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

Good morning, everybody. Hello, hi out there. Thanks for joining us this morning. Apologies to those of you on the West Coast for the early hour this morning, but we appreciate your participation in our first ever pyruvate kinase-R activation webinar here at AGIOS. So I'm Jackie Fouse, the CEO. I'm going to go through the agenda in just 1 second. I'm obliged to remind you of our forward-looking statements. So there they are on the screen. Here's our exciting agenda this morning. I will make a few brief opening remarks, and then very pleased to have Dr. van Beers with us this morning, an investigator we've worked with at Agios for quite some time, and I'll show you a snapshot of his biography in just a moment. Our Chief Scientific Officer, Bruce Car, will speak about the biology of PKR activation. Bruce has been with us for about a year now at Agios. Very happy to have him in the team. Many of you know, Dr. Chris Bowden, our Chief Medical Officer. He'll go through our clinical programs and the data that we've generated so far across 3 diseases in severe hemolytic anemias. And then we're very, very proud and happy and grateful to have Tamara with us this morning, who is a patient, a PKD patient, and she'll speak with you about living with this disease and our Christa Kerkorian, who is in our patient advocacy team here at Agios will host a little fireside chat with Tamara. So thanks to both of you. And then Darrin Miles, our Head of the U.S. and Global Marketing, will speak about the commercial opportunities across hemolytic anemias with our drugs. The patients have always been at the center of everything that we do at Agios. We brought our science of cellular metabolism to the treatment of acute myeloid leukemia. That's what our 2 approved drugs are indicated for. We have an extreme sense of urgency around helping patients like Tamara, and we'll talk a bit more about the diseases that we're moving into in the nonmalignant hematology space today. That same scientific platform in cellular metabolism has led to the biological insights that allowed us to bring IDH inhibitors to the treatment of malignant hematological indication, acute myeloid leukemia today. And that same platform is allowing us to bring the biology of PKR activation to the treatment of a variety of hemolytic anemias. So taking us outside of the cancer space, but all related to that same scientific platform in cellular metabolism that experience and expertise. And we have had hematology at our core since our founding back in 2008. So though we went into cancer first or malignant hem indications, what you can see from this slide is we have been in the clinic in PKR activation for 6 years. If we would add in the time that our researchers have been working on this mechanism and the best way to apply it to the treatment of serious diseases, it would be an even longer period of time. So more than -- for more than half of the time that we've existed as a company, we have been in the clinic studying PKR activation. I think that's very important. You can see some of the factoids on the slide here with respect to the number of patients that we've treated to date, 17 clinical trials that we have been or are involved in at Agios and some of the other data that you see there. We also take the -- our sense of urgency on behalf of patients very seriously, not only with respect to research and drug development but also in terms of working with those patients and physician communities and advocacy communities to support from that perspective as well. And so you can see some firsts that we've delivered in this area along the bottom of the slide here. We were the first company to build a global PK deficiency registry. We helped to establish the first international PK deficiency advocacy advisory council, which now is an independent body that's running itself. So those for PK deficiency, and we supported the first hemolytic anemia advocacy coalition meeting as well. So taking all of those things very seriously to make sure that we not only have medicines to treat these diseases but that we support the patient and physician communities, as appropriate along the way. This is a snapshot, and Chris will go into much more detail about this one with you in just a few minutes. This is our PKR clinical pipeline. We have a number of milestones coming over, starting imminently with the Phase III trial readouts for our ACTIVATE and ACTIVATE-T trials in the non-transfusion-dependent and transfusion-dependent settings of PKD. And then we have our thalassemia and sickle cell disease pivotal programs that we'll initiate in 2021. Again, Chris will talk much more detail about all of those. And we're moving forward with our pediatric plans in PK deficiency with mitapivat. Our next-generation PKR activator, AG-946 is currently in healthy volunteers. And we have a lot more going on in the portfolio, and Bruce will speak a little bit more about that in just a couple of minutes. So we see significant global opportunities. Darrin will talk about the marketplace in the U.S. and Europe and outside of those geographies. So he will talk about those global opportunities. But we see significant opportunities globally and across a broad range of hemolytic anemias and potentially other indications that you'll hear a little bit of a teaser about today. There's high unmet medical need across these diseases. We have been the company that's been the leader in PKR activation for quite some time with the longest experience in the clinic across multiple indications. We think we understand this as well as anyone else. You can see some of the highlights there for catalysts to come. And importantly, with respect to how we eventually take these drugs to market, we see a lot of synergy across these hemolytic anemia. So what we do in PKD can be built on for thalassemia and sickle cell disease. So it's now my great pleasure to turn the webinar over today to Dr. Eduard van Beers, Dr. van Beers very happy to have you with us this morning. Thank you so much for your time. You can see a little bit about Dr. van Beers here. We've worked with him for quite some time, as you can see under the second bullet at Agios, we're very pleased to have him speak about these diseases with us this morning. So thank you very much.

