. So when we think about our portfolio, our proven track record here of execution. Agios is uniquely positioned to truly leverage our cellular metabolism background across multiple indications and assets. Jackie talked about our hyper connectivity, and that is something that I just really maintain. We strive to maintain and build on a hyper-connected culture that ensures insights low across the company, not just from our ongoing research focus, but it could be across the business flowing with purpose and meaning. Some of the examples could be regulatory feedback on one of our programs will inform both the strategy and the execution for another of our programs or even be brought into new areas of interest that we're very excited about, some with some really good potential that Sarah is going to talk to you about in a little while. Another example will be -- could be our work with the patients that, again, Jackie touched on. Seeing the highly impactful sickle cell disease advocacy community and translating their successful approach as we work with the PKD community, has been incredibly exciting for us to see where that can go. The synergies across our pipeline are very easy to see. And there are several red threads that will -- you'll hear through the discussion today from my colleagues, whether it be our ongoing PKR or PKM translational biology and how those insights immediately are taken into our clinical pipeline. We pay close attention or where our focus is at the moment on bringing our therapeutics into the pediatric setting. Our current work in pediatric PKD will directly pull through to thalassemia, to sickle cell and in time, PKU. So whether it be pediatric formulation development or dose extrapolation, endpoint and patient reported outcome applications, clinical trial execution, they're all very real-world examples of how our hyperconnected teams are very well poised to make sure we can work with a real sense of urgency and efficiency. And lastly, I'll just point here to the tenant around our work with and for the patients. They really are our partner of choice, and you're going to hear more from Darrin as we start -- as he moves into talking about our preparations for the launch and myAgios. Next slide, please, Holly. Of course, along with our existing pipeline, which we're incredibly excited about, working very hard on, we continue to look at how to fuel a robust and balanced and differentiated pipeline on an ongoing basis. This encompasses bringing in assets that we believe we can really drive forward with value creation. We've talked about our sweet spots and our therapeutic expertise. And perhaps we're most interested in earlier-stage assets around the DC and IND milestone. But simultaneously, we are evaluating the opportunities that are signed uncover internally, opportunities that could be best served by a partner who have both the infrastructure and the experience to move things quickly forward for patients. So out-licensing is of equal interest and importance to us and could provide a valuable additional source of capital for us to reinvest as we move forward. The continual assessment of these opportunities for our pipeline is nothing new. But now with our clear genetically defined disease focused, it will ensure sustainable and impactful business over the long term for us to continue to actively pursue this. Last slide for me, I think, Holly. So as I hand you over to Bruce, who will take you through that next wave of promising programs, I will pause and just highlight the list of potential indications here on the right-hand side of this slide. It encompasses both those diseases that we are moving full steam ahead ourselves and some that potentially may be out-licensing or partner opportunities when the time is right. And I think it's -- for me, always gratifying to look at this pipeline and see these largely derisk later-stage assets and how that allows us to thoughtfully drive ahead near-term indication expansion and, of course, our next wave of innovation, which does take me over to Bruce, who is going to tell you a lot more about that.

Thanks very much, Charlie. It's really an honor to talk to you today about the progress we've made with our internal pipeline that speaks to our depth in cellular metabolism, our affected integration and some truly groundbreaking signs of innovation. Of course, I'm an ambassador today for a terrific team at Agios. So just a quick shout out to our Research and Development Sciences team. Moving on to the next slide. Briefly an overview, I'm going to give you a little bit about how, start with our earlier programs through to our more material programs and then a natural segue to Dr. Al-Samkari after a discussion of low to intermediate risk MDS. Next slide, please. So starting with our -- and Jackie alluded to this earlier, a very early nature publications on the role of 2-hydroxyglutarate in IDH mutation-driven cancers. Agios has been particularly prominent in advancing the cellular metabolism, both of genetically defined diseases and in the oncology space and stay very current with our publications in this area. Next slide. So what's our secret sauce? Our scientists have a unique and effective blend of cellular metabolism and biochemical expertise, of course, combined with all of the drug hunting disciplines. By focusing on GDD, we've enabled our research work to be much more translatable in terms of clinical efficacy than what it would ever be possible in oncology. I'll speak to it subsequently, but we've biased our target selection to targets for which multiple indications exist, generally starting with a sentinel genetically defined indication and then acting to multiple disease adjacencies. Next slide. So what is a genetically defined disease at Agios? Genetically defined disease is not rare genetic disease that's commonly used as it includes monogenic, polygenic, pathologic processes and an expediency towards demonstrating benefit in disease adjacencies that are not necessarily genetically defined. At its core, it's flexible and scientifically rigorous. Next slide, Holly. So we're a modest-sized team that heavily leverages the industry experience and an average tenure in my own leadership team of 22 years. And to get where we are after 13 years of leaders in cellular metabolism, of course, we've built and collaborated with an extensive network of scientists in this community. Next slide. So I'll spend a little bit of time on this. The framework for... [Technical Difficulty]

Bruce, I think, we lost you. Can other people hear?

I think we lost you for a second, Bruce.

Okay. Sorry.

You're back.

