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

All right. Well, it's 7:30, so we can go ahead and get started. A quick reminder for our attendees. So Dr. Kevin Kuo is with us, and we will be doing a short Q&A after his presentation because he has to drop off. And then we'll be doing a sort of additional Q&A at the end of the presentation. If you have a question, please submit it through the Q&A box. It should be at the right-hand side of your screen. You may have to click the 3 dots to see it. And if you have any issues, please shoot me an e-mail. And with that, I will turn it over to Jackie.

Great. Thank you, Holly. Good morning, everybody. Thank you for joining us early on this Tuesday morning, the last day of ASH 2021. And Holly, if you could click to the next slide, please. These are forward-looking statements that I happily will not read to you this morning. The next slide, please. This is our agenda for the day. We're very excited about ASH this year. We're excited about our presence at ASH this year and about our data and the evolution of the data, in particular for mitapivat and what it's telling us about the potential for this drug across all of pyruvate kinase deficiency, thalassemia and sickle cell disease. You're going to hear from a terrific group of people today that are shown up here on the slide with the topics that you can see here. Next slide, please, Holly? Many of you are probably familiar with Agios journey. This is just a reminder of that. I'm not going to cover it in a ton of detail, but one of the reasons why we're so excited about ASH this year is it's our first year following the divestiture of our Oncology business and transition of that business to Servier. And so it's our first time at ASH presenting only as a genetically-defined disease company, where we're very excited about our future and quite focused on it. And we've just got a terrific, at least strong showing at ASH this year, and we're very proud of what the team has delivered on in the -- under that genetically-defined disease umbrella. We've been the leaders in cellular metabolism for the last 14 years, and we continue to use that science to work with patients, to bring great therapies to market for them and work with physicians, like Kevin and others, to help us do the best we can to transform patients' lives for the better. You're going to hear from the team today some of the things that we feel differentiate us, and we've got this nice 14-year history that we're building upon, where our history in oncology was actually in hematology. And so we've got very strong connections across hematology that is going to serve us well as we move into our very bright future. Next slide, please, Holly. We don't just keep patients at the center of everything we do. We actually listen to them. It's quite easy in this industry to say that you're patient-focused and you care about patients because if we don't, then we shouldn't really be in this industry, probably. We actually listen to our patients and are bringing them more and more into our work so that we're working alongside with them to create solutions that they have input into, and you'll hear a little bit more about that as well. Some of those things include involving patients with our protocol designs and our clinical development program designs and strategies. So hopefully, some of that will come out in what we talk about today as we really think those -- our patients are helping us make an even bigger difference as we work with them and learn from them, frankly. Next slide, please. And we are the pioneering leaders in PK activation. You probably heard us say this before. We're probably going to say it even more as we continue to bring our medicines forward. We've been studying this mechanism in the clinic for almost 8 years, so since 2014. And I'm not going to go through all the details that are on this slide. But to the far left, you now see an expanding portfolio of pivotal clinical programs, and we'll hear more about those today. You can see on the far right, the diseases that we've already demonstrated, at least, proof of concept and or have data that we're moving forward for approvals for. And in the center and along the bottom of the slide, it is just a reminder of all of the things that we've done over the last 8 years or more with respect to publishing. And we've got very deep science in this area. There are some things that are emerging that we feel like we understand better than anybody else, and we think that's going to help us continue to evolve the therapies with this mechanism of action and continue to do great things for patients. And we've worked with patients and health care providers and investigators to establish a number of first in the PK activation arena, and you can see those at the bottom of the slide. Next slide, please, Holly. So with that, I'm going to turn it over to Sarah Gheuens, who's been our new -- she's not almost new anymore, but she -- we're going to still stay new for a little bit longer, Chief Medical Officer. She took over from Chris Bowden, who retired back in September. She's been with the company for a couple of years. And for those of you who don't know Sarah yet, it's an absolute pleasure to know her, so I hope you will get to know her over time. So thank you, Sarah. Please take it away.