Thank you for your kind introduction. As you said, I'm a clinician and I work only in red cell disorders. And so that's -- well, I see day in, day out, I see these patients, I'm very happy to see a company investing so much in my patients. And today, I'm going to give you a short overview of serious hemolytic anemias as we zoom in on PKD, thalassemia and sickle cell disease. Then next, I click on next? Yes. So when I teach students in my university about causes of hereditary hemolytic anemia, it's -- most causes are very easily divided in 3 groups. Because the red cell essentially is a bag full of hemoglobin. And it's a living cell. So it doesn't have organ cells, but it does need energy. So the main constituents are hemoglobin system for antioxidants and energy and the bag itself. So the most common problems are hemoglobin disturbances. So -- and 90% of this is caused by sickle cell disease or thalassemia. A disturbance in energy metabolism, so glycolytic enzymes. So PKD is the most prominent of them. And lastly, there can't be something wrong with the bag and these disease are spherocytosis and stomatocytosis and some others, which I don't cover today, but maybe next year. So and as a background, it's important to understand that hemoglobin is a protein, which build up of 2 alpha-globins and 2 beta-globins. And in each globin, there's a heme ring with iron, which is the oxygen carrier. So 1 molecule of hemoglobin will transport 4 molecules of oxygen. And why did we put it in a bag? It's because free hemoglobin is very toxic and osmotic. So you can imagine that when the bag falls apart, what we see in hemolysis, this is toxic for the body and will result to complications in the patient, where we'll see later on. And it's also in a bag because packed hemoglobin is much more efficient than free hemoglobin. So this is the main takeaway of today. My message is that PK deficiency, thalassemia, sickle cell disease all share common pathophysiologic pathways and all share major physical and psychosocial impact on their lives with common complications and some which are unique for sickle cell disease, such as vaso-occlusive crises and acute chest syndrome. And if we zoom in common pathophysiology, they all have insufficient energy, low ATP and hampered mechanism to maintain cellular homeostasis which results by various reasons in RBC shape changes and increased oxidative damage of the membrane and enzymes and the hemoglobin, which then remains unfunctional. And this will result in these patients in anemia, so low red blood cell counts, a lot of hemolysis with downstream toxic effects on the body and in some can give vaso-occlusion. So the patients will have lifelong, chronic fatigue and iron overload. This will result in challenges during development, development disorders, school and work activities, social interactions. And on top of this, potential serious complications, we will see later on. And taken together, these patients face major social, emotional and health impact on their lives. And another slide, which is a favorite for me, comes from the global burden of disease study. It's a study published in many journals, but the first seminal papers 2012 in the Lancet 2 issues of the Lancet combined in 1 only talking about this epidemic to effort to quantify disease on Planet Earth. And if we look here, the authors have stated that there are about 7 billion people on the planet Earth 2010, and the most common disability is anemia, about 10% of disability on Planet Earth is caused by anemia. And if we look into Western Society, so high income North America, and Western Europe, you will be really surprised, I was surprised, but they figured out the most -- and so the causes of years lived with anemia in these Western society top causes are hereditary hemolytic anemias. These diseases are rare, but you have to imagine that these patients are born with the disease and they die with the disease. And now we are -- because the support of treatment will get them into fifth decade. This means 50 years of being sick. So one patient adds a lot of years lived with disability. So that's why it's cause #1 expressed in years lived with disability. You can look at up Casbom 2014 in blood prime Hematological journal. So let's zoom on the diseases. So how -- what is pyruvate kinase deficiency. So as I said, it's a genetic disorder, whereas a mutation in the PKRL gene, which encodes a protein called pyruvate kinase. You see it here, and it produces energy, we call ATP in the red cell. It's the main energy source in red cell. So when it's not functional because of a mutation, there will not be enough energy in the red cell to make energy out of glucose. And this will disturb cellular hemostasis resulting in hemolysis, anemia and downstream effects on the patient. We'll discuss later. It's a rare disease, about 3,000 to 8,000 patients in high-income Western Europe and North America. There are currently no approved therapies for pyruvate kinase deficiency. And this will be a repetitive slide, but you have to see that these hemolytic disease, they share common problems such as iron overload, so they need iron chelation. They have a lot of breakdown products of the red cells, like gallstones, gallbladder problems, liver problems, gallbladder removal in more than 1/3 of the patients, spleen removal, of course, often because of spleen enlargement and pain or just an effort of the clinician to reduce the hemolysis and increase red cell numbers, despite this, a lot of patients need supportive treatment, such as blood transfusion and other treatments, such as phototherapy in infants to reduce bilirubin, important breakdown product of the red cell, and antibiotics, for instance, and iron chelation. And you will see this is very the same in other diseases. So in short PK deficiency has a lifelong impact to patients. They are born with the disease, they often need additional rest, difficultly with exercise and sports and problems with going to school, education. And sometimes I have a patient coming in my office at an adult age. And I ask to complaints, I'm doing fine and not so many problems. And then I ask, okay, good to hear. But what are you doing then? Yes. And then it's very painful to hear these patients doesn't work, didn't go to school after a certain age and only lies on the couch whole day. So doesn't participate in society, needs support from family, government and needs a lot of medication. So they don't complain a lot, but they need a lot of support. So major social and economic impact from my perspective as a clinician. Let's see next slide. I have a lag. So it should slide -- so I'm not sure if you see it, but thalassemia is comparable to pyruvate kinase deficiency in the impact on the body with some slight nuances here and there. Because, obviously, it's different. There's a mutation in the beta-globin or in the alpha-globin and that causes an imbalance in globins. And this imbalance causes 1 of the globins to accumulate in the red cell, which causes oxidative stress. And oxidative stress damages the enzymes in the red cell. So it damages also pyruvate kinase probably because we see all metabolic effects of low pyruvate kinase activity in the red cell but it also damages the membrane and the cells for hemolysis and the removal by spleen or the liver. So it's characterized by hemolysis, but a lot of these cells are already hemolyzing in the bone marrow. So we call this ineffective erythropoiesis -- increasing erythropoiesis -- ineffective erythropoiesis and iron overload even further. So look, the clinical picture looks fairly the same as pyruvate kinase deficiency with a little bit more iron overload and I have to go 1 back. Here, you see that, again, iron overload with a lot of little bit more endocrinopathies, which, in turn, affect the bone health, again, and we see real end-stage iron overload problems in the liver such as cirrhosis and hepatocellular carcinoma, and diminished life expectancy. So if we look at patient perspective, comparable lifelong disease with fatigue, anemia and a hard time to participate in society, but also pain, and so this is something which is often overlooked. Because people think that sickle cell patients are the ones with pain. But thalassemia and also PKD, they can have leg ulcers which are very painful. Liver often is enlarged, which gives a lot of abdominal discomfort and pain. Spleen can be very large when it's not removed, very painful. Extra hematopoiesis is an effort of the body to make more red cells outside of the bone marrow, which behaves like a tumor, which is also very painful and can even destroy other organs if it's not managed very well. And also osteoporosis can give a lot of painful fractures, and it's hard to handle. So really, the people, anesthesia pain teams know me very well because I have to consult them very often. So overlooked burden of disease for these patients. So if we then move to sickle cell disease, it's also a leading anemia, but the difference is that there is a gain-of-function mutation in the beta-globin. So this means that it acquires a new thing and that it can polymerize when oxygen is released from the hemoglobin, then the hemoglobin will clump to each other because of this point mutation. So it's very interesting. In contrast to PKD and thalassemia in sickle cell disease, all the patients have the same exact orientation. Here, I show you some slide with pictures I major my work at the NIH in Bethesda. And on the left hand, you see a fully oxygenate. You already see some Hamburger red cells. It's not completely normal. But if you turn off oxygen in a testing environment, you see that they start to sickle on the right hand, you can appreciate this really disturbed forms of the red cells. And in the middle, you see scanning electron microscope results of oxygenated red cell. It's amorphous cell with the biconcave shape of red cell within it just dissolving globin. And some red cell enzymes. And next to it see what's happened when it's deoxygenated. And you see that there are large cables form of hemoglobin which are polymerized. So one of the key things to treat this is try to get rid of the hemoglobin S or to make something that prevents it from deoxygenating and that can be done by lowering , which will be covered by next speaker. So -- and -- because in our lab, we saw that this oxidated stress risk provokes from the sickling of the red cells, we found that there is a thermal stability of pyruvate private kinase deficiency. And that's why I contact Agios to start an IST in sickle cell, which now we are enrolling and I'm very proud that this is currently being done in our hospital. So if we look at impact on patients, it's comparable to the others, they need rest because a lot of them have anemia. Let's move to the next slide. About half of them experienced vaso-occlusive crisis. And you think that's not a lot. But vaso-occlusive crisis in medical terms means hospital admission because of untreatable pain, which doesn't respond to oral pain killers. So they are in very, very severe pain. So it doesn't say anything about chronic pain at home or vaso-occlusive -- mild vaso-occlusive pain at home, which results in not working, not going to school, less social interactions. So it's the tip of the iceberg. Next to this common complications as we see in PKD and thalassemia, such as pulmonary hypertension, osteoporosis, liver damage, which is also coming up and something which I didn't discuss before, but all patients are talking about this is when they have low hemoglobin, there's low oxygen in the brain. And what the patient typically tells to me that they have brain fog. So they have difficulties with concentrating, and that's also something which is very known in sickle cell disease. If you give the patient more time to do their work and rewrite these letters to their schools, and sometimes they go to college, but it's exceptional they can manage if they get more time. So if they get time and support, they could do it. But Grade 4 is hampering them. And lastly, I guess you know that stroke is a major issue. So these untreated patients, 1/3 will have overt a stroke so at adult age, but there's also a lot of silent strokes if you do MRI in these patients who will find really a lot of changes. So it's affecting. Well, what I say to students, it essentially affects every organ where blood flows. So that's the whole body. I think this brings me to the end. I am very sorry for -- when I skip this slide, because my slide, I can't see the slides anymore at my computer. But I think we come to the conclusion of my talk is that PK deficiency, thalassemia and sickle cell disease, they have different molecular starts of the problem. They are inherited all and whatever the molecular mechanism, the final culprit is that there's a lot of oxidative damage in the red cell and the cell has not enough energy to maintain homeostasis, and this results in hemolysis and this results in anemia, all the downstream complication of hemolysis and in sickle cell disease, we have also indication to the vaso-occlusive complications. But the end for all basis is the same lifelong burden of fatigue, pain and non-social and no participation in society. Thank you very much, and I give the word back to next speaker.