So I started out with discussions of pipelines within a mechanism, and I think it's fair to explain how we select our targets. So we select targets that really fall within our bailiwick of cellular metabolism, challenging targets and targets accessible to small molecule chemistry. Of those targets that fall within our development and commercial expertise, we favor targets which there are potentially many indications beyond the initial indication, okay? We're also not looking at ultra-rare targets. If you look at the panel in the middle, the yellow stars, they represent a notion of targets with a patient frequency of generally more than a 1 in 100,000, and I'll speak to that a little more later. Within our early pipeline, we have a single target for [indiscernible], and that conforms to be a traditional one target on-disease paradigm that our remaining targets carry theoretical indications for potentially scores of indications and following on from something Charlie said, of course, many of those indications may represent medical needs or actually fall off outside of our internal expertise though offering tremendous potential benefit for patients. In which case, we'd consider partnering. It's a particularly compelling scientific case for medical benefit. Next slide. This is how we're organized. We have organized our discovery efforts into 4 hubs inborn errors of metabolism, each which is, of course, highly integrated with each other. And towards the center of this diagram, are the early programs, and by the way, of explaining the terminology we use in Agios, VT is validated target, BT is validated program that's entering lead optimization with strong starting chemistry positions and DC's development candidate, which immediately proceeds IND work. Those targets closest to or beyond DC are actually represented on the outside a rim of this diagram. Next slide, please. So how do we improve our chances of success and resource optimally in discovery, recognizing the size of our company? So in a modest-sized biotech, optimizing probability of technical success and return on investment, for investments in individual targets becomes extremely important and illustrated at the top is a more classic productivity model requiring a large number of shots on goal and considerable investment for an ultimate IND. And approximate numbers of scientists have been listed to the right. The build to the bottom of the slide, if you do the build, Holly, the bottom third of this slide is how we've evolved this model in Agios with a smaller and highly focused target discovery effort complemented by BD and a biased selection for targets with multiple indications, a smaller number of scientists is required for a greater return on investment. So that's the way we do things. Next slide, please. You've already seen this target. The area I'm focusing on today is largely in the bottom half, all of which are targets progressed well into the lead optimization space with a line of sight to a development candidate. An abbreviated list of the key indications around which we're building scientific validation is on the right of this slide. And of course, we have a pipeline of indications preceding these targets, which we feel is close to providing long-term sustainability to our portfolio but still allowing room for business development. Next slide. So I'll start with the programs now. So I'm starting with the earliest of our targets, BCAT-II innate lead optimization. So this is a target that is predicted to effectively treat 2 major inborn errors of metabolism. That's propionic and methylmalonic acidemia. In these 2 diseases and in approximately 14 additional rarer diseases, the body can't break down branch chain amino acids, leading to an accumulation of toxic metabolic intermediates. So our objective is -- of the program is a convenient oral administration, leading to a reduction of a toxic substrate that accumulates above the mutant enzyme. This will prevent the acute metabolic crises to characterize these diseases and then the long-term consequences and developmental delays associated with these disorders. And moving to the next slide, you'll hear more about these disorders. But just to give you an idea of how they fit, each of these is a little more or a little less frequent than phenylketonuria. So there are no more common of the rare genetic conditions. So the 3 branch chain amino acids are leucine, isoleucine and valine in the [ rich in ] muscle and in the diet and they breakdown in the event of certain enzyme mutations leads to the accumulation of toxic substances and particularly noticeable in these inborn errors of metabolism are episodes of acute metabolic decompensation associated with a variety of triggering factors. And these episodes can be very severe, even fatal. But the chronic manifestation of high levels of these toxic substances include delayed cognitive development in NMA, renal insufficiency and with a tendency towards more cardiac issues in PA and of course, a much shortened lifespan. So if you go to the next slide. And surprisingly, this is a very simplified version. At the top of the slide, you can see the 3 branch chain amino acids leucine, Isoleucine and valine. The way this cascade works is the normal metabolism of these amino acids cascades down and across in both directions. And we've chosen through very careful validation to selectively target BCAT-II, which is a mitochondrial enzyme and necessary for the production of PA and MAA that are in the bottom right. They are the toxic intermediates that accumulate where the enzymes that would take them a step further into [indiscernible]. BCAT-I is cytosolic and serves as a bit of a safety valve for potential target-based activity. So it doesn't contribute to either toxicity or efficacy. So we've made our molecules quite selective. This was some very careful validation that took place prior to my joining Agios. So each of the red in circle boxes actually represents a rare or an ultra-rare condition in some cases of substrate accumulation, each of which would hypothetically benefit from BCAT-II inhibition. Next slide, please. So it's some data. You've probably been waiting a while and now I finally have some data. We created a genetic model of methylmalonic acidemia for testing out BCAT-II inhibitors. In this model, we mimic the metabolic prices by administering high levels of branch chain amino assets to mice. And importantly, with this model and BCAT-II inhibition, we markedly reduce brain MAA. This is very important as to press those likely clinical benefit. And just by way of some topical information, the work was originally contracted out by Agios they must design and so on. But it was repeated just week -- just last week in our own Cambridge laboratories. And now we're able to show reduction of MAA levels of up to 90% in our own internal studies, and that should be quite sufficient for really demonstrating a very important clinical benefit. So the next slide summarizes our overall progress and the latest of the early programs that we have. We've demonstrated BCAT-II inhibition in an acute in vivo setting. And separately, corrected metabolic crises, both peripherally and centrally, and we're currently extending the work into more chronic models and the compounds that we have that we're producing look like drugs, and we're currently optimizing properties to push one across the line. There's a single-digit nanomolar comp down and it eventually produce a development candidate. Next slide, please. So moving on to phenylketonuria. I assume you have some familiarity with the rare disease phenylketonuria in which the enzyme, phenylalanine hydroxylase is deficient. The management of the disease involves some partially efficacious existing therapies, but combined with severe dietary restriction, and in a situation parallel to really how we stabilized and activated the PKR tetramer for pyruvate kinase deficiency, the subject of the recent NDA and MAA submissions, we've been able to create small molecules that stabilize the PAH tetramer. So we hope to be at a lower phenylalanine sufficiently to allow normal protein intake and significantly improve the entire arc of these patients' lives. Next slide, please. So very simply on a normal diet without the ability to clear phenylalanine by converting it into tyrosine, PKU patients developed severe disease, are characterized in part by intellectual disabilities. And we consider this unmet need particularly high. So moving to the next slide. We've studied both mutant and active PAH enzymes in detail at Agios over the years. We see many mutations. The mutated enzymes misfold and are degraded very quickly. But with our proprietary small molecules, the tetramer is stabilized, thereby preserving its activity and resisting that slate of degradation. The stabilized enzyme is active and resumes the normal clearance of phenylalanine. And so how do we put that to the proof is in the next slide. On the left, you can see the presence of the cofactor biopterin marketed as KUVAN and PAH degrading phenylalanine to tyrosine. And on the right is one of our PAH stabilizers, actually one of many. And you can see how it's able to reduce the phenylalanine levels to a normal range. That's the dotted line. And the 2 colored -- the blue and the red colored lines are 2 doses of the same compound. And we think that lowering to the level of that dotted line will really be sufficient for normal dietary -- for dietary normalization to be sustained in these patients. So we really have very potent molecules that we think will be tremendous advances in this field relative to existing therapies. Moving to the next slide, just summarizing the progress here, and this is updating some of the information you may have received from us earlier. We have a very mature chemistry in this program. And we earlier announced that we had a development candidate. This followed on quickly with several chemistry breakthroughs that really leapfrogged the position that we're in, significantly improving a number of properties all of that earlier molecule that had been advanced. And so specifically now with reduced clearance in other properties, we believe the dose will be much lower and the CMC advantage to the extent that the long-term development type lines of any of these new crop of molecules will actually be substantially less. And by that I mean, potentially up to 2 years less development time from improved chemical properties. Based on that, we decided to bring one of the new generation forward. You can see from the arrow in [ lidar ] or how close we are to identifying and moving a development candidate forward. Moving to the next slide. Now moving to pyruvate kinase activation of which you've -- and you will hear very much and will be the subject for all of the work in the remaining slides. So since our inception a little over 13 years ago, we built a leadership position in understanding biology and biochemistry of PK activation. And I believe because of that, we possess a significantly differentiated advantage in this space as we're able to dial activity, disposition like brain penetrance and an understanding of the activity of the different PK isoforms and enzyme activity. Our earlier research focused on the benefits of PKR activation in hemolytic anemia, the success story since early in 2020 in our discovery labs, we're focused heavily on studying the benefits of PKM2 activation in a variety of disease indications. But importantly, we believe the improved delivery of oxygen to the tissue with PKR mechanism couples with the tissue-specific benefits of PKM2 activation in a synergistic manner. So that story will unfold in the next slides. So if we move to the next slide, Holly. We've really developed a deep pipeline of assets in this place. Of course, it includes the molecules you know in mitapivat, 946 brain penetrant molecules and other development-ready molecules with a variety of different properties. And it lets us tailor specific drugs to specific indications driven by both scientific and commercial considerations. We cover PKM2 indications in our patents of the 2 lead drugs as well. And I strongly believe, and this is a personal opinion I carry, that the next major pipeline and the mechanism in our industry will be PKM2 activation where there's potential to have a transformational impact across a large range of diseases. But understanding PKR activation is simpler in that it has a very direct positive effect on the energetics of a red cell, which lacks mitochondria. PKM2 affects are similar but much more complex, and I'll describe those in subsequent slides. Next slide. Specifically this slide. So importantly, there's potential to have an accelerated positive impact on disease by improving delivery of oxygen to tissues with PKM2 activation correctable pathologies. So PK, our activation improves the health of red cells by improving -- increasing the ATP content; and secondly, improving oxygen affinity, red cell count and hemoglobin concentration. So that story has been told many times by us and others. However, PKM2 similarly enhances the conversion of glucose to create ATP. But in doing so, shunts intermediates and synthesis of serine or other biomolecules in a manner potentially very specific to and beneficial to many diseases that we've studied. And in the cells in which PKM2 is active, unlike in red cells, pyruvate and lactic may be transferred to mitochondria and even more efficiently converted to energy. Next slide. Just sort of broadly summarizing the indications for PKR, there's a strong rationale for the treatment of hereditary anemias as well as anemias with acquired PK deficiency, whether they have a genetic basis or not. But for PKM2 activation, there's an equally strong rationale for the treatment of renal disease, hereditary and acquired neurologic conditions, retinal disease, anemias of ineffective arthropyosis, which is also known as dyserythropoiesis and several other diseases with an emerging literature such as an ASH. Next slide. So heavy data slide here. And I'm going to spend a little bit more time on this slide as I believe it's particularly important. This slide illustrates both the compelling case for disease indication, but it also our process for the validation and selection of different disease indications of PKM2. It's a complex area. So it's a careful study, and this is now I'm talking to the bottom-left slide, careful study demonstrates the presence of PKM2 immunohistochemistry in a broad range of tissues. So what you see is the darker brown stains here shown in a kidney and particular attention is paid to the specific cell types in which it's positive. So our combined PKR and PKM2 activators are highly effective at enhancing PK activation in the kidneys. And you can see that in the slide above, the black line is the lack of any activation and then you see a dose response relationship of a potent PKM2 activator that also has PKR activity. The example shown to the right is actually a disease model. And this model was used translationally to support the advancement of SGLT2 inhibitors for the treatment of renal disease. So positive outcome in this model can be paired in terms of its translational relevance to another molecule. And in this model, exposure to high levels of adenine creates a progressively worsening and really quite severe renal cortical injury as shown in that red untreated line. And this inexorable worsening of renal function is really typical of renal injury. It's a self-perpetuating vicious cycle. The effects of PKM2 activation here really rather striking in stabilizing the renal injury parameters and the 2 graphs, one on the left, is blood urea nitrogen; and the one on the right, creatinine. To limits, even though you can see a separation between that and the vehicle bar, the limits are really well within what is considered a normal renal function, the outside limits of normal renal function. So the renal cortical disease is associated with an acquired anemia, and we also demonstrated a modest benefit there before I mentioned acquired anemia is also profit from PKR activation. So the ability of our dual activators to mitigate the impact of renal injury is particularly relevant to our current portfolio. So severe chronic hemolytic anemias are often associated with worsening renal function. And this is particularly the case in sickle cell disease, where renal failure is an important cause of morbidity and mortality. If one looks at the safety parameters from our clinical trials as they pertain to renal function with mitapivat in sickle cell, I believe, there's clear evidence of the clinical translation of the effects in animals that I show above. So this is very real nonclinical research for which we feel strongly there is a clear clinical correlates emerging. If you move to the next slide, Holly. This is a slide showing same format as the last exquisitely localized distribution pattern of PKM to an hemin histochemistry panel bottom left. So allow us to hypothesize very specific disease indication. The one right on the left, the green cells are astrocytes. If you go from there to the cartoon, those astrocytes are allowed to -- are able to transfer substrate for energy creation to neurons which they can do with PK into activation. But more importantly, perhaps, very significantly impact brain ferritin and glycine levels and downstream biomolecules from that pathway. To the right is one of several repeated animal models with different molecules, where you can see the effect of a combined activator, that's PKR and PKM2 on a model for multiple sclerosis known as EAE. There's such a clear benefit in reducing clinical scores in these models without the side effects of dexamethasone. Dexamethasone is the red line. It's used as a positive control and the blue open and closed circles are 2 doses of the PKM2 activator. And we know this effect now is enhanced with -- further with brain penetrants and is likely also driven by an effect specific to TH17 lymphocytes in the brain. And most exciting here is that this effect is not system for our compounds would have had host defense issues. They don't. The low central serine concentrations, we believe, creates a brand-specific immunomodulatory patent that could be transformational in multiple sclerosis patients. And beyond MS, we have generated strong data sets supporting additional neuropathological indications and also including very specifically -- very specific genetically defined diseases. And most importantly, we believe this mechanism of reducing or reversing potentially severe neuropathology is actually quite safe, okay. Moving to the next slide. Just broadly summarizing a large body of research in PKM2 activation. The renal and neurologic disease indications emerged first with the most compelling cases that we've got active research and promising results across a broader range of indications, both internally and with collaborators. The literature, however, is absolutely replete with these indications. And much of it is highly flawed and has been based on work with a nonselective tool molecule, TPP46, that has many people barking up the wrong tree. So we really feel we have a strong internal -- a differentiated advantage here from our understanding of the molecules. We're putting a DC with particularly interesting properties and exquisite selectivity through its paces right now and have several additional candidates approaching this point with a range of properties, including brain penetrants, okay? And I'm just going to segue with this next slide towards the end. Dr. Al-Samkari will speak, it's considerably more depth on a technical basis for PK activation, benefiting low to intermediate risk myelodysplastic syndrome. But specifically, towards a correction of the severe anemia observed in many of these patients. But supporting this indication at Agios, we've conducted experiments evaluating effects on hematopoiesis and erythropoiesis. And following the theme of the last few slides, I'd like to illustrate that we hypothesized as potentially important complementarity between PKM2 and PKR activation. So PKM2 is expressed in early bone marrow progenitors. And actually, if you go back to slide. That's right. PKM2 is expressed in early bone marrow progenitors, transitioning to exclusive expression of PKR in red cells and other leukocytes continue to express PKM2. Improving red cell health allows for a longer lifespan of red cells, but we believe the impact of PKM2 early in hematopoiesis confers very positive effects reversing ineffective or dyserythropoietic potentially very important for this disease. Next slide. This is my last data slide. Underpinning the overall hypothesis that treating MDS anemia with a PK activator is actually quite old and is an abundant literature supporting the acquired deficiency at PKR and red cells in MDS patients. So we recently conducted the POLG model recapitulating this effect. And this is a study done at pilot scale in our Cambridge labs. And although preliminary, we saw consistent improvement in red cells, hemoglobin as hypothesized and a reduction in reticulocytes very consistent with both improved red cell lifespan and health and possibly the correction of the dyserythropoietic state. So I'm going to summarize this. I guess we can -- I've already spoken to this, Holly, so we might as well move directly to my summary slide, the last slide. Okay. So our 13 years of research and development focused solely on cellular metabolism field is unmatched in our field. We've deliberately selected targets with the potential to address medical need across multiple indications. But generally founded on research in a sentinel genetically defined indication. Our PAH stabilization program has unique potential for directly correcting the disorder leading to phenylketonuria and our genetically defined disease approach is both thoughtful and expedient allowing our generation of the maximum return on investment for studying targets of inborn errors of metabolism. In my opinion, our current pipeline has the breadth and depth able to sustain a level of productivity through the greater part of this decade. And with that, I'd like to introduce you to Dr. Hanny Al-Samkari. Dr. Al-Samkari?