Thank you, Jackie. So I'll kick us off. I want to highlight a little bit of our differentiated approach to global development that we're taking here at Agios and our community partnerships. But then I'm joined by Ahmar and Mike and Dr. Kuo to highlight our data from ASH as well. So we'll be highlighting the data of our extension study in thalassemia patients, also in beta thalassemia patients. We will discuss the sickle cell disease program and then also, of course, our PKD program as well, and the long-term extension data that was presented at ASH as well, but also some very interesting iron overload data that shows impact there. Holly, if you can progress to the next slide. Thank you. So a reminder where we currently are with our clinical development program. So of course, the pivotal program for pyruvate kinase deficiency has completed, and that's an ongoing extension study right now. That program allows us still to move forward in pediatrics. So we are very excited to initiate, ACTIVATE KIDS and ACTIVATE KIDS-T for pediatric patients with PK deficiency, and it's a very similar approach covering the entire spectrum of PK deficiency for children. Then the alpha and beta thalassemia program and the sickle cell disease program with mitapivat, both programs have their pivotal studies initiated. And then, of course, at the bottom of the slide, we have 946, which is currently in healthy volunteers with a sickle cell disease component in the same study. And we also announced at Investor Day that we were moving forward with MDS and so we're very excited to initiate that program very soon as well. And then fueled by connections also, of course, means that we're very much working with our key opinion leaders and the physicians in the community. And so the highlights that will be presented here today as well is our collaboration with the NIH and with the University in Utrecht on sickle cell disease and the data that we have generated through those programs. And then at the Investor Day, we also announced that we are initiating via a similar approach, the program in hereditary spherocytosis. So what is really different in the context of our program. So Jackie already highlighted part of it in her opening remarks, but we have truly a global reach. So we solicit regulatory feedback, both from the U.S. and Europe at the same time to incorporate that in our trial designs. We have site selection focused on going where the patients are, which is very important in certain competitive landscape here. And then, we do remove barriers for clinical trial participation by proactively listening to patients all over the world -- in the U.S. and in the rest of the world. We have a top-notch team. So we have broad industry experience throughout all the levels of our clinical organization. Our medical team includes academic physicians with detailed knowledge of the disease states. And you'll see Mike and Ahmar here today. So I'm very excited about that. And then where science meets heart is, I think, critical in the context of the diseases that we are working in because it allows us to actually foster very meaningful connections with the patient community and also with our key opinion leaders, and so I'm very excited that Dr. Kuo is here today with us as well. And then Jackie mentioned in the beginning as well that we have been working in cellular metabolism and in hemolytic anemias now for a while. So we have -- that allows us, of course, to foster those connections in a continuous manner. So how did the patient input help shape and validate the study design? So we have listened to their enrollment concerns. So it's clear that inclusion of alpha thalassemia was very important from physician community, but also for the patients living with this disease. So that's -- hence, our program is focused on alpha and beta thalassemia. We take an approach immediately to generate data for non-regularly and regularly transfused patients for thalassemia. And then for sickle cell disease, it was clearly very important that we allowed hydroxyurea to be present in our trial. So there's concomitant use allowed and occasional transfusions as well in this community. And then we did incorporate proactively feedback on the enrollment criteria with the hemoglobin levels being encompassing 5.5 grams per deciliter to 10.5 grams per deciliter, broad definitions of pain events were applied. And so we think that is very important for the success of this study. And then the study endpoints to that same point, we listen to the patient population on what they find important, and that is where you'll see incorporated in many of our secondary endpoints as well. But of course, the primary endpoints to be here, both pain and hemoglobin are important. So for sickle cell disease. That's how our trial is designed. And then the most important patient-reported outcome measures are included as well. And then proactively, we also aim to provide as much flexibility and support as possible by giving patients truly a range of options of home visits, in-person center appointments, telemedicine appointments, wherever it's possible and locally allowed. And we go where the patients are. So you'll see that our thalassemia program and sickle cell disease program are global programs, but that the clinical trial presence is slightly different with sites in Asia for thalassemia and for instance, sites in Africa for sickle cell disease. Now all of these hemolytic anemias, what they have in common is insufficient energy, increased oxygen radical energy (sic) [ injury ], abnormal red blood cell shape changes. And we aim to correct for that by increasing the red blood cell energy, health and longevity. And that's the premise that we are studying with our PK activation throughout our different programs, because we do want to make an impact on all of these hemolytic anemias because they do cause major complications and impact patient's quality of life, as highlighted on the right side of the slide. And with that, without further ado, I'm going to hand it over to Dr. Kuo to discuss our long-term data in thalassemia.