Thank you very much, Dr. van Beers. This Bruce Car in Agios. I'll be talking to you today about the biology of PKR activation. You'll hear many of the concepts that were raised by Dr. van Beers recapitulated and explained a little bit in more depth with respect to the red cell biology in my talk. So moving right along. Could you please move the current slide to slide 30? I'm stuck. Okay. Looks like we're on Slide 30. So you'll be aware that red blood cells deliver oxygen to the tissues carried by hemoglobin, to do so red cells have to squeeze through small capillaries. They maintain a discoid flexible shape. They also do many other things. They scrub the circulation of carbon dioxide. They maintained lad and red cell Ph, and they synthesize high levels of antioxidants, which are necessary to keep hemoglobin iron in the reduced state that allows it to carry oxygen. Then in hemolytic anemia in hereditary and acquired hemolytic anemia, this all goes wrong. Patients with hemolytic anemia have red cells with insufficient ATP. That's the form through which red cells release energy that's required for all of the processes that I just mentioned. So increased energy is required in these abnormal red cells. And red cell shape changes, very unusual shape changes occur that are as shown in this slide, you can see a normal red cell with a lifespan of about 120 days and in the diseases of the red cells to the right, pyruvate kinase deficiency, thalassemia and sickle cell disease. The lifespan of those red cells are anywhere from 1/12 to 1/4 of the lifespan of a normal red cell. This shortened red cell lifespan, as Dr. Van beers mentioned, can lead to chronic fatigue, iron overload and many other very serious complications. And this happens in pyruvate kinase deficiency because that engine for producing ATP energy pyruvate kinase itself is mutated in thalassemia and sickle cell disease, there are increased energy requirements, and there's a relative deficiency of production. So there's a relative deficiency of that pyruvate kinase. PKR, the R isoform a pyruvate kinase is the rate-limiting step for red cell energy production. And it's necessary to maintain a high level -- the appropriate levels of ATP in the red cell. It's very important for helping synthesize antioxidants. I mentioned, which are important for keeping the iron in the reduced state in the circulation. And in particular, regulating 2, 3 DPG levels through the flux in this pathway, you can see here to the left. The regulation of the 2, 3 DPG levels governs the oxygen binding to hemoglobin in hemolytic anemias. 2, 3 DPG levels are very often high in a variety of different acquired and hereditary hemolytic anemias. And PKR is necessary to keep that down. Moving on, mitapivat, our proprietary pyruvate kinase activator has the potential to be the first agent to transform the course of hemolytic anemia by increasing red cell energy, health and longevity. And how does it do that? It does it directly by activating PKR, which increases ATP production. That then matches the red cell energy needs, which are really significantly increased in thalassemia or sickle cell disease. And of course, the production of which is quite deficient where the enzyme itself is deficient. Mitapivat is able through increasing the flux through this pathway to decrease 2, 3 DPG, and that reversibly increases oxygen affinity for hemoglobin. It's a very important concept because this allows us to potentially reduce the sickling in sickle cell disease and the abnormal shape in the red cells of other hemolytic anemias. Very importantly, mitapivat enables the production of increased ATP and the synthesis of antioxygens. And in a variety of preclinical models that have been undertaken in Agios and elsewhere, we've shown that mitapivat is able to reduce the reactive oxygen species and thereby reduce cellular damage. All of this is collectively improving the health of the red cell and increasing its ability to live out at its normal 120 days of life carrying oxygen from the lung to the tissues. There is tremendous potential of pyruvate kinase activation as a biology and biochemical pathway for clinical development. You can see in the graph to the bottom right, Agios was founded in 2008. And beginning at that time with some of the research from our founders, Agios has invested in the biochemistry and biology and have built a deep understanding of this field and invested in this field, both internally and externally. And you can see the number of publications that have resulted from that. We've reached a point. And if you go to the top of this slide, you can see we've achieved clinical proof-of-concept in pyruvate kinase deficiency, the sentinel indication for this work. And in addition, where pyruvate kinase is actually expressed normally and hemoglobin is dysfunctional. We've been able to show clinical proof-of-concept in alpha and beta-thalassemia and sickle cell disease. By extension, and it's very well understood that ATP is deficient and 2, 3 DPG levels are generally high across a variety of hereditary and acquired hemolytic anemias. So there's a certain obviousness to the extension of the indication to a couple of the indications that Dr. Van Beers mentioned earlier this morning, spherocytosis, elliptocytosis and so on. But there are many hereditary and acquired hemolytic anemias, for which there is potential near-term expansion of properties of this particular biology. You'll see a number of other indications supported by the literature on the left-hand side. So not only has Agios worked on PKR biology since its founding in 2008. It is more generally deepened its and the world's understanding of the biology of PK activation, including PKM2, and we've developed compounds that are also highly active against PKM2, and there's much literature and also internal research within Agios that supports strongly indications in chronic kidney disease anemia. So that's another anemia. But beyond that, in musculoskeletal, cardiac, metabolic, neurologic, retinal disease, and also there's a very strong case for the role of PKM2 in cancer. So with that tremendous potential of the biology of PK activation, and we've talked most about PKR activation in hemolytic anemias. I think it's appropriate for us to move on to clinical phase of the presentation, which will be conducted by Dr. Chris Bowden.