Bruce, thank you so much. It's a pleasure to be here. My name is Hanny Al-Samkari. I'm a hematologist and clinical investigator at Massachusetts General Hospital and Harvard Medical School in Boston. So I'm just going to start -- I'm going to have a section here, right? I tell you a little bit about MDS and the unmet need in MDS. And then later on, I'll also be speaking to pyruvate kinase deficiency and the impact of PK activation in patients with PK deficiency. Next slide. So myelodysplastic syndromes are an extremely heterogeneous group of clonal hematopoietic disorders. These are really rare, mostly low-grade hematologic malignancies although many of them function very much like a chronic benign hematologic disease. Patients with MDS have isolated or multiple cytopenias. They can have substantial anemia, which can be isolated, they can be accompanied by leukopenia, can be accompanied by thrombocytopenia. These MDS can result in just about any hematologic, any combination of hematologic abnormalities when it comes to cytopenias in patients who have it. And it's really due to a problem in the factory. The bone marrow produces the cells, the bone marrow stem cells over time can develop mutations that lead to essentially gumming up the works of the factory. Patients will be less able to produce the red cells -- the volume of red cells needed to maintain a normal hemoglobin. Same thing with platelets and white cells in order to maintain normal counts. We diagnosed MDS. First, we have a sense for patients presenting with MDS clinically based on their CBC findings and their clinical symptoms. And in order to confirm the diagnosis, you need to do a bone marrow biopsy and actually observe dysplasia on the marrow cells. Molecular testing is now really an indispensable aspect of both diagnosis and prognosis in MDS and we recognize the specific mutations and characterize patients clones over time as we follow their disease and treat them. The patients themselves, they just know that they feel very tired. They don't have the energy that they were able -- they don't have the energy that they had in the past. They're not able to do the same things that they could before. Maybe they can't work part -- maybe they can't work full time anymore, have to go to part time. They're not able to travel. They're not able to carry out daily activities due to chronic progressive anemia that ultimately, in many cases, can become severe and transfusion-dependent. Other cytopenias can lead to other complications of MDS. Severe thrombocytopenia can lead to bleeding complications, bleeding propensity. And of course, neutropenia can lead to infection risk. Patients with MDS by and large, are older. And so many of the historical treatments for MDS, and I'm going to review this, but they fall on the chemotherapy spectrum. Hypomethylating agents are cytotoxic therapies. They're chemotherapeutics. And we also use other agents like lenalidomide to treat patients with MDS as an immunomodulatory amide drug. And these agents are often very poorly tolerated in elderly subjects, elderly patients with MDS, and it can put us in a bind. Next slide. So as I mentioned, primarily in older patients, but can occur in younger patients as well. the -- like all clonal hematopoietic disorders, acquired clonal hematopoietic disorders, this is a disease that gets more and more frequent as people age. And really, we see the majority of our MDS patients that we see in clinic are in their -- essentially their sixth, seventh and eighth decade of life. This is a bit more common in men and then also do slightly worse. The one exception here is that MDS with isolated del(5q), which is actually a more -- as a more positive prognosis overall among the MDS syndromes, this is more common in women. Next slide. So MDS is a very complex classification scheme, that has been defined and redefined and redefined previously by the French-American-British classification system and now the WHO. And WHO definitions for MDS. We have, generally speaking, definitions that relate to what we see in the patient's bone marrow on the biopsy whether they have a single lineage dysplasia, multilineage dysplasia. If they have at least a minimum number of what are called ring sideroblasts are a kind of admiral bone marrow cell. And patients with isolated deletion 5q, deletion on chromosome 5, this group of patients presents differently and is treated somewhat differently, so they have a different overall classification. The ones I just mentioned, this is -- this group forms together patients with low to intermediate risk MDS. Patients who have excess blasts are generally on the higher risk spectrum. And we classify patients with MDS, we do a risk stratification at the time of diagnosis with what's called the IPSS-R, this scoring system. And most patients fall in either the very low, low and intermediate risk on the score. Next slide, please. So we have our treatment algorithm here that we generally will follow in most cases. So obviously, we want to take care of low-hanging fruit and make sure that the patient is B12 to rig fleet and so on and so forth. Make sure there's no attritional issues. But then we get into whether or not they have deletion 5q or not, if they have del(5q), we will -- the first-line therapy, assuming the patient isn't so elderly that it could be a problem is lenalidomide. I have patients that are quite elderly who I have concerns about their ability to tolerate lenalidomide. And even though they have del(5q) and they can be directed toward other options. The vast majority of patients do not have del(5q). This is about only 10% have del(5q). And so the vast majority of patients then are treated along the right side of the algorithm. And we look to see if there are like to be a responder to erythropoiesis stimulating agents or not. And this is generally judged by their baseline serum erythropoietin level, their endogenous EPO level. About half of patients are below our cutoff of 500, which means that they're likely to respond to an erythropoiesis stimulating agent for at least some length of time and that often becomes the treatment of choice for those patients, even patients who are above 500 because of such a lack of good therapies for low-risk MDS and treating patients with anemia. We often will still try an ESA in those patients. If ESAs fail or if a patient progresses once they're -- progresses through an ESA then we can think about, depending on the patient's fitness because, again, lenalidomide is not well tolerated by everybody. We can think about using lenalidomide off-label in these patients for those patients, this small cell population that have ring sideroblasts, we can use luspatercept in that group of patients. Luspatercept can potentially be used off label in patients that don't have a high percentage of ring sideroblasts. But again, the efficacy, we're talking about very low likelihood of a decent response in that setting. And ultimately, I talk about all of these drug therapies, many used off label, but we end up dealing with is transfusions. Our MDS patients often just need regular transfusions. Sometimes we can get away with patients on maximal ESA therapy, giving them transfusions only when their hemoglobin drops low enough that they have substantial symptoms. But this is a progressive disease in many patients and over time, they often need more and more transfusions and go on a regular transfusion regimen. Occasionally, a patient with low-grade MDS can be considered for hypomethylating therapy or if their disease progresses to a more high rate disease, then that would be the time to consider hypomethylating therapy. But again, hypomethylating therapy is not tolerated by everybody and a lot of our patients are on the more elderly side. Next slide, please. So just for this short piece on MDS, I think, my key takeaways are that low to intermediate risk MDS forms the majority of patients that have MDS. And the -- a lot of the therapies that we have right now are best used in patients with more high-risk disease, like, for example, the hypomethylating agents. Current treatment options for low intermediate risk MDS are really inadequate. Patients often have to come in for regular transfusions or they have to come in for regular erythropoiesis stimulating agent administration, which is, again, that's a subcutaneous administered agent in the office. There is a lack of a easy-to-take oral therapy in these patients that would really dramatically impact the care of these patients as well as their quality of life and really, we need to work on reaching that goal in this patient population. Because these patients will go years with low-grade MDS, just getting transfusions, getting ESAs. And many -- much of the time will never progress to leukemia but need something to restore their ability to live life and treat their fatigue, improve their exercise tolerance, allow them to do all the things that they used to do. So that's my presentation for the moment. You can go to the next slide, and I'll turn it over to Sarah.

Thanks so much, Hanny.

My pleasure.