Good morning, everyone. Good morning, Sarah. Thank you, Sarah, for handing off. Good morning, everybody. This is Kevin Kuo. And I wish you can all be here with me today in Sunny, Atlanta. But nonetheless, we're here together this morning. Thalassemia, as many of you know, is a red cell disorders, where there is an imbalance between alpha and beta globin, and this excess in either alpha or beta leads to precipitation of these excess chains, which then generates reactive oxygen species and hemichromes, which are very damaging to the red cell lifespan. This results in an ineffective erythropoiesis and hemolysis. And the thalassemic red cells do not have enough ATP, which are essentially power packets, to try to repair these damages that are caused by the reactive oxygen species and hemichromes. And as a result, this can lead to things like anemia, bone marrow expansion, extramedullary hematopoiesis, osteoporosis, bone deformities, iron overload, gallstone and splenomegaly, I can just go on and on with the complications that my patients suffer from. Now the treatment options, as many of you know, up to this point is completely supportive. If the patient needs -- have a very bad anemia, we would transfuse them, but then we would need to chelate them, of course. But there's really nothing that can actually treat the underlying cause of the disease or to modify the disease itself. Mitapivat is an investigational, first-in-class, oral, small-molecule activator of red cell pyruvate kinase, or PKR, which is a key glycolytic enzyme that regulates ATP production. Next, please, Holly. So this brings back to the dreaded biochemistry from your undergraduate course, where you see the glycolysis pathway on the left-hand side, and where PKR is the final step that converts phosphoenolpyruvate into pyruvate and generates an ATP. And this is where mitapivat fits in and that it can increase the activity of the PKR enzyme. Next, please. So as I have talked about previously, hemoglobin is 2 alphas and 2 beta globin chains that have merged together to form this essentially an oxygen-carrying molecule. And when there is an imbalance, either excess alpha or beta, the alphas would actually pair up into a tetramer or the betas would actually pair up into a tetramer as well, but these are very dangerous tetramers because they are very unstable, and if they are unstable, they fall apart. The cellular machinery tries to maintain their shape. But in doing so, it expands ATP. But at the same time, when these tetramers become unstable and generates reactive oxygen species and hemichromes, it creates oxidative damage, hemolysis, and ineffective erythropoiesis and results in anemia. Holly, you can just keep clicking because there's a bunch of animations. Yes. What mitapivat does is that it enhances glycolysis, increases ATP, so it reduces oxidative damage, reduces ineffective erythropoiesis, hemolysis and so improves the anemia. In addition, because it -- we hypothesized that it can improve the ineffective erythropoiesis, it can also reduce the dysregulated iron overload leading to a reduction in iron overload. Next, keep clicking. I know it's a lot. I make this animation. So I'm very proud of it. So mitapivat, and the data to support this, preclinical data to support this, as many of you know, is that the mitapivat increase PKR activity and ATP levels ex vivo in red cells of beta thalassemia patients. In addition, in the mouse model of thalassemia, mitapivat also shown to ameliorate ineffective erythropoiesis, iron overload and anemia. Next, please. In the Phase II study of mitapivat in adults with either alpha or beta non-transfusion-dependent thalassemia, the core period consists of 24 weeks, where patients were on 50 milligrams of mitapivat twice daily for 6 weeks and then escalated to 100 milligrams twice daily for 18 weeks. What we're going to focus on today is the long-term extension data. And the inclusion criteria for being able to enter the long-term extension is that the patients have to complete the 24-week core period, achieves a primary hemoglobin response defined as either increase in hemoglobin by 1 gram per deciliter or a delayed hemoglobin response, which is, again, increase in hemoglobin by 1 gram per deciliter for at