[Technical Difficulty] underpinning the clinical consequences and outcomes from several hemolytic anemias. And Bruce walked you through some biochemistry and then showed you the potential that's here and the future in his last slide. And what I'm going to do now is walk through our 3 programs that he showed on the top of his last slide where we have demonstration of proof-of-concept. And it's a very exciting time for us because we see Agios is having the potential to transform several of these diseases with the fundamental mechanism of increasing red cell energy health and longevity. The core -- one of the fundamental issues with thalassemia, sickle cell and pyruvate kinase deficiency is that red cells die early. So if we can have them live longer and be healthier, we think that can translate to some important clinical benefits for individuals living with pyruvate kinase deficiency, thalassemia and sickle cell disease. Our first indication, however, many years ago, 6 years ago, is pyruvate kinase deficiency. And I will start there. And I'll start with the slide that those of you who have been following us know pretty well, and this slide is really important because it does several things. It demonstrates that activating mutated pyruvate kinase for individuals who have pyruvate kinase deficiency is associated with rapid robust and durable increases in individuals who respond to the drug to mitapivat. So if you look at the panel in the top left, what you're seeing is the increase in hemoglobin that starts within 7 days for responders and stays elevated, and it was a really impactful development when we saw the first demonstration of activity of this drug, raising hemoglobin in responding patients by 2, 3, 4 and 5 grams. And by virtue of activating mutated pyruvate kinase and a fundamental aspect of the program has been to continue to demonstrate the durability of those responses in responding patients. This -- the panel on the right shows a reduction in reticulocytes over time, a very important secondary endpoint -- translational endpoint that we always look at in all of these diseases that supports the mechanism of action and demonstrates reduction of hemolysis and the prolonged lifespan of those red cells. We learned a lot about the genetics of pyruvate kinase deficiency, as shown on the panel on your right. And we demonstrated from our DRIVE PK study that we needed to have at least 1 missense mutation. That is about 80% of the overall population of individuals, who have pyruvate kinase deficiency. And we incorporated that into our ongoing ACTIVATE studies that I will speak to in subsequent slides. I just want to point out that -- again, hammer on that aspect of durability, both from an efficacy perspective, but now we've got patients, who are out 3-plus years, and we continue to follow the safety profile and mitapivat is demonstrating that it has a very manageable and acceptable and excellent safety profile when given as a chronic administration. These data were sufficiently compelling to be published in the New England Journal of Medicine. It was a great accomplishment for our research scientists as well as for the investigators that included Dr. Van Beers. So with that data from Drive PK that I just walked through, we initiated our ACTIVATE studies, pivotal trials to get a global label for adults with pyruvate kinase deficiency. Those who are not regularly transfused as well as those who are regularly transfused. And as Jackie Fouse alluded to in her opening remarks, we will be imminently releasing top line results from the ACTIVATE study. This trial completed accrual, and we're now in the process of cleaning up the data and getting ready to do that analysis. Let me remind you that ACTIVATE is a randomized placebo-controlled trial in 80 patients, who do not receive regular transfusions. With the primary endpoint of the proportion of patients, who achieve at least a 1.5 gram deciliter increase in hemoglobin over baseline that sustained over multiple visits. The ACTIVATE-T study will be releasing top line data for this in the first quarter of next year. So a little bit after ACTIVATE, and it has a longer treatment and follow-up period. This is a study that's open-label, single-arm in 27 regularly transfused adults, who have a minimum annual transfusion requirement. And here, the primary efficacy endpoint is the reduction in transfusion burden of at least 33% over a 6-month period compared to the patient's prior transfusion history when they come on to the study. These trials both roll into an extension phase. And that will allow us to continue to follow them for both safety and long-term efficacy. So this is a very important component, and as Bruce said, the sentinel indication that underpins our PKR activating clinical trial portfolio. I want to spend a few minutes talking about our pediatric PK deficiency studies where the planning is well underway. And what you see here are 2 randomized trial designs in children, who are not regularly transfused as well as those who are regularly transfused. And both of these trials have open-label extension periods. And what we seek to accomplish here will be to demonstrate clinical benefit in children with a diagnosis of pyruvate kinase deficiency. Again, across the broad spectrum of individuals, who have a diagnosis. One of the things that's important, as Eduard van Beers pointed out, is that given the lifelong nature of hemolytic anemias, in this case, pyruvate kinase deficiency, a major goal for us is to improve outcomes. And for individuals as early as possible, and I think you'll get some sense of -- real personal sense of the burden of disease when Tamara Schryver and Christa Kerkorian are talking. This is an important part of our program to demonstrate the efficacy and safety of mitapivat in this population of children. And we're working on a number of factors that we need to pull this together from whether it's getting regulatory input, which has gone very well to developing formulations and other aspects and look forward to being able to provide more details on these trials as we move forward. Let me turn our attention now to thalassemia. This is a very important part of and a fundamental aspect of demonstrating that activating wild-type PKR can bring clinical benefit for individuals with thalassemia, and subsequently, I will also speak to sickle cell disease. And Bruce talked about this aspect of a relative ATP deficiency on the basis of that underlying hemoglobinopathy. We have some preclinical data that you've heard us talk about in the past. And we wanted to see if that data would translate into improvements in hemoglobin and other measures in individuals with thalassemia. And this is our open-label Phase II multicenter trial that we conducted and presented the results for the first time at this year's EHA meeting. A couple of important parts about the inclusion criteria is that we included both beta-thalassemia and alpha-thalassemia patients. We had a great group of advisers, who were working with us, and they pointed out that patients with alpha-thalassemia have no approved drugs, and this is an important group of individuals with an unmet medical need just like those with beta-thalassemia. The primary endpoint of this pilot study, proof-of-concept study was to demonstrate a hemoglobin increase of at least 1 gram per deciliter at any time in the first 4 to 12-week dosing period. And a number of secondary and exploratory endpoints that you can see on the slide were also set up and of course, understanding safety is a critical aspect that while we have data for 3-plus years in patients with pyruvate kinase deficiency that is very compelling and encouraging. We want to continue to build that safety database for -- in these individuals since we anticipate that chronic therapy will be indicated. You can see the study design below at the bottom of the slide after a 42-day screening period, patients started at 50 milligrams of mitapivat orally. And then at the 6-week mark were escalated to 100 milligrams. All patients who entered the study did get escalated to 100 milligrams. The total sample size is 20 patients, and you can see that like all of our trials -- Agios sponsored trials we implement an extension period so that patients, who are benefiting can continue to receive the drug, and we can continue to capture important efficacy and safety data. What you see here is the demographics and disposition data from our publication at the European Hematology Association Virtual Meeting that was conducted this summer, and you see the baseline characteristics for 18 patients non-transfusion-dependent. As one would expect, it looks very similar to other trials in this space. If you take your eyes down to the middle of the table on your left, you can see we had 5 patients with alpha-thalassemia and 13 with beta-thalassemia. They were all anemic. It was required that you have a hemoglobin less than 10 to come on to the study. And of course, there was evidence of hemolysis by virtue of their findings on indirect bilirubin LDH with an EPO, erythropoietin as well. And you can see on the right is the disposition slide -- we -- with 18 patients enrolled by March 2020. 13 had completed week 12, so they were able to do -- be put in the primary analysis and 9 had completed the 24-week 6-month dosing period. 8 of those patients had entered the extension and one did not. So moving to the next slide then. This is the primary endpoint, hemoglobin data. And you can see in the top row for the endpoint that 92% of patients, 12 out of 13 had a hemoglobin response of 1 gram or greater in that 4 to 12-week period. Now you can see that the hemoglobin response is sustained because as you move down, you can see that the next row shows hemoglobin responders during the 12 to 24-week period, and that includes only those patients who completed the 24-week period. So when we presented these data, not all the patients had made it that far. And then what about the roll-up at the bottom, you see the breakout according to several different ways of looking at the information, whether based on the type of thalassemia and the duration of actually being on study. And this shows the mean change from baseline for hemoglobin. So for all patients, all 13, it was 1.3 grams. If you take your eye down to 1, 2, 3, the fourth row, you see the beta-thalassemia responders had a mean change from baseline of 1.6 grams per deciliter and all responders in the 4 to 12-week period almost 1.5 grams. So this is very encouraging and compelling data that gave us proof-of-concept and is driving us to initiate our Phase III studies next year. As you heard me say with pyruvate kinase deficiency, secondary endpoints that allow us to investigate the impact that mitapivat is having on hemolysis are critical. And so we pay a lot of attention to indirect bilirubin, LDH, erythropoietin and other markers. And this slide demonstrated that we were increasing anemia by addressing the underlying mechanism of action that is improving the lifespan, the longevity and health of red cells, such that they would live longer, improving ineffective erythropoiesis and thereby reducing hemolysis. Safety was consistent with our experience with mitapivat to date. We had some Grade 1 and Grade 2 adverse events. There were no serious adverse events leading to treatment discontinuation. Importantly, the increase in dose from 50 to 100 milligrams was well tolerated, which is what we expected from our DRIVE PK experience in patients with pyruvate kinase deficiency, where we studied a range of doses from between 50 to 300 milligrams BID. Again, emphasizing the wealth of experience we have with mitapivat across a number of indications from an efficacy, safety and translational market perspective. Post data cut, we had 1 serious adverse event of renal dysfunction, which is reported, and that resolved upon treatment discontinuation. These data are summarized on the next slide. Here, and this is the first clinical study that evaluated PKR activation as a therapeutic option for both alpha and beta-thalassemia. We demonstrated proof-of-concept with that greater than 90% of patients meeting the primary endpoint, demonstration of activity in patients with alpha-thalassemia, sustained hemoglobin responses, a well tolerated and acceptable safety profile, and that is now moving us into initiating Phase III studies in transfusion-dependent as well as non-transfusion-dependent individuals with both alpha and beta-thalassemia. We're working on putting those pivotal plans together and we will disclose further details at an ASH event that we're going to be having in just a few weeks' time. With that, let me spend the last couple of minutes of my time on sickle cell disease, another important area with patients with individuals across the world with a high unmet need. And it's very exciting to see the new therapies that have come on and are becoming available to individuals with sickle cell disease, whether it's gene therapy, voxelotor, the P-selectin inhibitor from Novartis. At the same time, we understand from talking to clinicians, patients that there's still an unmet need and an important disease-modifying therapy can bring improved clinical benefit and improve outcomes for patients, and we plan on demonstrating that and working through that. It started with and is ongoing with our NIH study, that's being run by Dr. Swee Lay Thein, who's the chief of the sickle cell branch at the National Institutes of Health. This is a busy slide. And the top trial design is what was initially implemented. And then if you look at on the bottom design, you can see where we are now. And that is adults with sickle cell disease undergo screening period, they enter the trial. And then over the course of 8 weeks, are treated with 4 successively higher doses of mitapivat, starting at 5 milligrams and finishing at 100 milligrams. Importantly, along the way, we are checking laboratory parameters, including hemoglobin and secondary endpoints and then also looking at pharmacokinetics and safety, of course. At the end of the 2-week 100-milligram dosing period, individuals undergo a dose taper and then are followed up for 28 days. This is our first trial in individuals with sickle cell disease. So the primary endpoint -- primary outcome measure was to understand the safety by looking at the frequency and severity of adverse events and also looking at changes in laboratory parameters that I just spoke to and that you see outlined on the slide. Important secondary measures include looking at exposure of mitapivat across these increasing doses and looking at changes in 2, 3 DPG, PK-R, ATP, as well as understanding what's happening with oxygen dissociation. And so this is going to be an important aspect as we've been trying to understand what relationships we can glean between exposure, pharmacodynamics and then clinical outcomes. We presented some top line data at the EHA meeting virtual meeting in the summer as well, in addition to our thalassemia data, where 7 of 8 efficacy evaluable patients had a hemoglobin increase, and 5 of those 8 patients had a hemoglobin increase greater than a gram from baseline at doses of 50 milligrams BID or lower. And we also saw associated improvements in hemolytic markers. We also saw important decreases in 2, 3 DPG and increases in ATP and sickling and oxygen dissociation assays were consistent with decreases in both sickling and hemoglobin polymerization. The safety profile was consistent with what we've previously reported with mitapivat. We had a VOC during the drug taper in the first part of the study, and what we did that was possibly attributed to mitapivat. So we increased the taper period slightly and -- in order to address that. That was high top line data. And the NIH team is -- we'll be presenting the first -- making the first presentation at a medical meeting of the data from this trial at the virtual ASH meeting that's coming up in a couple of weeks' time. This is the table that they provided in their abstract, and this provides some insight into why we declared proof-of-concept and are moving forward with mitapivat and individuals with sickle cell disease. A lot of data here. Pharmacodynamic and sickling measures as well as clinical laboratory measures that you hear us talk about in the setting of hemolytic anemias, whether it's hemoglobin, or reticulocyte counts, bilirubin, LDH and MCV, a marker of some interest in the sickle cell disease community, demonstrating that we're seeing effects that we would expect to see with mitapivat in this patient population, including increases in hemoglobin. So at this point in time, we're looking forward to that presentation. And we'll be updating data on 11 patients that the NIH will be updating in their oral presentation at ASH. We have proof-of-concept, and the study is ongoing with a planned sample size of 15 to 25 subjects, who have completed 6 to 8 weeks of treatment. And we are -- like with thalassemia, we're working very hard to initiate our pivotal trials next year. So thank you again for your time and for your attendance today. And it's a really great privilege now to turn the webinar over to Christa Kerkorian, who's our Director of Patient Advocacy and Tamara Schryver, guest speaker. What you'll do is -- what you'll take away from this is how we're working on clinical trials in populations of individuals with pyruvate kinase deficiency, because we want to address and improve outcomes for individuals. And so with that, let me turn it over to you, Christa, to take us into the next part.