So I have the pleasure to walk you through all of our clinical programs that are currently ongoing. And so before we circle back to MDS, I'm just going to outline for you what you'll hear today in this part of the presentation. So first, I'm going to highlight how we're the pioneering leaders in PK activation. Bruce already touched upon it though be it with a slightly different angle. Then I'll circle back to MDS 946. And then we'll be ending on our ongoing pivotal programs with thalassemia and sickle cell disease while we are poised for success there via our global clinical development in our patient physician partnerships. And then also how those programs are set up to cover the full spectrum of patients with PK deficiency, thalassemia and sickle cell disease. So regardless of transfusion status or disease subtype and also highlight how we are moving into pediatrics. So if you can -- thanks. So as you know, we've been studying PK activation in the clinics for many years since 2014. We started with PK deficiency, but with PK deficiency and the data that we've gathered there, we were able to move forward with other hemolytic anemia. So we are building expertise with these diseases by starting on one and expanding into others. It allowed us to achieve a proof of concept across those 3 diseases, and we're now -- we have completed our moving forward with the pivotal programs there. And that is really built on a lot of firsts as well. So it's true the connections that were highlighted throughout the presentation that we have -- we're able to have a lot of firsts. And the one thing that I really want to highlight is through the collaborations with patients and physicians and their excitement and collaboration that we are the first company that have a clinical trial that evaluates treatment for alpha thalassemia as well. The approach to clinical development here is highly differentiated. And what I mean with that is we start with a global reach from the get-go. So we prioritize both feedback, regulatory feedback for our trial designs at the same time by going to the FDA and to Europe and incorporate feedback from both regulatory agencies immediately in our protocols. We also select our sites, knowing where our patients are. So very decent feasibility feeds into our clinical development programs always. And through all of the collaborations that we have with physicians and patients, we are also trying to remove as much as possible barriers for clinical trial participation. And we do that by listening to patients all over the world as different issues may come up where we go. In addition, and this is -- we have a top-notch team, if you can go back, Holly, which -- and a top-notch team across the board. So there is a large group of people supporting our clinical trial programs across the organization. All of them are excellent and very passionate. So there's a broad industry experience in all of our different organizations that support the clinical trials, including in the clinical development team but our medical team also includes academic physicians who have just transitioned into industry with very detailed knowledge on disease state and excellent ties into the community. But most importantly, we have a slogan, where science meets heart, and that is truly what is felt through out of our teams. It's because there is a passion to make a difference for patients with -- who clearly, there's a huge unmet need for the patient populations that we're studying. It's because of that passion that we're really moving forward, but also able to build that extensive network on the right-hand side of the slide. It allows us to build meaningful connections with patients and allowing to incorporate their feedback back into the clinical trial program. It allows us to have strong ties with investigators across all of the disease states. And all of that work really has led to name recognition across industry and academia within hematology. And so that work, it's -- this slide is actually very pleasant for me because I think it has allowed us to move forward very quickly from one disease into other diseases with mitapivat. So as you know, pyruvate kinase deficiency, we have filed our pivotal programs for review, and that process is actively ongoing. But it's because of that data that we can now expand into the pediatric population as well. And then at the same time, we have initiated ENERGIZE and ENERGIZE-T, which are our pivotal trials that will support alpha and beta thalassemia. And then our rise up, which is a sickle cell disease trial is right in same phase of development. Now at the bottom of the slide, you see 946. So as you know, 946 is currently in healthy volunteers with a sickle cell disease component starting within that same Phase I very soon. And then I'm very excited to talk to you how that healthy volunteer data will also allow us to move forward in MDS. And then at the same time, I want to highlight some of the ISPs on the right because it's because of strong collaborations with investigators that we are able to look for proof of concept and efficacy signal via investigator-sponsored trial. And as you know, that has been an approach we've taken for sickle cell disease with a trial at the NIH, further supported by a trial in the Netherlands, in particular by Dr. van Beers, and we're now taking a similar approach for hereditary spherocytosis. So circling back to AG-946, which is our novel PK activator, which creates optionality for clinical expansion of PK activation. So at ASH, you will see the first clinical data from that trial, both from the single ascending dose and multiple ascending dose cohorts of that Phase I study. And what we see in those data sets that it's well tolerated following single-dose administrations up to 30 milligrams and also well tolerated in context of multiple 14-day dosing with 1 milligram and 2 milligrams once a day. The PK profile supports once-a-day dosing. And what we also see is that there are sustained dose-dependent increases in ATP and decreases in 2, 3 DPG to pick in the figures on the bottom of the slides. And the way that healthy volunteer study is set up, of course, it allows us to pursue multiple clinical paths in parallel, if the data continues to support advancements, which it does right now. So the Phase I healthy volunteer study is finishing up the math. It allows us to trigger that sickle cell disease Phase I cohort. And that trial, we look at that trial as generating data both for sickle cell disease and other hemolytic anemias. Then at the same time, because the healthy volunteer study is part of that trial, it allows us also to move forward into MDS, and I'll talk to you more about that in a little bit, and then other potential indications. And of course, after each phase of development, there are go-no-go criteria that determines if we move forward into the next phase of development. So the therapeutic rationale for the PK activator in lower-risk MDS, which encompasses very low to low to intermediate risk MDS. So we have evidence that we impact in effective erythropoiesis, and that can be translated to MDS as well. The features of ineffective erythropoiesis are very similar between thalassemia and MDS. And you see some longer-term data at ASH on thalassemia that impact, but also some data on PK deficiency, where we impact in effective erythropoiesis. We also have the knowledge that PKR activation can improve survival and differentiation of erythroid cells in the bone marrow, as Bruce also has discussed. And then we know that it improves red blood cell functionality. We are increasing ATP. So improving energy, nucleotide biosynthesis and antioxidative stress responses via activating glycolysis. And then we also know that in MDS, acquired PKD deficiency has been observed. Another piece of information that suggests that PKR activation may work in MDS-associated anemia. So now moving into the clinical development plan. So this clinical development plan is at the end of the development phase will support an indication for the lower-risk MDS group. So at the top of the slide, you see the overall clinical development plan. But where I want to focus on today is on the first step, which is the Phase IIa/IIb trial. So it's a seamless Phase IIa proof of concept in a dose-finding Phase IIb study in one protocol. So the first part of the study will be an open-label Phase IIa in which 20 patients will be exposed for 16 weeks to a high dose of AG-946. And that trial -- that part of the trial is meant to evaluate the impact of AG-946 on anemia via a hemoglobin response. So that component of the trial we enriched for a population that has a low-risk MDS. And then because of the open-label nature of the trial, there is flexibility around when we can announce proof of concept, which then allows us to move on into the Phase IIb for 24 weeks in which multiple doses will be tested against placebo. And that will be an endpoint that will be focusing on hemoglobin response and transfusion reduction. And so both of these trials of participants in either the IIa or in the IIb trial will have an opportunity to roll over into the open-label extension. And then, of course, at each phase of each part of development, again, there will be go-no-go criteria to determine if we move forward. And so we're anticipating to initiate that study in the second half of 2022. Now it's, of course, that program is really building on PK activation again. And so we highlighted already last year at the PK our investor event that our clinical focus is to transform the course of hemolytic anemia by increasing red blood cell energy, health and longevity. And so that is something that we have demonstrated in PK deficiency and continue to demonstrate in thalassemia and sickle cell disease. And but of course, these diseases have in common is that the red blood cells have insufficient energy increased oxygen radical injury, and then -- and they have all abnormal red blood cell shapes. And that leads to patients having multiple complications and impacting quality of life as described on the other side of the slide. So now I'll walk you in order through thalassemia, scale cell disease and PK deficiency before I hand it back over to Hanny. But the thalassemia program, so both alpha and beta thalassemia patients experienced the build in chronic symptoms and have serious complications regardless of transfusion status, and that is something that is more and more understood that both nonregularly transfused beta thalassemia patients and alpha thalassemia patients suffered from same co-morbidities. And so anemia and fatigue, pain and fractures, they can get transfused in the context of infections or needed chronically. The -- because of the chronic disease, there is a huge economic burden and inconvenience, both by the disease and by the treatments for the disease. And of course, there is a risk of organ damage and infection as the disease manifests itself. And so where -- we believe there is a significant opportunity as there are 18,000 to 23,000 alpha and beta thalassemia patients in the U.S. and in 5 European countries, but there is significant opportunity outside of the U.S. and EU as well. And there is an unmet need. There are no approved therapies for alpha thalassemia, very limited options in beta thalassemia and then specifically, if you're not transfused, that's definitely the case. And then as I mentioned, the nonregularly transfused beta thalassemia and alpha thalassemia are less understood. But there is a lot of work going on right now in those 2 as well. What we believe we're set up for success with our program is that we are evaluating mitapivat as of now already across the full spectrum of the disease, that we do have a global approach to clinical development, which I touched upon earlier and that we are leveraging our connections with the patient and physician communities. And so a reminder on the next slide of the clinical data is that we did see hemoglobin response in our Phase II trial, which was nontransfusion-dependent alpha and beta thalassemia focus. And that was supported by the secondary endpoints in which we did see a sustained hemoglobin response and an impact on hemolysis and erythropoietic markers. And the mechanism of action was supported by increase in ATP and safety was very similar to what was observed. You will see extension data at ASH. There is a long-term extension data with multiple, multiple weeks on treatment, and that continues to support this message that you see sustained improvements in hemoglobin, hemolysis and ineffective etoposide and no new safety findings. That, of course, then allowed us after the core period of this trial to design the following 2 trials: So 2 global Phase III randomized controlled trials, ENERGIZE and ENERGIZE-T, one focused on the nonregularly transfused population, the other one on the regularly transfused population. And the endpoints here are relevant to those populations in the sense that one is focused on hemoglobin increase, but supported by other secondary endpoints and the other one is focused on transfusion reduction. And this pivotal program will deliver on the totality of the data we need for the totality of the thalassemia population. As mentioned, the enrollment criteria are broad with alpha and beta thalassemia, the study end points allow us to show that benefit across the entire patient population, but to -- I forget already who said it, but we learn and we leverage from our interactions. On other programs, hemoglobin end point, we know it's not enough for nonregularly transfused patient population. So the secondary endpoint support clinically meaningful end points on how patients feel and function as well. And then very importantly, and this came even up in a patient conversation today, one of the big things patients request is to make it easier to participate in clinical trials and to be allowed to be part of clinical trials with not additional impact on their quality of life by participating in a clinical trial. So we are trying to provide as much flexibility and support as we can in all of our trials by giving participants options of home visits, in-person center appointments, telemedicine appointments, wherever possible. So flexibility here is key and has been implemented. I've also mentioned that we go where the patients are for our thalassemia program, you'll see that there is a big trial presence along the Mediterranean, everywhere along the Mediterranean and in Asia as well to cover alpha thalassemia as well. So moving to sickle cell disease, another very serious disease. The big difference in these patients also have hemolytic anemia, also manifesting itself with low hemoglobin and transfusions but they also have vaso-occlusive crises, can have strokes and real short life expectancy. And then again, the red blood cell lifespan is severely reduced in this disease as well. Very similarly to thalassemia, the global reach, it's -- there is significant opportunity for sickle cell disease also outside of the U.S. and the EU. The unmet medical need, there is no approved therapy that addresses both pain and anemia and there is the continuously is a need for innovative treatments in this disease with convenient and oral administration. The success factors here on the clinical development side, it's similarly on the global approach to clinical development and our community connections. This trial is set up very innovatively with a seamless Phase II/III design, but with a lot of focus on reducing enrollment barriers and addressing key aspects of the disease as heard by patients as well. A reminder of the trial data that underpins this. So we have the 2 collaborator-led studies but it was the trial data at the NIH that allowed us to call proof of concept. And we did see hemoglobin increase, a decrease in the hemolysis markers the changes that we wanted to see on the pharmacodynamic markers and safety was consistent with what we've expected. A reminder of RIZAP. So Phase II, the first part of the trial is the dose-finding component and we'll be looking at the hemoglobin increase in safety that then allows us to trigger a Phase III component to the trial in which we test mitapivat selected in the Phase II to the matched placebo randomized 2:1 with 2 primary endpoints to address that unmet need, one on the anemia with a mean hemoglobin increase that we're looking at and then the annualized rate of sickle cell pain crises. If you can move on. It's an input from the community that helps validate the sign. So we did lower our hemoglobin limit to 5.5 grams per deciliter. We are allowing concomitant use of hydroxyurea and we have data in those investigator-sponsored trials of patients who are on hydroxyurea. And then we have brought definitions of pain events and episodic transfusions as well to help reduce barriers. And so then the study endpoints are paying in hemoglobin as we -- that were considered 2 very important end points, but we also have in our secondary endpoints, patient-reported outcomes that further support this. And then again, to execute on this trial and make sure that this trial is successful, we have aimed to provide as much flexibility and support as we can here as well. And then you'll see that our country selection is different because we're going where the patients are with sites in Africa and Brazil being a heavy focus for this trial as well. And then last but not least, PKD. The data from our pivotal program that we were able to submit and that is under review. So a similar principle as the other programs, right? They both support each other and allow us to provide data across the broad spectrum of the disease. The primary and secondary endpoints as we know, were achieved across both studies and the safety profile was generally consistent. But what you will see at ASH is that the long-term extension data, the 011 study continues to reinforce this and patients who were switched to placebo are behaving very similarly to the ones that were originally exposed to mitapivat. And then on top of that, we continue to see a maintenance of response over time. So we're very excited about those data. I'm very happy that it is under review right now, but we're also very excited because these data allow us to move forward in pediatric indication as well. And so on the next slide, you see that we will be taking a very similar approach to pediatric development with 2 trials supporting each other so we can cover the entire population there as well, it will cover children age 1 and up both of the trials. And so those are on track to initiate as well next year. And then last but not least here, ASH, there we have great data across the 3 hemolytic anemias with multiple oral presentations. In addition, I know in the press release, we have 3 oral presentations mentioned, but we have one that in the meantime, got upgraded to an oral presentation as well, which highlights how mitapivat improves ineffective erythropoiesis and reduces iron overload in patients with PKD. So we're very excited about that. And then there are other select poster presentations on the right there as well. So very excited about our upcoming ASH. And then with that, moving on to the last slide. I hope I was able to highlight to you how we are the pioneering leaders in PK activation from the clinical development side. Very excited to be able to announce our MDS plan today with 946. And then the third and the fourth message go hand-in-hand because it's through our differentiated approach with global clinical development and the partnerships we have with patients and physicians that allow us to design these trials that will -- are poised to impact the full spectrum of the patients living with these 3 diseases regardless of transfusion status or disease subtype. So with that, I'm going to hand it back over to Hanny to give his perspective on PK deficiency and his views on how mitapivat may potentially transform care for patients.

My pleasure. Thank you, Sarah. So we can go to the next slide. So let me tell you a little bit about pyruvate kinase deficiency. So pyruvate kinase deficiency is the most common cause of congenital what we call non-spherocytic hemolytic anemia. It's not a common disease by any stretch, but it is the most common cause of this sort of rare bucket of hemolytic anemias. This is a very heterogeneous disease, but one of the things that unites the vast majority of patients with pyruvate kinase efficiency is they develop multiple short-term and long-term complications from this disease. So it is a hemolytic anemia. So obviously, the consequences of anemia, the fatigue, the reduced exercise tolerance the inability to focus at work or school, the inability to maintain a full-time job or be a full-time student. These are all things that can impact patients with PKD, the severity of their anemia notwithstanding, some patients with relatively moderate anemia, they still experience rather dramatic symptoms. But the consequences of chronic hemolysis touch just about every single patient with pyruvate kinase deficiency typically in multiple ways. So patients will develop pigment gallstones that can result in the need for whole cystectomy. They develop just patients that live into old age, almost everybody will eventually develop iron overload whether or not they are transfusion dependent, whether or not they've ever even received a transfusion, the pathophysiology of the disease is such that iron overload just occurs over the course of life. Patients develop bone disease. They -- 75% of patients with pyruvate kinase deficiency have DEXA's T-scores, DEXA being the bone density scanning methodology that is used most frequently DEXA T-scores in the osteopenic or osteoporotic range. And that's at a median age in the 30s and age 30. So this is a really dramatic impact on multiple organ systems. Iron overload can have a very dramatic impact on the endocrine system and result in multiple endocrinopathies, can result in thyroid disease and growth hormone deficiency. These things can impact patients at all stages of life from childhood to young adulthood to later adulthood. Patients not infrequently are transfusion-dependent when they are infants or small children. Very frequently, they have their spleen taken out, splenectomy is really the -- up until this point has been the primary effective treatment modality in this disease, although not everybody responds to splenectomy, and splenectomy has its own issues, but patients will often have their spleens taken out at a young age and then they may have a period of time where they do generally well without transfusions. But as patients age, enter the 40s, the 50s, the normal cardiopulmonary decline that occurs with advancing age often means that these patients need regular transfusions again in order to live semi-normal lives. So patients, once they have their spleens out, they are at increased risk of thrombosis for the entire rest of their life, their increased risk of infections and sepsis for the rest of their life. We like spleens. We like to keep them in bodies whenever we can. And so taking a patient spleen out is never a decision taken lightly, and it certainly has its consequences. Next slide. So the life of a patient of a typical average patient with pyruvate kinase deficiency go something like this. When patients are younger, they are often unable to keep up with their friends in school, in terms of academics and athletics due to the consequences of chronic anemia. This is experienced differently depending on the severity of the disease, but it's very, very common for this to be the case. My adult patients tell stories about how they couldn't play sports when they were kids or they could play sports up until sports became even remotely competitive and they can no longer play sports. And then patients enter the prime working years and it's really quite common that patients are unable to work full time due to fatigue and anemia issues. A simple viral infection can result in a dramatic crash in the patient's hemoglobin and put them in the hospital. So we're living in the pandemic era right now, but even before that, viral infections for patients with pyruvate kinase deficiency could provoke in a plastic state or a hyper hemolytic state that put them in the hospital needing massive numbers of units of blood transfused in order to get them out of there. The patient's chronic disease complications ultimately catch up with them in many cases. Iron overload would not adequately addressed results in liver disease, can result in liver cirrhosis, can lead to liver cancer, can result in chronic heart failure. The bone disease, bone fracture and a large study of over 250 patients with molecularly confirmed PK deficiency, bone fracture occurred in 17% of patients. And these aren't elderly -- predominantly elderly patient population. These are patients across all spectrum of age. And it's not a surprise given the impact on bone density and by just sort of middle adulthood, patients with an average age of 35. Next slide. So one question that we get asked, well, okay, does this disease impact life expectancy? And some recent data suggests that it does. In a study done with patients at the VA, patients with the pyruvate kinase deficiency were compared with matched controls from the general VA population. And there was a significantly lower time -- significant lower survival time in the patients that had PK deficiency compared with those who didn't. And this is very consistent. It's what we -- it's not -- doesn't come as any sort of surprise to us based on our knowledge of the disease and the manifestations we see in our patients, but nonetheless, recently shown in a more data-driven manner. Next slide. The iron overload and PK deficiency very frequently gets overlooked. So patients with PK deficiency sometimes are not even diagnosed until middle age or later in life. I've diagnosed a few patients with PK deficiency and there are 50s and 60s. And if you don't carry a diagnosis, then no one is going to bother looking for iron overload and trying to prevent it with chelation. And this, unfortunately, results in quite a lot of patients developing iron overload even when the diagnosis is clear, patients will develop it over time due to transfusions as well as the pathophysiology of the disease and will often need chelation. Obviously, needing iron chelation is a significant cost burden and it impacts on quality of life. Next slide. So up until recently, our therapeutic modalities to treat PK deficiency beyond supportive care and transfusions related to splenectomy, which has all of these mentioned before, and hematopoietic stem cell transplantation, which is limited to the most severe of the severe agents and it really has only been done in a handful of patients with this disease. And with the recent publication showing [ 16 ] patients of K-series getting stem cell transplant, 5 of those patients died to product versus host disease. So we recognize that with central transplantation. We're trading 1 product disease for another. And so it's not a favorite modality. With edited as a potential all therapeutic -- a targeted therapeutic, a disease-modifying therapeutic in this disease and this is -- this figure that I have here on this slide is from the Phase III ACTIVATE study. You can see on the left, patients treated with mitapivat and on the right, patients treated with placebo. The threshold for a response, the primary endpoint was a sustained response in the fixed dose period of this study. Patients were initially treated for 12 weeks with mitapivat and a dose escalation period, followed by a 12-week fixed dose period. And the primary endpoint was 1.5 grams per deciliter improvement in hemoglobin or greater at 2 out of the 3 assessments in the fixed dose period. And you can see that 40% of the patients on the mitapivat arm achieved this and none of the patients in the placebo arm achieved it. You can also look at just the overall magnitude of change, how almost every patient on mitapivat had some improvement whereas most of the patients on placebo had no measurable improvements or even a decline. And we talk about endpoints, okay, 1.5 grams sustained but look at the magnitude of the improvements in many of the responders, 6 grams of hemoglobin, 5 grams of hemoglobin. This is not just a disease response. This is essentially a physiologic normalization. I'll get to it momentarily when I talk about share some anecdotes. But what a patient goes from a hemoglobin of 8 their entire life and all of the consequences of that to having a hemoglobin of 13 completely normal, no longer jaundice, no longer fatigued. Everything in their CBC looks stone cold normal for the first time in their entire life. -- it's -- I mean it's an understatement to say that's obviously a life-changing experience that individual. And it's been really wonderful to be able to offer treatments like this on clinical trials to patients with PK deficiency and see these sorts of responses. Next slide. So obviously, efficacy is only one side of the coin, right, and the safety piece is obviously very important as well. So this drug in the randomized ACTIVATE study was very well tolerated. There were 0 patients on the mitapivat arm that had any dose reduction, treatment interruption or discontinuation and certainly no deaths at any point during the study for adverse events. So you can't ask for any better than that with anything better than that when it comes to safety. But on top of it, the safety profile was similar to placebo. The 3 most common adverse events reported in the mitapivat arm are actually more common in patients receiving placebo. So that was very heartening and is consistent with what we see clinically and patients receiving this drug on study. The ACTIVATE-T was the PARTNER study to a ACTIVATE looked at patients more regularly transfused to ACTIVATE. I may not have mentioned that ACTIVATE was limited to the not regularly transfused population of patients PKD. ACTIVATE-T was regularly transfused patients. ACTIVATE-T also in the safety profile was similar to prior studies, both the DRIVE -- Phase III PKD study and the ACTIVATE study. And it's really -- with the outcomes in ACTIVATE-T with [ 47% ] of patients having a substantial reduction in the transfusion burden. That's obviously is very heartening when you have a patient who requires regular transfusions a couple of units of blood every month or every 6 weeks and be able to reduce that dramatically that makes a substantial -- and that's a substantial improvement in their quality of life, as you can imagine. But many of these patients actually achieved transfusion independence. They were converted from being dependent on transfusions to not requiring any transfusions. And some of those patients normalize their hemoglobin. So again, physiologic normalization possible and even the most severely affected patients with PKD. So we've obviously been thrilled with these fundings. Next slide. No matter how we subdivide the patients, look at them in the various prespecified subgroups the mitapivat arm was favored in ACTIVATE. So whether we think about it based on the severity of the underlying anemia, patients that have hemoglobins less than or greater than 8.5, whether they had more expectation of a more severe, more drastic phenotype having 1 non-missense mutation in addition to missense mutation or just having 2 missense mutations expected to be a less drastic phenotype whether they're older or younger male, female, it didn't matter. This was favored. Next slide. ACTIVATE-T, again, not randomized, but just looking at the results by, again, similar prespecified patient subgroups. It didn't really matter what subgroup was examined. We found that the transfusion reduction response was robust. Next slide. So this slide I have here for patient case story, I sort of have this as a placeholder to just share a few anecdotes. I mean, I already mentioned what can happen when a patient goes from a hemoglobin of 8 to 13, it's complete normalization of their physiology in many ways. But just -- it's been really wonderful being able to see this with so many of my patients see such a dramatic improvement, one of my patients was very far away his wife was a nurse and brought him to me to put him on this study because he has led his whole life at a hemoglobin A is basically essentially spent most of his time on the couch at home was getting older and developing more and more fatigue and age-related typical cardiopulmonary decline is being dramatically exaggerated because it is chronic anemia and multiple long-term hemolytic complications as well that we have to deal with over the course of life and we'll continue to deal with. And on mitapivat, he went from her dragging him into my office, to her complaining to me that she could not keep up with him because all average hemoglobin came up to normal right in the middle of the normal range for man of hemoglobin of 14 or 15 all we wanted to do was go do social things, see friends, go to restaurants, all this stuff. And I had to remind here that it was for that brought him in to see me in the first place because he was spending all the time on the couch. That's just 1 example of what the change anemia can do. But I think it's also really instructive to recognize that chronic hemolytic complications can be really problematic for patients even beyond anemia. And one thing that I see, and I've seen it in a number of other patients, but just to share one other anecdote kind of before they yank me off the stage with the hook here, is a patient's younger woman that I've taken care of, who -- she had chronic anemia for whole life that was across that she has to dare or something that obviously impacted her ability to do what you wanted to do. She just told me when she saw me to go on the study. She said, "look, I just don't want to be yellow anymore. The chronic jaundice that she had experienced her whole life, the sort of social castigation. Obviously, children [indiscernible] cool and as she is a woman, no longer a child, but having gone through that whole and now trying to live young adult life and all the things that come along with that. And just her complexion changing from tan to normal for the first time in her life from being on mitapivat stopping that chronic hemolysis in the hyperbilirubinemia was just a complete game changer for her. She's not the only patient that I've had in here in my office in tears of happiness from the impact of the drug. And I never thought that I would have patients with chronic Pyruvate Kinase deficiency who were on the edge of being transfusion dependent, have a therapy that 1 day it lets them participate in major athletic activities let from participate and BoxFit cost fit, let them participate in -- one of my patients is repacking RV and is now going to drive it across the country. So this is -- it's normalization of their disease, but it's normalization of their life. And I think that, that has been the most profound aspect. So obviously, as an investigator and an academic, it's just so wonderful for me to be able to see this improvement in my patients. So I'll stop there. I'll give some time back. I know I probably took more time than I should have. But thank you for let me share some of those anecdotes.