Thank you, Chris, and good morning, everybody. It is my pleasure, my privilege to be here and introduce our special guest, Tamara Schryver, who is joining us to give us a glimpse into her life so that we all can have a better understanding of what it's like to live with PKD. So thank you, and welcome, Tamara.

Thank you.

And as you sit here today, you are at 51 years old. But let's go start at the beginning. Can you share with us what you know about your condition, when you were born and what led to your diagnosis with PKD?

Sure. When I was born, basically, the doctor and my parents knew that something was wrong or But they didn't know what was wrong. They know -- they knew that I had a low hemoglobin and that it was really jaundice, but they didn't really have any idea. I had 2 blood transfusions at the time, but other than that, they just weren't able to diagnose it.

Okay. And then finally, a few years later, you got sick and ended up in the hospital. What happened with that?

Yes. Basically, I got a cold that I couldn't get over. So I was basically getting -- going into a hemolytic crisis. And so I ended up in the hospital. Again, they were doing more blood tests. And at that time, they sent my blood to Rochester Mail. And that's where they were able to make the diagnosis of PKD.

And how old were you at that time?

I was 6 years old when that happened.

Okay. Okay. So what can you tell us about what it was like to grow up with PKD?

I actually had a really good family. So I do want to just put that out there, and I do have some good memories, but I do have a lot of medical trauma. And I think just starting from all the appointments that I had every 3 months, I would go see the doctor, and he would do my height and weight and then ask a series of questions just to see how I was developing. I took folic acid. At the time, there was really no therapeutic intervention for me. It was just watching me to see how it's doing. They were also -- I was developing gallbladder stones or started gallstones. And so I was managing those, which were very, very painful. And then my spleen was growing large. So they were trying to figure out whether or not to remove my spleen, which we didn't do until I was 26. So there's a lot of just watching and managing. But I did get my gallbladder removed when was 13. And then like I said, I did get my spleen removed when I was 26. So it was -- go ahead.

I was just going to say, can you tell us a little bit about socially, emotionally during childhood and adolescence, what that was like for you?

Yes. I think that was really difficult. It's one thing not to be able to run and do physical activities with your friend because you're too tired and you just can't. But the hard part was just being jaundiced. And so kids in the class -- I remember one time in fourth grade, one of the classmates that told everybody else that I had hepatitis and it really set me back for about 2 years in terms of not having any friends. Nobody would play with me. I had a lot of unwanted attention that I could go into detail about, but just people asking me, why I was yellow or trying to prey over me or trying to ask me where I got the drugs I got. So there was the unwanted attention really, I basically developed a eating disorder during my childhood and high school years. So it was tough. So it was really tough.

And so all this time going through childhood adolescence, you're seeing your hematologist every few months being monitored. Can you tell us about when you mentioned you had your spleen removed in your 20s. And I know that was a time that kind of triggered a lot of other complications. Can you tell us just what you went through?

Yes. So when I was at 26, I had my spleen removed. And the idea was that it would elevate my hemoglobin, which is normally between 7 and 8. And I developed a portal vein clot and first of all, my spleen was 5x the size of a normal spleen and I had an additional spleen on top of that. And then I developed a portal vein clot that grew -- I now had esophageal varices and it sort of cut off the -- my intestinal health. And so that took -- and then I had a lot of scar tissue from all the abdominal surgeries that I had afterwards. So basically, the outcome of that was, I really have a lot of problems with my eating and with intestines. I also developed scar tissue. I was unable to have biological children and I have esophageal varices that are banded quite regularly. So that was a pretty tough time for myself and my family.

Can you tell us more about that? So you're in your 20s and your 30s and all these complications are layering on top of each other with PKD underlying all of it. What was your life like at that time?

I was pretty active. I was a student, who was getting my Ph.D., and I was working on my career in nutrition. It was a year out of my life, basically, where I was at home disabled I wasn't working. So it took a long time to get to recover into develop my intestinal tract. I just had constant diarrhea, and I lost quite a bit of weight. And so it was really hard to recover from that. And yes -- go ahead.

Yes. So I think that -- you throw in there that and you got your Ph.D., while you were dealing all this with I think -- which I think is remarkable for a person without a blood disorder. How did you -- what did you have to adjust in your life to get through...

I was highly, highly regimented. I really only lived -- live, eat and sleep at my school. That was it. I wasn't married at the time. It was either school or sleep, school or sleep. That was it. Very highly disciplined and I had no kids, I had no other responsibilities. So I was able to focus on just that, but it was a very -- I had 1 hour free time a day to myself. That was it. Other than that, I would be sleeping. My life consist -- at that time, I could sleep less. So I could sleep 8 to 9 hours a day. Now I sleep 10 to 12 hours a day as I'm getting older, it's getting tougher.

Okay. Okay. And so you mentioned you weren't married at that time. And today, you are married. You and your husband have adopted 2 beautiful children. Tell us about what your life is like a little bit more today.

Unfortunately, I'm not working full time. I've been -- I just don't have the energy to do it. I don't have -- I tried to work 4 days a week, but I was having problems with -- I started to develop atrial fibrillation, and that over the process of about 10 years, I just got to the point where I was in a hospital so many times getting cardioverted and then would have cardio ablations then I finally got a pacemaker. So the pacemaker has been existing. But it's been a tough -- it's between that and just the fatigue, I haven't been able to work full time. So my life is basically just trying to manage my time each day and my children's requirements.

So you had mentioned to me when we spoke previously that the -- your decision to basically give up the career that you had worked so hard for had to do with fatigue and brain fog really just taking their toll and making it impossible. Can you just -- let's just start with fatigue. Can you describe for us what it's like to have fatigue when you have PKD?

Yes. We've had this discussion a few times. There's a -- I mean, there's just not enough work to describe fatigue in the PKD world. There are so many different types of fatigue. But I think a few ways that I describe it is, if I've had enough rest, then a normal PKD day looks like -- and just kind of like I've got -- right now I've brain fog -- that I have weights on my chest and weights on my feet, and I'm just kind of having to pull those through my day. So it's just added weights or it just feels like I'm in quicksand, and I'm trying to get out of the quicksand. And then I think another really good analogy, which I'm experiencing right now. It's just like the Energizer Bunny. Like you're like, dude, dude, I'm going so fast, I feel so good. And then just within a matter of 2 to 3 hours, it's like boom. I'm undone. I have no more energy. I'm going down, and I need to rest and recuperate to get back to my normal self.

Yes. And it's -- I even know -- in knowing you over the last year or so, that it's your brain. Like, can you say what you said to me like your brain wants you to keep going. But what happens?

Yes. I just feel drugged. I mean, I just feel like I can't put words together. I can't write an e-mail. I don't sound coherent. I forget conversations that I'm in. I forget conversations that I've had. I'm not able to keep up the high workload, which was a primary reason that I left work was I just couldn't keep up. I fell asleep in a meeting, which was an horribly embarrassing and got back to my boss. So I was just constantly behind. And I was like a really smart person, who was not able to be smart anymore. So it was a pretty -- you just felt like a loser. But that feeling goes away when you get enough sleep, it's just that you constant -- it's like this and you sleep, now I'm awake and happy. Now I sleep. Now I'm awake and happy. I am asleep and now I'm awake and happy, and it's just this constant cycle of needing sleep to rejuvenate.

Can you tell us about -- so especially over the last 5 or 10 years, what your PKD care, your health care has been like? Have you continued on the same regimen that you had previously? Or what's changed?