Please did not apologize. We could take another hour or 2 hearing those stories. It's good one. It's incredibly powerful and normalization of their lives, right? This is exactly what we proposed to do here. We have the opportunity to do in the next years. So thank you, doctor and good afternoon, everyone. We're going to shift gears here a little bit and focus on where we are with regard to launch readiness in anticipation of mitapivat's approval in the U.S. in Q1. And I'm going to focus my comments on the U.S. specifically. As we've said at other times, our intent and we used to actually ensure patient access to mitapivat and find the right deal with the right part out. In the meantime, we continue to sort of critical path activities that enable a launch in to stay on track, including disease education, KOL engagement, patient profiling and what not. And we'll share more on that in the coming months. But the day for today, I'd like to focus on the U.S. And if I could give you any -- just 1 thing to take away from today is that we are just about ready we made substantial progress in preparing the organization, the product, the market for launch and we were approved today, we'd be able to do what we need to do to get the product to treatment. That's right productive patients. So as you see it, there are about 3 essential components of a successful commercial plan from our perspective, right? Get the right people together, give them what they need to support patients and providers out yourself and your focus on intimate understanding of the patient and the provider experience so that you can have clarity about what their needs are and where we need to be able to bring value to support them. And then last, I think make the complex simple when it comes to patient access to treatment because that experience may be fairly overwhelming for them. So if you look to the next slide, and I want to start by sharing a bit about the profile of our customer-facing commercial team. We've touched on it in previous settings, but I want to do just a little bit more detail here. We've been here before, right, in terms of building highly performing commercial organization that delivers for patients, for providers in oncology, and we've leveraged that experience and adapted our model to the unique requirements in the orphan disease market with a chronic treatment. We've been braced what we refer to as the One Agios concept, which is a step-up from our oncology experience because it requires that only sort of the different depth of experience and understanding of their disease, but a level of seamless coordination between functions. It's quite about single patient education, access, treatment negotiation, treatment support and maintenance, oftentimes in ways that were not essential in oncology, we also -- we have 6 MSLs. We've been at the forefront of our insight generation, disease education amongst other activities. We have 18 sales representatives. We call hemolytic anemia specialists and 3 clinical nurse educators who've taken up the responsibilities for disease and patient and provider profiling and also made all the difference in terms of moving the needle on behalf of our patients of the business. Our myAgios team, right, it's our patient access and reimbursement support function. I think since midyear has been enrolling with patients who opt in to our services, seeking credible accurate information about their disease and once they're confirmed -- they have a confirmed diagnosis of PKD. They want to know how to connect with their providers and they want some direction on how to connect with others in the patient community, which we seek to provide. This function has been staffed by 2 clinically trained professionals that we call patient support managers. And they build the supported intimate relationships with these patients. I do take a relationship that's going to last the duration of their treatment. And they engage with these patients on a monthly basis, and I'll get to a little more detail on that later on. In addition to the patient support managers, we also have 3 national account directors that are focused on the payer, PBMs and the distributor relationships just to ensure that we've got everything in place to be able to facilitate patient access to treatment. I mean all of these functions are regionally aligned just sort of following this One Agios concept. It allows them then to have better local coordination, routine reviews of the state of the business and perform action planning on behalf of patients and providers as the need arises. So if you go to the next slide, I'm particularly pleased that we're able to supplement sort of the depth of experience that we developed related to what it takes to successful commercializing in rare disease by attracting incredibly talented, experienced and talented group of professionals as you can tell by the figures here. And we've accomplished much in relatively brief time at Agios. In just a few months, they were able to take a potential customer list. Over 4,000 potential physicians that was generated via machine learning-based predictive modeling process, and both confirm and validate all of those customers. Just about the entirety of that list is completed. And we think it will ultimately little down to about 2600 classical hematologists and hematology oncologists. You split about 50-50 between those in an academic institution setting versus those that are more community-based. And I remind you that's only with 18 hemolytic anemia specialists. The talent, while essential is not sufficient. So we also evolved our analytical capabilities, applying advanced analytics, machine learning and building integrated omni marketing capability that allows us to pull sort of disparate pieces of data generated internally and externally from every touch point with the community to ensure that we have a real-time view of how we're executing to inform adjustments to our strategies in real time and producing sites that will support our ability to be able to identify and support more patients. So we move to the next slide, we've got the right team, and we're arming them with the right tools. and we're experiencing the impact of that work today and moving the needle in many ways. So what I want to do is now turn our attention to our second pillar, which is optimizing that patient and provider experience. So move to the next slide. In an attempt to make the complex simple. It's important to view how Agios can best support the community of patients and providers by viewing their experience through their eyes and really focuses on what counts most. That is understanding what it takes to achieve an accurate diagnosis putting the gaps in the community's understanding of the burden of disease, also understanding how physicians intend to use mitapivat and ultimately to whom they intend to prescribe it. And then lastly, once they're on treatment, how do you support patients to adhere to their physicians' direction. And at each one of these steps, right, there are opportunities and there are challenges. And we're prepared to address them with much of the work already started and we'll continue through the approval in Q1 of next year. So in order to do that, I want to start by focusing on the patients. So let's move to the next slide. So starting with diagnosis, I think you're already familiar with the focus that we've had in supporting patients and physicians and trying to improve the diagnosis rate and as I mentioned earlier, anything we do needs to come from an understanding of the patient and provider experience. So I want to introduce you to one of the patients that we've come to know over the year. You can hear a story from I think directly on our no PK deficiency by YouTube channel, where he leans out in great detail, his experience living with PKD. And so making right, person about 40-year-old from Idaho who's originally diagnosed with PK deficiency at birth. He also happens to have an older brother who also was diagnosed with PK deficiency. And based on this transfusion history, he falls into that subcategory of PKD patients considered less frequently or rarely transfused, which is the far majority of PKD patients. And he was diagnosed a young age and it was still challenging for him to find a position who is sufficiently informed to support him and as he manages disease. And so as we've experienced for many PKD patients, he has to travel quite a good distance to find someone who could help him. So I would just note, this is a young man who now suffers from osteoporosis, right? Hanny talked about that experience earlier. -- we'll talk more about Nathan specific experience as we go through the balance of our discussion. Let's go to the next slide. Nathan's story to find local experts is not entirely unique, unfortunately, right? So filling the gap in awareness, which is key to bending the curve in relative diagnosis has been a work in the prelaunch period. And we've seen improvement in provider recognition that PKD is significantly underdiagnosed. We need from what we observed last year, 40% of the providers agreement with that notion to now over 50% in the early part of this year. And I would suspect that we're well north of that now. Our research also indicates that the majority of potential treatment physicians have familiarity with the disease, which is also a significant improvement over prior years. And those who consider themselves very familiar expert in their understanding has been a driver of this improvement, particularly about academics, which we would expect. And about that's about twice that of what we're seeing amongst community treaters. And though we move the needle on understanding and awareness when we presented a sample of blinded patient profile, patients with a range of hemolytic anemias, only 20% of physicians were able to accurately identify the PKD profile. And that's understandable given the prevalence of the disease, but also reflects the challenges of diagnosing PKD up until now, right? So if you look at the illustration on the left, I think it helps to tell the story and we've walked through this before. And without sort of the level of understanding of the disease, the long-term patient experience and the lack of disease-modifying treatments, there is a be hard press to persist until they're able to include or exclude PKDs as a diagnosis. I think like Nathan, some patients with general anemia are diagnosed early. But between the work that we've done with patient profiling, our extensive market research, we believe that about 1/3 of patients in the U.S. north of 1/3 are diagnosed, and we will continue to see that accelerate, certainly up to and through the approval for the next year. But we believe the bulk of undiagnosed patients are in the group of patients, labeled a hemolytic anemia of unknown etiology, right? So this is where we directed much of our efforts and before the availability of Anemia ID the physicians would have to use upwards of 51 -- 52 different enzyme assays to reach a definitive diagnosis without a great deal of incentive to do so, right? So we've been focused on educating offices on the availability of Anemia ID to help patients to overcome this diagnosis spiral. But this is only 1 component of our overall profiling work. So I'd like to share a little bit more on that with you now. So let's go to the next slide. We essentially have a very simple sort of two-pronged approach to this, right? So leverage the analytics and customer engagement to identify potential patients. And then once identified, give them what they need to be able to reach a definitive diagnosis, leveraged machine learning applied to a patient claims data to provide a starting point for our team to start their profiling efforts as I sure earlier. We've been doing that since the end of Q2. We've also considered how electronic medical records can aid us in the search and coming at it from a couple of different angles. The simplest package has been to work with the digital practices and It's too easy to explore how to use a basket of ICD-10 codes and CPT codes that we believe are most predictive of potentially undiagnosed PKD patients, network is ongoing. We're also collaborating with 1 institution on exploring the development and validation of a fairly sophisticated algorithm, which can be used to identify patients also in their system. And if the algorithm can then be applied to a number of different institutions over time. So is where they're still ongoing. It's somewhat early days, but seems fairly promising, and I think we'll add meaningfully to our work on the patient profiling identification. We talked previously about our collaboration with 23andMe where they explore their global records from the R486 most common PKD mutation in Southern Europe. And that result in identifying thousands of patients who were carriers of the mutation and those patients received a sort of newly developed carrier report, e-mail everyone who appropriate from the 23andMe database. Now we intend to expand that collaboration by supporting 23andMe and potentially offering genetic counseling and information about genetic testing options with those patient can go on to confirm will be a [indiscernible] second mutation, which could result in PK deficiency diagnosis, and those discussions are also ongoing. Our second strategy focus is on extending our support for patients and providers simply to confirm the PKD diagnosis for the patient and providing the patients with the information that they need to be able to manage their disease. And so they share the last earnings call, we've collaborated with InformedDNA to provide free genetic counseling for those patients diagnosed with PK deficiency through Anemia ID. And this is really important because it empowers patients to be able to initiate the testing process on their own and the support they need to interpret the results, right? And understand how to discuss those results with their physician. And all of this is done in full cooperation with their treating physician. Anemia ID has been well received. We talked about this previously, right? We've now just more than 2000 kits distributed thus far, and we expect it will continue to be. So -- and with our research indicating that about 85 -- or physicians would tell you, at about 85% of the hemolytic anemia patients when the etiology will qualify and be eligible for testing via Anemia ID? And remember, I mean, Anemia ID can result in a diagnosis range of potential hemolytic anemia is not just pyruvate kinase deficiency. And those data obviously are going to be useful in helping probably physicians to build up their treatment plans with the patient. What Agios ultimately receives is an aggregate report of those findings. So we can get a sense then of the volume, how many are PKD patients versus others and it helps to clarify our understanding of the true prevalence of the disease and that it gives you an opportunity to be able to -- for the -- percentages to be able to follow up with the practice, they don't know the results of the test, they don't know anything about the individual patient. We just know that the test was order to buy that practice. And so if the practice and the is willing, they can engage in discussions with the representative to better understand the outcome for that individual patients and then decide whether Agios can provide an additional support for that patient, mostly through our MyAgios program. So diagnosis alone isn't sufficient to ensure all patients are optimally treated, right? So the sense of urgency to provide more active intervention for PK deficiency. It's largely anchored in a solid understanding of the disease burden, regardless of transfusion history as Dr. Al-Samkari just walked us through. So let's go to the next slide, talk a little bit more about disease burden. And this is Nathan's experience to some extent, this is the experience of many patients. And I think that Dr. Al-Samkari explained it beautifully. I think what patients like Nathan often face, particularly those who are rarely or never transfused is sort of a minimization or oversight about the true impact of the disease on their lives. And so on the left, you see some of the coming misperceptions, right, that we hear from patients. They're being told that you're not really transfused, then your disease is mild, right, not recognizing the issues attended with chronic hemolysis iron overload in these patients. You must only suffer then what did these associated with no, but if you can regularly transfused on why that is not necessarily the case. And oftentimes, there's a completeness of the psychosocial implications for patients, right? And this is particularly challenging when you consider the volume of patients, classical hematologists and hem-onc have to see on a daily basis, right? Because uncovering psychosocial issues, the burden on those patients require some digging, some discussion with the patients because many are not volunteering any details on their experience. But the data are critical in dispelling the myths such as the appreciation for the wide-ranging persistent morbidities, complications associated with PKD, especially the utilization. And as we learn from our own study findings with natural history study that these complications are experienced across the spectrum of patients without regard to transfusion history. But it's the psychosocial implications that I think just require even more consideration. Go back to Nathan's story, he tells it best, the inability to engage with his kids as fathers you'd expect fathers commonly do because of the extreme fatigue, the chronic bone pain, right? The isolation that comes from the fear of contracting infections, right, because they're sort of guarding against exposure to other people, especially if you're [indiscernible] had a transplant as Hanny indicated, which means that fewer social interactions, relying on our firmness to deal is the way that he's able to develop friendships, but they're virtual, right. And forget taking any vacations, right? So for Nathan, this is his normal. For those of us looking in, we know that Nathan them deserves better, and that's the promise, right? That's the promise that we have with that, we believe. So this burden profound set a component to understanding the overall experience for these patients. And so the next question is what are you doing about it? So let's go to Slide 98. Excellent. So we're focused on educating and supporting the expansion of this community of experts, right? The work that they also carry and as colleagues are doing to sort of level the community's understanding of the natural history of the disease is incredibly important, especially the notion of that transfusions, even a [indiscernible] not confirm disease severity, right? We're fortunate to have a good deal of data in the literature with which we'll able to tell the story, right? which is greatest publications, the move experience of these patients, approaches to treatment management, the natural history study, the peak registry, continue to produce great insights and an ever-growing list of publications. The -- especially the Bosco paper, right, which clearly illustrates the range of complications and what bits experience by patients across the spectrum disease-spectrum of transfusion staff. And we have our new understanding about the implications in bone health over time, right? Remember, Nathan is only 40 years old and has significant osteoporosis, right? and already shared, that's not uncommon. So these data, which you'll see a lot more at ASH in a matter of weeks are amplified via publications, digital media, obviously, pulling in congress presentations and a good deal of live programming as well in terms of tactics that we employ. We also support patients directly through offerings in myAgios, right? Acts as simple as a disease discussion guide for patients, right, to help them understand what they really need to be sharing with their physicians during their routine visits. I think it's particularly important and helping patients to give voice to their experience, especially the this up for a long time. And their current state is, as I mentioned before, they're normal with no notion that they could live like as any different from that. So if we do our jobs on driving diagnosis, filling the gaps in the committee's understanding about the metrics of the disease, the burden of the disease for these patients, and we could turn our focus to supporting physicians and their inclination to prescribe across the spectrum of patients. So let's go to the next slide. We've done extensive work to understand how physicians intent to use mitapivat across a number of different patient profiles, right? So the key takeaway, I think, is summarized by the Hanny on the slide. Based on are their understanding of the safety and efficacy profile mitapivat they are inclined to prescribe fairly broadly to the population inflected in ACTIVATE trials or ACTIVATE-T and the [indiscernible] and you'll see a slightly higher inclination to treat all of the regularly transfused patients versus the others, but the difference is actually quite immaterial. The key takeaway here is that regardless of transfusion history, physicians in those who are well educated, well-versed on the ACTIVATE and ACTIVATE-T data would like to be able to prescribe fairly broadly. And this is particularly encouraging because what we initially hear from some folks who have less familiarity with this disease, has been really considering those patients with treatment dependent sorry, transfusion dependent are truly the most severe patients. But without having a really good understanding of what the long-term complications are for these patients. So what isn't shown on the slide though, but was equally interesting was to see the physician interest in describing to patients who were not studied in the ACTIVATE trial, right, but may have been in drive PK, right? Those who had double non-missense mutations, hemoglobin that was above 10, even older pediatric patients, right? We're seeing integration to prescribe of 40%, 50% for those patients as well. And while that's interesting and promising observation from our data, I think those expectations have to be tempered by a real world consideration of payer restrictions and in some instances, the absence of data. And that's what we want to be. So we led by the data. So go to the next slide. I think here, what we've seen and as Hanny shared earlier, we've seen in both physician anecdotes and our research is that when it comes to assessing response, right, providers will consider the totality of the patient's experience, right? Meaning hemoglobin response while certainly important is only 1 piece of the picture for many of them. So as you saw on the graph that I showed earlier, the 40% of patients achieved the primary end point improvement 1.5 grams per deciliter robin hemoglobin. But we also see that up to 1/3 of patients saw improvement between 0.5% to less than 1.5 grams per deciliter as well. And a particular interest of those patients who -- about 5% of them, who achieved an improvement between 1.0 and just under 1.5 grams per deciliter improvement. So you'll hear when you engage with physicians, and I think Hanny expressed some of this himself is that the -- this a good portion of the patients who were studied show at least some measure of improvement and physicians will take into account other markers of as such as bilirubin, haptoglobin, LDH, reticulocytes particular sites as they assess whether this patient is indeed responding to treatment. They also are going to look at the patients to functional experience, the quality of life impact from this as well. All of this will be important as physicians advocate to continued treatment, particularly for those patients who may not have achieved a 1.5 gram per deciliter change of hemoglobin. So we expect, based on is our engagement with the community that the assessment of clinical benefit will largely be done around 3 months or so following initiation of treatment. And so this is where all of this will come into kind of consideration as physicians design whether continue patients on treatment or not. So what should a patient expect if the physician decides that mitapivat is appropriate to them? Let's go to the next slide. I think the for many patients, they have the process from the time that the script is written to fulfillment to be maintained on treatment, particularly for a chronic treatment like this. it can be filled with hurdles and some complexity, right? So challenges can include some wrestling with the out-of-pocket costs, plus share burden, the struggles with compliance and persistency, once they're on treatment, particularly when you consider that it can be a lifeline treatment. So we adapted our distribution and patient support programs in light of those challenges. So after the potential approval Q1 of next year, I think once a physician determines whether a patient is appropriate for treatment with mitapivat, the practice will complete enrollment form, which will be send to myAgios for processing. We tried to create single point of contact for practices and for patients for the duration of their time on treatment. Once enrolled, we're employing a single specialty pharmacy to administer logistics of getting the treatment to patients. While the sufficient support manager builds the longer-term relationship with the patients, familiar as to what everything can expect as they initiate treatment and what they can expect to receive or experience over time. I think all scripts will move through myAgios, just about all, right? So this streamlined approach is sort at the best possible experience for patients, right, that allows us to be able to have a line of sight that enables us to be able to help patients at various points along that journey. It reduces the complexity of initiating treatment. But it also gives us -- because we can sediments individual patients appropriately blinded, but we can see their experience. It allows us to get the best picture of what utilization treatment management looks like, and that's incredibly important. So of course, all identifiable health information is protected. So the patients can feel confident that they can enroll in our program and that their information will be general responsibly. So if you move to the next slide, a little bit more on myAgios. The fundamental benefits of myAgios and short a patient but just going to take some comfort in knowing that they about someone who's tackling the obstacles on behalf of a patient and tailoring the experience to new needs of each patient. So this direct line to patients allows us to educate them about the availability of co-pay support of, let's say, determine whether they qualify for free drug in the event, if that they can afford it or rendered -- essentially render and insured, even ensuring access to treatments if circumstances warrant and there's some sort of disruption in their coverage. I mean all of this and more is available to patients through our dedicated patient support manager with who will develop a relationship over the duration of their time on treatment, which will include monthly check-ins, disease education, connections to other patients in the community from whom patients on -- that may be seeking support as well. So let's move into the next slide when I talk about the last pillar, which is around broad access. We're working at the experience for patients and providers as burden less as possible. But fundamental to doing so is doing the work with payers and other stakeholders to ensure access. And so that's what I want to focus on next, right? So I want to be able to share a little bit of insight about what we've learned that there are some of the key components of the proposition, the story that we have to bring to payers in order to maximize access for patients. The extensive work through our market research, but most importantly, I think with one-on-one information exchanges with payers. I think based on the ones that we've completed to date, we've covered payers who are responsible for the majority of lives in the U.S. and to discuss the breadth of data, both the disease, product efficacy, safety data, we've solicited their responses and requirements to ensure access. And I think what we see there's 3 key components to the story, right? So clarifying the unmet need, in particular, the disease burden in natural history, coupled with the realization that there are no approved disease-modifying options for this population. Second is providing a suitable evidence of risk benefit, clinical value, which is compelling. And third is helping them to understand the financial impact, right? What is key there to realization that we're referring to an ultra-orphan indication, which limits anyone payers exposure. And sharing the data that we generated about the lifetime direct costs of managing PKD are helpful as well. And the key for us is that similar to physicians, right? The initial inclination is to favor treatment or those who are regularly transfused. But when you're effective and telling the whole story, leaning the data out and walking folks through it, the natural history in disease burden, benefits efficacy and safety data, payers understand the room for access across the spectrum of patients regardless of transfusion status. So a little bit more that will be important for you to know about the payer dynamics here on the next slide. We anticipate that the payer mix over time will be similar than that of overall population, the majority of patients covered through commercial insurance and the equal split of Medicare and Medicaid patients as well. Look at many new products and conferred to our study of rare disease analogs and coverage will evolve over time, right? So formulary coverage, we determined at the pharmacy and therapeutics or P&T committee meetings over the course of the year. Those aren't fixed schedules and new products have to fit into those times full schedules. But in the interim, access will largely be granted through a medical exception process. And that's entirely normal than expected. What's key to appreciate is that this move that we can expect steady and continuous liberalization of access over time, especially in the first year post-approval. But we wouldn't expect this to have a material impact on the physician inclination to prescribe. But in the early months, meaning a prolonged period between when the script is written and when the drug is ultimately dispensed. So peak adoption remain unchanged, but the ramp to peak will then accelerate, obviously, over time. So what is going to be increasingly helpful I think in a number of ways is the adoption of the newly approved it 10 code for PK deficiency is shown on the bottom of the slide. And you've already picked it's been used over 60 times since it's been -- since it was approved late summer, which is encouraging. Over time, it will help us to get a better sense of the true prevalence of disease as well. All right. So let's talk a little bit about prior authorization. So on the next -- on this slide, you'll see we expect utilization management to be fairly straightforward based on our interactions with payers. On the left, you'll see what we expect in terms of prior auth criteria. The payers are telling us that they don't manage either to the specifics of our label or clinical trial criteria amongst other predictive elements such as age, baseline hemoglobin and others as you see here. And as I mentioned, we expect fulfillment to be longer earlier in the launch, but improved significantly over time, so later in the first 12 months post approval. Now on the other right, we will also see the likely requirements for reauthorization, right which is common. We just take the authorization to be required anywhere between 3 to 12 months depending on the payer with most being somewhere up somewhere in the middle. So those patients who show a 1.5 gram per deciliter improvement in hemoglobin and will show stability over time, reauthorization should be fine. But for those who show a more modest improvement, this is potentially where a treating physician will need to build their kits, right, for why a patient should be allowed to continue on treatment. And this is where consideration of the patient's overall experience, overall impact on to the functional ability to function improvement at the markers of hemolysis that we talked about earlier are going to be incredibly important. So overall, a pretty straightforward picture of what we can expect in terms of access as long as the price responsible. So let's move on to the next slide The -- just to close out this section, I think as I reflect on the work that the team has done, I think there's a lot that makes us excited about our prospects for this launch and our ability to do the most that we can for patients. I think we've seen that growing understanding of the real patient experience by physicians, by payers or we certainly see the very clear clinical benefits and remarkable safety profile of mitapivat in PKD. I mean everything is in place with regards to supporting diagnosis. And we've seen a nice acceleration of that, particularly over the last 2 quarters. And certainly, the spontaneous development of patient advocacy groups has been phenomenal, right? So there are now 2 new entirely independent groups who are championing the interest on this patient community. And that's incredibly important to success. And so if we can continue to build on this and execute exquisitely. I think we can realize not just the pacing impact of mitapivat but an attractive commercial opportunity as well. I'm going to share a little bit more on that with you here on the next slide. So I think -- I know everybody wants to refine their forecast models. And so we thought it might be good to give you a few things to consider as you do. So for the purpose of exercise, I will assume the midpoint in the U.S. prevalence of the disease, right? So we've said 3,000 to 8,000 between U.S. and EU, about 50% each midpoint then would be 3,000 patients. The -- as I mentioned earlier, we believe that about 1/3 of the -- a little more than 1/3 of the prevalent population has been diagnosed between what we've seen to our individual patients confirmed and then what we picked up in market research as well. And this is continuing to accelerate, we'll certainly accelerate as we get through the approval as well. Now approximately 80% of the prevalent population, we expect to be adults. And I think based on what we've reserved in peak and the natural history study, we estimate about 30% of the PKD population has a hemoglobin above 10 and somewhere between 9% to 15% also possess double non-missense mutations as well. So we reviewed our of our sense of prescribe on what the physician inclination to prescribe is likely to be earlier in our discussion. But I think it's important to consider that while many physicians will treat a broad swath of their PKD patients, those patients will be assessed anywhere between 3 to 6 months post-treatment initiation. So to determine whether there's adequate clinical benefit to support continuing treatment. And that obviously will be important as well as the deal with payers. And we assume that our forecast then that payers will want to reauthorize, and we're between 3 to 12 months that would be the majority end up around the 3- to 6-month range. Lastly, as we discussed earlier, we expect to see in the general population what we saw in ACTIVATE and ACTIVATE-T. And we believe the physicians who want to continue treatment for a proportion of the patients then who do not achieve 1.5 gram per deciliter improvement in hemoglobin despite payer restrictions. So some of that needs to be considered in modeling as well. And then lastly, because this is a chronic treatment that you have consideration of adherence over time, right? -- if we've determined looking at number of different analogs to get a sense of what long-term chronic compliance persistency can look like and then apply the support that we put in place to ensure -- to minimize patient event of treatment. So all of this adds up. It's a very meaningful opportunity in PKD alone. And if we do the right things for patients, this is going to be -- is going to have a very significant impact of this. community into obviously very meaningful for Agios as well. So for plan, let me just go to the next slide. This launch in pyruvate kinase deficiency has implications for more than just than just PKD, right? It sort of sets the stage and positions Agios for success depending on data in both alpha or beta-thalassemia and sickle cell disease, right? So you've got there with new options, there's still unmet need in these settings. I think what we saw is we built a profile for the target community, a target physician community for PKD is that those physicians -- oftentimes those physicians who have 1 or 2 patients, PKD patients under management over the course of the last year. often have 3x as many beta-thalassemia patients under management and 15x as many sickle cell disease patients. So always to say that these physicians are oftentimes the same physicians we're going to be treating thalassemia and sickle cell and other disorders. And their experience with familiarity of the pivot and PKD is going to be meaningful when it comes to any potential future use in these diseases and others. And of course, we anticipate in terms of sort of risk benefit profile, and the low formulation that will continue to sort of distinguish us fairly well versus existing and future options for the patients in this setting as well. What's important is that there's plenty of room for multiple options for these patients and so, if it coexist right. All right. So with that, I'm not going to take you through as the time is precious right now. We'll take through all the key takeaways. I think the bottom line is, is that we've got everything that we need in place to be able to have a successful launch, the right people, the right strategy, the right tacticals and analytical support. We've got the right understanding of what it would mean to deliver for patients and clearly for the business. And as we do that well, then we're going to be able to realize a very significant opportunity for Agios. And so before I end, I want to just take the opportunity to introduce my good friend and colleague, Richa Poddar. Richa has been with Agios for some time now and in a moment, she can introduce yourself directly. But before she does, -- You may not be familiar with Richa. Richa has been part of the Agios leadership team. And as a small organization everyone on the leadership team is involved in everything in Agios and so in that capacity and as part of the steering committee for commercial launch readiness, Richa has been in the sick of all of the work that's been ongoing to support the launch of mitapivat in the next year. And so that makes this transition between Richa and over the course of the next few weeks all the better because well, I need to help fill and maybe a couple of things, for Richa because she comes from this commercial organization originally, and our familiarity with all of the details. She'll be able to hit the ground hunting. And so Richa, won't you say a quick hello to the...