Yes. So I am currently seeing 2 different doc, 2 different hematologists. I know that there are other PKD patients that get some really aggressive care with transfusions. My doctors are very, very conservative about transfusions. In the last 2 years, we've been able to agree that if my hemoglobin gets below 8, I can get a transfusion. So in the last 2 years, I've probably had 4 transfusions each year, but it is like pulling teeth to get a transfusion. And I understand that part of it is the scarcity of blood with the coronavirus. But the other part of it is I do have iron overload in addition to that. And I know that they're really concerned about any more iron overload obviously. And it's just like even we have this agreement. If my hemoglobin is below 8 like right now, it's 7.3, I have a cold, and my doctor will not agree to a transfusion. And it's like -- I don't know what the magical word is to get a transfusion, but it's -- they're pretty tight with the blood. And blood transfusions have been pretty helpful in the past or when I do get them. And then the other thing was I was on EPO for about 1.5 years, and that was helpful. So like the EPO and the transfusions together were like nirvana, it was great. But the EPO was sequestering too much iron in my liver, so I had to go off the EPO. So it's been sort of a battle right now to get the right type of care. It's hard because there are no standards of care. So my doctors are being very conservative because of the iron overload, and it's really affecting my personal life and my quality of life because they're being conservative. So it's really -- it's been really frustrating. I mean they are good doctors, but it's just -- it's really frustrating.

How has it been for you and your family through all of this? You mentioned your quality of life. How is it for you as a family unit?

I -- when I'm feeling good, I'm like the mom. I'm the glue, I keep everything together. But when I don't feel good, which is like I'm in bed 12 hours a day, well, let's say, a few minus eight, that's reasonable. And then there's 4 extra hours a day that I'm in bed plus naps. I'm not there for them. I'm not there to make dinner. And I'm not there to take them to their appointments. I'm not there to make those connections, those love connections, those phone calls, those, hey, how are you doing or to check on homework and homework is a big deal right, now because it's online. And I just -- I don't have the time and I don't have the brainpower to navigate online homework right now. So it's been -- I feel like I'm letting them down, and I feel like I'm letting me down. It's been rough.

Yes. I think that kind of brings me to my next question, which is about what you hope for the future for yourself and for other people with PKD?

I mean I was told that pyruvate kinase would never be researched, and there would be never be a drug that would be developed for it. I am so thrilled that this is going on. I hope that, first of all, that there is medication that is developed to help treat patients. I think that's so important for the quality of life. And then I think that we need standards of care so that there's uniform standards that everybody no matter where they live, if they're rural or in the city or international are getting the same treatment and that, of course, that we're able to access it and pay for it. So I just feel like it's important work that you're doing, and it's so encouraging because like I said, I was told that would never never happen. And so thank you, thank you very much.

And well, thank you, and let me just wrap up with 1 last question about -- can you -- if there was -- if there's any one thing that you wish people understood about living with PKD. What would you like to leave us with today?

I think that people can get really hung up on what is the right hemoglobin level to transfuse at or to like what is the optimal. And certainly, that's important as a baseline. And each person has their own range. But I think it's also to important to understand that, one, you had to push that -- even small pushes like 1 to 2 grams per deciliter are meaningful and add to the quality of life. So I really feel like there's preventative care like we're going to avoid a crisis and then there's quality of life care. And that's really where we need to start looking at is what is the quality of life care that we can provide for PKD patients.

Okay. Thank you. Thank you so much Tamara for being here and for sharing your life with us. I will go ahead and hand it over now to my colleagues, Darrin Miles, who is the Head of U.S. Commercial and Global marketing. Thank you again, Tamara.

Thank you. Thank you very much for the opportunity. Thank you.

[Technical Difficulty] focus on basic disease education. Compared to other disease areas, especially as it relates to conveying the true burden of disease for these patients. And furthermore, it takes greater focus on working with the physician and patient advocacy community to identify these patients, who often go way too long -- oops I'm seem to be having a bit of a bandwidth issue here -- but these patients often go way too long without being accurately identified. And that's much of the work that we're focusing on here at Agios. And as Chris stated earlier, we believe mitapivat has the potential to be transformative for these patients with a range of hemolytic anemias. Based on the clinical profile that's not only effective but well differentiated from existing and potential emerging treatments. And I think this graphic that's on the this slide in front of you is a simplified view of the framework we employ to organize our thinking about the market for mitapivat and hemolytic anemias. I think note that the -- that starting with the pyruvate kinase deficiency and extending to sickle cell and thalassemia the magnitude of unmet medical need remains high despite the newer treatment options that are available in some of these settings. And we also benefit from the overlap of the physician community, right? So it's the same hematologist treating these patients with PKD, sickle cell and thal. This is particularly important since we will have built long-standing relationships with this community, who will have great familiarity and comfort with mitapivat and Agios as we bring [Technical Difficulty] now the notion of deep relationships being a competitive advantage [Technical Difficulty] and we work with the community to refine and confirm our understanding of the prevalent PKD population, which we estimate to be between 3,000 to 8,000 in the U.S. and the 5 EU, maybe as high as 10,000 when we include all of the EU. They work with us in a number of ways to better characterize this otherwise poorly understood disease and to help capture the patient journey much of this time as shared with us earlier. And in the setting of PKD, we anticipate the data will show not just a meaningful impact on controlling chronic hemolysis and the associated comorbidities, but that the clinical benefit will translate into a meaningful improvement in quality of life. And an avoidance of the complications often associated with current treatment approaches. And we think all of that will be transformative for this population. Also I think that fundamental to successfully commercializing mitapivat in PKD is engaging the physician and the patient community to evaluate the relationship between this constellation of comorbidities associated with the disease, to truly understand and communicate the value or communicate the true burden of living with PKD. And I think this sets the stage for us to demonstrate the true value of mitapivat in terms of the treatment outcomes and the health economic impact, which are both essential for developing the value proposition, important for payors and some health authorities. These relationships, not only with physicians and patients, but [Technical Difficulty] dedicated to raising awareness of the disease, the need to accurately identify and take action once effective treatments are available. So this has been the bulk of the cross-functional work, I think, executed to date and in the lead up to approval. And so all of this is based on the notion that Agios is committed to becoming a trusted partner in the fight against this disease. So our commitment starts with improving our and the community's understanding of the patient journey, which in the case of rare diseases is often poorly understood as we've been mentioned often today. I think essential to that is understanding how the disease develops, how it manifests in patients over time and provides the foundation for further clinical development, as Chris walked through. I think starting in 2013, in partnership with Boston Children's Hospital, Agios initiated a comprehensive registry to assess the scope and incidence of symptoms, treatments and complications related to PKD. A number of you are familiar with that. We then extended those work in 2018 with the addition of the PEAK Registry, which is also a global longitudinal noninterventional study of PK deficiency. But with the objective of integrating the natural history study, with additional patients and longer follow-up across an expanded geography. I think these studies are crucial for tracking the development of PKD over time and have established our understanding of the demographic, genetic and other clinical variables, which correlate with the disease and outcomes. I think PEAK also provides a global repository for potential data from other PKD related studies, which ultimately can support aggregate analyses over time. So talking more about Agios as a trusted partner. We've been dedicated to becoming that partner with the physician and the patient community for some time. And it's been evidenced by the active engagement that we've had with numerous domestic and international nonmalignant hematology working groups and patient organizations as illustrated on this slide. I think one of the critical roles we can play supporting the free exchange of learnings amongst the developing network of international experts. And we've shared insights gathered from the natural history study with a number of physician groups, who are interested in developing consensus guidelines for the diagnosis and management of patients with PKD. Groups such as the MCGRE in France, [ with our ] pathology group in Spain have developed such guidelines for their communities and can be leveraged internationally. I think similar engagements ongoing through societies like ASH and EHA. And there was a U.S.-based KOL, shared at a steering committee we recently held as regards to education and diagnosis of PKD stated, Agios owns it. This is sort of the fruit of the work -- of the effort that we've invested here to really engage -- appropriately engage the community. We've also placed a spotlight on the need for better patient advocacy support and inclusion of the patient voice and health authority interactions, much of the work that's been led by Christa, who you just met. And Agios has been active in supporting the development of networks between international rare disease advocates in hemolytic anemia, investigators, patients, caregivers, like-minded individuals who are interested and focusing on PKD and patient needs. Now momentum is building, and you'll begin to see more of the fruit of these efforts in -- over the course of 2021. And in the U.S. specifically, Agios supported NORD's efforts to host the first externally-led PKD patient-focused drug development meeting with FDA, with over 60 patients and their caregivers in attendance in addition to others. This was a great opportunity for the PKD community to communicate directly to the FDA, their lived experience with PKD. The daily burden of the disease and their preferences and hopes for potential treatments. And when FDA administrator described the gathering as I quote, "a potential watershed moment for the PKD community." And the session resulted in the development of a preliminary benefit-risk framework for future PKD treatments potentially under review by the agency -- for consideration by the agency, ultimately. And this experience, I think, also activated the patient community, who were involved, who are now working with NORD and others on developing their own PKD focused foundation with NORD support. So the FDA meeting reflected the power of the collective PKD community, advocating for themselves with decisions -- with decision-makers in particular. And this is an essential step for orphan diseases. But it alone is not sufficient, right? So education and awareness is important, but only to the extent that it establishes the urgency to diagnose. And this is where we are now appropriately focused. I think under-diagnosis is a significant challenge for these patients. And our focus has been on driving the differential past the diagnosis of hemolytic anemia by focusing on education on the burden of disease on outcomes and the need to test further. Appropriately removing the barrier of testing is critical to this effort. So we've revamped our testing efforts to reach even more physicians and our work is twofold. First, we engage with physicians, who have already diagnosed patients, who -- and I think up to date, we've identified between the U.S. and the EU, about 1,000 patients, and that work is ongoing. But our second sort of book of work is also focused on driving the differential to make sure that we diagnose those patients who are sometimes lost in the shuffle and support testing where appropriate. I think while some are identified today, most are not, because the communities had little incentive to move beyond a diagnosis of hemolytic anemia. I think through education, raising awareness, of support -- the support that we're providing for testing, and we can support the community in accurately identifying more patients with the correct diagnosis. I think we're encouraged that our work is making a difference in better understanding the true prevalence of the disease by what we've observed in a number of different settings, right? We've supported an IST in Spain, which offered next-gen sequencing for patients with hereditary anemias in Madrid. We screened about 84 samples with 25% identified as PKD patients. And I think these data were recently presented at a Spanish hematology meeting. This also mirrored what we've observed with our ongoing testing program in the U.S., right, through ARUP, which has been largely with academics. Physicians submitted samples of patients with unknown hereditary anemia and also showed 25% patients identified with the PK-R gene. I think our experience with these programs gives us greater confidence in our estimation of the true prevalence of the disease, but more is required here. So for an orphan population, I think, with a long-term chronic disease, patient education support is essential. And we're fortunate that with some adjustments. The sort of long-term support required can be fairly easily layered on top of the infrastructure we already have built for our oncology treatments through a program called myAgios. In this setting, we apply even greater sensitivity and focus to the development of educational materials, consideration of the numerous touch points we'll have with these patients and their caregivers, even before the approval of mitapivat. Pre-approval, we're raising disease awareness, reducing testing barriers, improving overall disease management. Those are our key objectives. Upon approval, we'll continue those efforts along with testing support, but then we add treatment specific education, support for reimbursement, access and adherence. So before we move on to sickle cell and thal, I want to share just a couple of thoughts related to the potential competition in PKD, which is potentially gene therapy. And by their own count, I think gene therapy is likely to be positioned for the most severe patients. And it's been reported that the population could be limited to about 250 to 500 patients between the U.S. and the EU, including those patients with a double non-missense mutations, who wouldn't otherwise be treated with mitapivat anyway. So gene therapy, we're successful in this setting. I think the community will need to consider the potential for sequencing treatments for that small portion of the overall patient population where we potentially would overlap. I think based on our anticipated profile for mitapivat, which you see here on the left-hand side of the screen, I think we may well decide -- they, the physician community, may well decide that one would need to fail the PK activator before offering gene therapy as represented in a recent paper on management of patients with PKD by Rachael Grace and colleagues published in Blood, I believe, in September or so. So now let's turn our attention to thal and sickle cell, right. And I think as I've mentioned at the start of the segment, the work that we're doing in PKD will lay the groundwork, important groundwork for the launch of mitapivat for the treatment of alpha and beta thal and sickle cell, particularly given the overlapping prescriber and advocacy communities. I think in beta and alpha thalassemia, a substantially larger population than PKD, we anticipate that mitapivat's ability to both reduce hemolysis and improve ineffective erythropoiesis in both populations will be important differentiators, which can have a clinically meaningful impact on transfusion burden, the need for other supportive therapies and severe chronic fatigue, potentially leading to improved quality of life for patients. Now let's take a look at the overall profile for -- expected profile for mitapivat. I think what you see on the left-hand side here is a very high level, simplified view of what we expect to see from mitapivat in the treatment of thalassemia, both the nontransfusion-dependent and transfusion-dependent populations. And on the right, we have the prioritized number of desired treatment attributes physicians tell us they want in future medicines. So as you can see, reduced transfusion burden, improved hemoglobin and convenience that can -- that often can result in improved compliance are of greatest importance to this community. And I think on all of these, we expect mitapivat will compare favorably relative to competitors, particularly given the impact of improving hemolytic anemia and ineffective erythropoiesis on transfusions and improved hemoglobin. Not to mention the benefit of a convenient oral treatment versus physician-administered and -- physician office-administered options. Now add that -- add to that the demonstrated efficacy that we would expect in both beta and alpha thalassemia and I think we're highly differentiated. Now let's turn our attention to sickle cell. I think in this disease, which is a substantially larger patient population than both PKD and thalassemias, I think we have the same themes we saw on thal and PKD. We have the same treating physicians, sort of this continued unmet need despite the availability of newer options. And in this market, we believe mitapivat's dual modality with improvement in hemolytic anemia and impact on sickling will distinguish it significantly from potential competition. Now here, we have the simplified product profile on the left-hand side, much like we saw on thal, and the desired attributes for sickle cell disease treatments, as told to us by physicians, on the right. So reducing VOCs, right, and the resulting, hopefully, decrease in the need for hospitalization, improving hemolysis and hemoglobin levels are all the attributes we expect to observe with mitapivat as monotherapy and are potentially highly differentiating given the limitations of existing and emerging treatments. And then we also see that the work that we're doing in PKD, partnership with the physician community, partnership with patient advocacy groups, will also benefit us as we extend or bring new indications for mitapivat to market. So as we progress the clinical development programs in thal and sickle cell, we'll continue these partnerships, extending it further into thal and sickle cell disease networks. I think one way we've begun to do that is by supporting the development of coalitions between the PKD, sickle cell and thal advocates and the industry to explore opportunities to focus on shared unmet needs and amplify their collective voices to advance their interest. And I think this is where the work in establishing Agios as a trusted partner in PKD is incredibly important to our future success in these other hemolytic anemias. But before we end, there's a bit more. I think it's important that we not only focus on the major markets, right, so much of what you've seen in terms of patient populations we focused on, on the U.S. and the 5 EU, but in fact, the greatest need and opportunity for mitapivat extends far beyond the major markets and becomes an attractive opportunity for potential partners. And when we consider those rest of world markets with favorable pricing and reimbursement mechanisms, such as the Middle East, Asia, Brazil, Greece and elsewhere, we believe mitapivat has blockbuster potential that approaches what we anticipate in the U.S. and the EU. And this also puts us in a stronger position to be able to find mechanisms to make it available in other geographies of high unmet needs. So if you take nothing else away from our time, I think at the very least, remember that the opportunity for mitapivat is substantial, both in terms of meeting patient need and commercial potential. We're focused on deepening and broadening the understanding of this disease and the community and supporting the improvement of accurate diagnosis of these patients and appropriately supporting the organization, the physician and patient communities as they advocate for the treatment of this disease. And though there are meaningful differences between the 3 diseases, there are many important similarities as well, which I think position Agios well for an exceptional launch of mitapivat in PKD and eventual expansion into other hemolytic anemias. And in so doing, it's transforming lives and will transform Agios as well. So I think with that, I'm going to thank you for your time, and I'll turn it over to Jackie. Jackie?