Thanks, Darrin, for the introduction. I'm really excited about this new opportunity, and we're really looking forward to getting to you all of you guys as well.

All right. Great. So with that, I'm going to turn it over to our fearless leader. Jackie.

Thank you, Darrin. Our fearless leader was trying to get off mute. So these are some things that we've talked about in the past, especially after we decided to divest our oncology of business and focus our science and all of our efforts, including commercial, clinical and otherwise, on genetically defined diseases, and I'm not going to deliver the points on the slide, but the attributes that have made Agio, Agio though the last 13 or 14 years in green here are attributes that we're going to continue to leverage in the future, and we're really excited to be on the eve of our first commercial launch in genetically defined disease with PKD with a drug that we did is going to do great things for patients, and we're very excited about all the connections that we are forming here, we'll continue to form with physicians like Hanny with patients across a variety of hemolytic anemias. And with scientists and continue to take this science forward the hemolytic anemia and other diseases that you saw in some [indiscernible]. So with that, before we move into Q&A real quick. I do want to take a moment to thank Darrin for all of his contributions to Agios over 6 or 7 years that he's been with us, we're not happy that he is going, but we understand we've got a very different opportunity than what he was experiencing with us and we are going to look for his future success. So we're extremely happy to have Richa in our team and be able to promote her as Darrin successor, I think you'll all enjoy getting to know her and the commitment you have from all of us, including the people that presented here, today is a highly successful PKD launch in the U.S. and continued strong execution on all of our programs and advancement of our research pipeline as well on behalf of all of the patients that we are so happy to work with. So with that, I think we're going to go into Q&A. And Holly is going to moderate for us.

Great. So just a reminder to all the participants, if you have a question, please submit it in the Q&A box versus sending it to individuals. And so I will go ahead and get started. So this 1 that comes from Anupam at JPMorgan, and he asked for mitapivat. How do you think of maximize the asset via pricing as in pricing for PKD and cell versus sickle cell? Would it require a price to decrease in a class of competition in this indication?

Yes, I'll take that, Holly. So we've shared and discussed before, right, we're going to price PKD or price mitapivat for PKD based on its overall clinical profile, and the fact that this is an ultra-orphan indication. And we think based on that and certainly, ultimately, depending on what data looks like in thalassemia we think that, that price may be sustainable in the thalassemia as well. For sickle cell, it's a substantially different population, right? So it's a significant step up in the size of the population. There are more options for patients in that population. But we also believe that we're going to have a pretty well differentiated profile for sickle cell disease based on our dual mechanism of action. That said, our base case assumes that we will take a price decrease in -- for sickle disease. And we'll do that through concessions via contracting. Now exactly what that looks like will ultimately depend on data and data what the market looks like at that point in time. We could sensibly choose to maintain the price. right? The -- but the position -- you'll end up positioning mitapivat differently, right? Given the size of the sickle cell population, you really owning a very small portion or sort of push for patient share in order to be able to make up the difference in terms of the price you're at for PKD and [indiscernible] versus the revenues you got -- you'll end up getting if you have to take the price down to accommodate sickle cell disease. So the company has options ultimately, it will be determined based on the data and market conditions at the time of that approval.

Because we've always said it's -- you have more options. As Darrin said, when you come with the rarer disease first with a clearly beneficial package of clinical data and then you're expanding from there over time so.

So the next question comes from Kennen MacKay at RBC. So the question is on mitapivat VOC serious adverse events. Where any of the new VOC events detailed in mitapivat's ASH abstract seen in patients on stable dose and not due to drug withdrawal. And are there any common features across the patients who experienced VOC?

So there is 1 VOC in the Netherlands data set that is while the patient was stable dose escalating and the patient continue to dose escalate with no problems and participated in the trial. And the others are due in a state of [indiscernible] to when the patients are off drug. There is not really like the patients have triggers of sickle cell disease if you see the data. I think we totally unexpected VOCs to occur in the context of Sickle cell disease with the patient slowly dose escalating when patients will be on an relocations will be coming up drug, which is as part of their disease, and it's not the therapy is like to reduce the annualized rate over time. But that is an answer that we will only be able to get at the end of the life of trial as a [indiscernible] program is renewed for long period of time to study this in mitapivat treated versus the placebo-treated group.

And as sort of a follow-up to that, can you talk about the success rate of the drug taper protocols that were instituted after the initial VOC events?

Highly successful. So the taper originally started in the PKD program. And so far, papers have been implemented in all of the programs successfully and we'll continue to do so.

So a couple of questions from Marc Frahm from Cowen. And these are for Dr. Al-Samkari. So in sickle cell would you be able to talk about what the natural incidence of VOCs in patients with sickle cell in any given year? And then in PK deficiency of all the carriers that are identified through the [indiscernible] and what would actually have symptoms of PKD if they were asked about it?

Yes. Yes. I can address those questions. I mean sickle bone disease is very heterogeneous disease. I mean there are so many things that factor into the a patient's VOC rate. Patients that have more severe disease find themselves having multiple disease each year oftentimes with hospitalizations or day hospital stays. This is something that is highly variable and some patients will have hereditary persistence of fetal hemoglobin. They won't have very many VOCs at all or they may not have VOCs for a long time. Other patients with more severe disease will have them all the time. So that's sort of difficult to give a specific number for the entire foundation, not a monolith. In terms of the question about PKD, the PKD symptoms -- that they have PKD symptoms. I mean, over 90% and it's -- even if you have a high hemoglobin and you don't -- a relatively high hemoglobin, your hemoglobin is, let's say, it's 12 and your adult male, and I have patients like this, you still have chronic hemolysis. So the impact of decades and decades of hemolysis mean that at some point, you're going to develop biliary colic and you'll need the gallbladder out. And then later on in life, maybe your spleen will become enlarged enough that it starts to cause pain, abdominal pain, it starts to push on your stomach and you have early satiety. You find out that you have a fracture at age 50 and why do you have a fracture and you find out you've osteoporosis.. So I mean all sorts of reasons why chronic hemolysis is very bad. We focus on anemia because it's something that is very direct and something that we can see improve very quickly. But once -- if I had access to a drug that I could prescribe to my patients with PKD, it's hard to think of a reason why I wouldn't try the drug on every 1 of them. So this disease is extremely genetically heterogeneous. We talk about [indiscernible] with not responding with mitapivat. That comes from a DRIVE PK study, where there were maybe 7 patients or 6 patients that had that genotype. So it's not a destiny that patients don't respond. So it's very, very -- the -- just about -- I mean, every patient of PKD, I have, has complications of their disease, all of them. And there are patients that have very rare patients that have very, very minor disease that 1 might say, okay, well, maybe this person doesn't complains of it, but that person is still very likely at some point to develop some complication or multiple complications of their disease.

Great. And last 1 for [indiscernible]. Just curious as to how many total patients would you say have been identified through the Anemia ID program on drugs through clinical trials and expanded access program?

Yes. I mean as I've mentioned, we've been pretty pleased with the reception of Anemia ID in the community, and we're just over 2,000 kits distributed, as I mentioned also. What we haven't been doing is providing specific numbers on those -- on the number of patients that are identified through that. I think it's still fairly early. We want to be able to go through, particularly see how it evolves as we go through the approval as well and you have far larger broader adoption of the Anemia ID as well as I think will give us more accurate sense of what we will be able to ultimately identify through the program. And the -- there isn't a patient access program -- or sorry, an EAP expanded access program in the U.S. for mitapivat if I understood your question previously.

Great. So this comes from Salveen Richter team at Goldman. Can you just what considerations you would evaluate for the go, no-go decisions for the Phase IIa study of AG-946?

So first for any clinical development program, we always take safety and tolerability very seriously, and that is something that always in every trial, so that is a given, that is the first thing we look at, And then other than that in typically a mix of criteria in this case where hemoglobin is responsive things like that before we decide move forward.

And this comes from Alethia Young at Cantor. So when you think about 946 and sickle cell, is it a life cycle management tool? Or do you see it as a drug that could have a better profile than mitapivat?

So this is something if you come after an existing drug, and then the goal is it's a life cycle management tool that typically then means there is something that still about to compound that makes it work further developing into the complex of that specific disease. So those are things that would be incorporated in continued development decisions for sickle cell disease.

Great. And then another question from Alethia. On MDS, why are you planning to start with a high dose in the Phase IIa and then do different doses in the Phase IIb?

Because we are trying to be very efficient in this development program and moving forward with a high dose, it allowed us to look very quickly at a proof of concept, but then we still need to do a dose-ranging study as part of development. So -- and that is set up, it's really allowing us to move forward in a very efficient manner and all the prospects of development to bring them forward into Phase III.

Great. So I'm not seeing any other questions in the Q&A. [Operator Instructions]

So I have a question that was sent to me. PKR, this is for Mark Breitenbach. A PKR activator presumably would not address leukopenia or thrombocytopenia associated with MDS. In addressing anemia without the other cytopenia is going to help MDS patients. So a couple of things to address there. I'll answer the second question first. On agents that only address anemia without the other cytopenias absolutely help MDS patients. The most common problem for MDS patients, noted in a number of MDS patients is anemia and the symptoms of anemia requiring transfusions. Thrombocytopenia and neutropenia do cause problems with this population, but it takes rather profound thrombocytopenia and neutropenia before it truly is a highly clinically relevant issue. So most of these patients they present with anemia symptoms or problems related to their anemia. And so a therapeutic that addresses anemia, even if only addresses anemia would be very helpful for these patients. It's not -- it remains to be seen if, these [indiscernible], for example, appears to have an ability to improve other thrombocytopenia patients with MDS, and that was not initially anticipated. So it's -- there can be improvements and maturation -- Sorry, lost the picture of saying there. There can be improvements in red cell maturation, excuse me, in other bone marrow borders [indiscernible] beyond red cells in patients with MDS lineages, potentially, that's a theoretical improvement with the PK activator.

Great. Well, if we have no other questions, then we can give everyone the time back. I really appreciate everyone being here. Great job to all the presenters. Jackie, I don't know if you have any closing remarks, but.

It's either late in the day or we were so abundantly clear -- or we've given so much information. We've got to process that's endogenous at all. So I just want to thank all of the presenters today. All of the presentations were terrific individually and the team. So thank you very much. Thanks to all of the investors and analysts and anybody else who joined us for 3 hours. I know it's a long walk of town to do virtual event and hopefully, the next one that we do will be in person. And we have ASH coming up in about 3 weeks or so. And some of you, I guess, we'll see there in person some of you may be on screens. And then we've got the ever popular, JPMorgan big Healthcare Conference in January coming up as well and hopefully on to progress on things between now and did. So we look forward to seeing everybody soon at those future events.

Bye, everyone.

Thank you.