Thanks, Darrin. So let me just stop real quickly and thank all of our panelists. Everybody did a terrific job. We hope those of you in the audience have enjoyed the different sections of the presentation today. So we -- Dr. van Beers, terrific. Thank you so much. Tamara, we can never thank a patient enough for spending time with us and sharing your experiences with us, especially when those experiences are so difficult in terms of life experiences compared to what most of the rest of us have to deal with in our lives. So thank you very much for that. Christa, Chris, Bruce, Darrin, terrific job. So we -- I'm going to just do a quick summary on the -- I'm the one who's supposed to click it. There we go -- on the next slide for our audience in terms of some of the significant catalysts that we have coming up. As Darrin said right at the end of his comments, he used the word transformational for patients as well as for Agios. So we are on the brink of moving into our first approved medicine for a noncancer indication. It remains within our core expertise in hematology. We're very excited about this and about continuing to demonstrate the productivity of our terrific scientists and the cellular metabolism-grounded research platform that we have built over time. So we have a number of catalysts coming up, as we mentioned at the beginning of this time, and I'm just going to reiterate it a little bit to make sure that all of you who are watching us don't miss anything as we move forward over the next weeks and months. We think we have a drug in mitapivat that can be a blockbuster drug across a variety of hemolytic anemias. We have a broad portfolio that we're continuing to explore, and over time, you'll hear more about that. Mitapivat may be the first potentially disease-modifying drug for pyruvate kinase deficiency, and we're very proud of that. We're proud of what we think we're going to bring to the treatment options for these patients. We have run a global clinical development program. And so we will be able to file in both the U.S. and EU almost simultaneously and that will come in 2021, and then we'll expect approvals in both of those geographies in 2022. We are also, with mitapivat potentially the first-in-class therapy for both beta and alpha thalassemia, we're the first company to produce clinical data for alpha thalassemia patients, and we're very proud of that as well. And we may also be the first-in-class therapy for sickle cell disease. Both of those indications are moving into pivotal development in 2021 as you heard from the team today. And as you heard from Darrin and others and certainly, Dr. van Beers can speak to that as well, every -- all of the work that we're doing is highly synergistic across these different indications as we bring this treatment option to hemolytic anemias in general. So even though you have the specifics associated with each disease and indication, what we're building at Agios in terms of our platform to serve hemolytic anemia patients has quite a few synergies across it in terms of relationships and the experiences that we're developing up to now. So with that, I am going to, I think, open it up for Q&A. One last thing, and maybe somebody wants to ask Dr. van Beers a question about this, but when Tamara described her experience, I think that she has been generally characterized as having mild PKD. So you might imagine, based on what you've heard from Tamara, what it would be like for a person that has what would be defined as severe PKD. So again, grateful to all of our panelists. Thank you to the audience for joining us, and we're now going to open it up for Q&A, I believe. Please feel free to ask questions on any...

[Operator Instructions]

And our first question comes from Mohit Bansal of Citigroup.

So a question for treating physicians. I mean when we talk to doctors, oftentimes what we see about PKD is that I treat one patient, I treat 2 patients and I -- it's hard -- it's very rare I see a PKD patient. So I mean Darrin also mentioned that the diagnosis is low. So why is that, if there are 3,000 to 8,000 patients out there, why the diagnostics is low and oftentimes, it is misdiagnosed as anemia? So what -- so I know, Darrin, you are doing a lot of work there. But can you help me understand how the physicians would probably diagnose this more often than they are right now?

Thank you for your question...

Oh, I'm sorry, Dr. van Beers. You go ahead. I was going to call you.

So I think that if a patient has a lot of problems but doesn't need transfusion, then sometimes they are -- isn't [ follow up ] very much and that -- and physician doesn't treat the complications and wait until there's too many complications to treat. So that's one of the problems. The other problem is that diagnosis was very difficult. So even in expert centers in Stanford, there was one of the people who's working on the office [ of Bill Wader ] and he was in his 60s and he was diagnosed by [ Bill Wader ] with PKD very late on despite having many complications. So it's hard to diagnose. But this will change because what is now going on is patients with undiagnosed anemia, they will get gene panels. That's the future. And then it gets very easy because they all have a gene problem and pops up right away. So that's what you see also from the Spanish experience, so 25% undiagnosed anemia, they have PKD. So there's a lot of undiagnosed, but this will change very rapidly and especially when there's drug available because one of the arguments was, "Oh, there's no drug. So why should I follow these patients? I can't do anything for them."

Got it. Got it. If I can -- if I may ask one more for Darrin. So you have this effort in AML where you are talking to some hematologists though they are treating cancers. How much it is leverageable for diseases like sickle cell and PKD? And if there are some overlap there, if you can help me understand that.

You mean AML? Can you hear me?

Yes. Dr. van Beers, I think he's asking, do you often see -- how often do you see these patients, nonmalignant heme patients, being managed by oncologists, by [ heme docs ], as opposed to [indiscernible]?

Well, I think that's something which still happens in a lot of hospitals. But especially in the EU, European Commission, they made directives, there are European laws, and they're really pushing for expert centers where dedicated doctors like me treat patients. And I think also new medications will only become available via these centers, which are appointed by health ministries. And this also has big funding implications for academia. So academia will be very challenged to get these patients in because it's about their funding. So we have -- in [ MEMS ], for instance, we have something we call academic charge for what we do. So if I just treat regular hematology, I don't get my bills paid. So I have to go for rare diseases, which academia excels in. And that will drive treatment in the future in the European Union.

Yes. And I think in the U.S., maybe just to speak to the other side of it, there is a fair amount of overlap between the sites that we call on today for our oncology program and where we believe a number of these patients are also being -- a number of heme patients are being managed. The commercialization effort, though, is different. The kind -- the level of engagement, the amount of education is substantially different than what we have -- what we would normally do for oncology. And so -- but it doesn't require a huge commercial investment, right? So we're going to have feet on the ground over the course of the next year. And it's only going to be a fraction of the size of our current oncology sales team, which is already quite modestly sized at about 30 representatives.

And our next question comes from Alethia Young of Cantor.

We really appreciate all the information today. Very, very helpful. I kind of, I guess, want to stay on the similar time frame. Just could you just talk, maybe the experts and even Darrin as well, about kind of the diagnosis pathway like for PKR and how that's evolved since you guys have started running natural history? And then just how often are these patients kind of seen? I guess I've seen some points where it seems like patients kind of get out of the system for a little bit because there's no option. So I guess just how do we think about bringing those patients back in?

Eduard, why don't you start and give us a flavor for the various ways that individuals with a diagnosis of pyruvate kinase deficiency come into your care? And then like you did in the last answer, Darrin, you can provide a little extra color in terms of what we might see in other parts of the world, including the U.S. Go ahead, Eduard.

So as I just mentioned, there are more directives in the European Union which regulates care for patients with rare diseases and something like [ cross-border ] medicine. So it's a really big thing in the whole EU. Ministry of Health has to appoint centers of excellence. These are findable now on the Internet. They are accredited, and they are -- so now in the Netherlands, everybody know, if you have pyruvate kinase, you have to go to Utrecht. And if you have something with anemia, which I don't understand, you also have to go to Utrecht. And we now, since a couple of years, we have gene panels available. So to me, how I see it, a physician sees hemolytic anemia, which he doesn't understand, picks up the phone or does -- calls our lab, diagnosis by gene panel, very easy. And often then, he sends a patient already to me for me to confirm the diagnosis and then the patient is in my office.

Yes. One other point, Eduard. Over the course that we've been involved with this pyruvate kinase deficiency by virtue of our research effort, that shift that you talk about to molecular testing, it seemed like 7, 8 years ago, it wasn't nearly as prevalent and you were relying on an enzyme test that -- so this is a big shift, right?

Absolutely. So I think there are a lot of misdiagnosis because the assay of PK activity is very difficult to perform, so you really have to go to experts, and also interpretation. That's due because the enzyme, pyruvate kinase enzyme, declines when red cell ages. So in very young red cells, it's very active. But if you have hemolytic anemia, the lifespan of red cells is very short, so PK is very high. So there are a number of PKD patients who have normal PK activity. But if you compare it to the activity of other enzymes, many oncologists don't do, you miss out in the diagnosis. But that's now solved with gene panel entering as a first-line diagnostics.

To your question, the -- if you're not being transfused, you're going to be seen perhaps less frequently than those patients who are getting transfusions for obvious reasons. But in terms of an under diagnosis, the -- I think Tamara spoke to it best, right? The need for standardization, right? Because it is an orphan indication. And for -- and given that as physicians work through the differential, the testing that was previously required, right, before you had maybe more routine use of gene panels, was laborious, right? Hence, the focus for us and for others on removing testing as a barrier and actually positioning it more as the gateway to be able to more easily move through the differential to diagnose these patients. And then lastly, once you actually have a treatment commercially available, right, when you -- just to [Technical Difficulty]

He just cut out.

Oh sorry, did I over...

Darrin, go back and say what you -- once you have a treatment available, can you just say that again, please? Because you cut out for a second.

Sure. Can you hear me now?

Yes.