least one assessment after week 12. And they should not have any ongoing grade 3 or higher treatment-emergent adverse events that are related to the study drug. Next, please. And so here, we will report that -- we will talk about the long-term efficacy and safety. As we know, 80% of the patients in the core period achieved the primary response. But here, what we're going to talk about is beyond the 24 weeks. We're going to talk about the changes in hemoglobin from baseline, markers of hemolysis, ineffective erythropoiesis and safety. Next, please. So from the core period where there were 20 patients enrolled, 17 moved on to the extension period. I would like to point out that 4 of the 5 alpha thalassemia moved from the core period into the extension period and 13 out of 15 moved from the core into the extension. The hemoglobin baseline, as we can see, is anemic at 8.5 gram per deciliter, and the LDH and the total bilirubin are also elevated with a marked range in the values. The right-hand panel is quite telling because you can see here that we have a very diverse genotype, encompassing both alpha and beta thalassemia and not only that is that in the beta thalassemic population, we have a mixture of different types of alpha and beta thalassemic mutations and duplications. This illustrates that despite the heterogeneity of the genotype that we have a very uniform response to these patients. Next. Here, we see that the hemoglobin rises very rapidly within the 4 weeks to at least 1 gram per deciliter, and we can see that the hemoglobin increase is maintained and sustained through not just the core period, but also through the extension period. And we can see here that at 60 weeks, the hemoglobin rise is 1.5 grams per deciliter and there's almost a 2 grams per deciliter by the time we hit the week 72. Next, please. In addition, we see continual improvement, sustained improvement in both markers of hemolysis and erythropoiesis, regardless of the thalassemia subtype here. Next, please. In terms of treatment-emergent adverse events, there is 13 treatment-related TEAEs in the core period, but only 2 in the extension period, and notice that there's no grade 3 or higher treatment-related TEAEs. Next, please. In this table of safety profile, I would like to point out to you that while there were 50% of patients, who had initial insomnia, this did not carry through into extension period showing that the insomnia is transient. Adverse events that are occurring at more -- at least 15% or more of the patients during extension periods were headaches and back pain, and none of them were grade 3 or higher. And as you can see in this table, there's no other new safety findings that are reported in the extension period. Next, please. So many of you are going to ask about bone health. And you can see here that for those patients who we do have data, and again, the data is limited and the reason is because of COVID. When COVID hit, we weren't able to get a lot of the patients to come in to have the bone density done in person. And so of the patients who we do have the data, you can see that their bone densities are maintained and almost up to week 72. Next, please. So in conclusion, we can see that here that there's a favorable efficacy and safety profile that's observed with the long-term treatment in mitapivat in both alpha and beta thalassemia patients. And I must emphasize that this is the first clinical trial aimed at disease-modifying therapies for alpha thalassemia. We also see consistent and durable improvement in the hemoglobin concentration, markers of hemolysis and ineffective erythropoiesis. They were observed up to week 72 of treatment and despite the heterogeneity of the globin genotypes. There is no new safety findings. The bone density remains very stable. And we think that mitapivat may represent a very novel therapeutic approach for both alpha and beta thalassemia, as such we have ENERGIZE and ENERGIZE-T, which are 2 Phase III studies for both alpha and beta-thalassemia for both non-transfusion-dependent and transfusion-dependent patients. Thank you.

Great. Thank you, Kevin. So again, everyone, Kevin is going to drop off here in a minute. But if you have any questions for him, please submit those to the Q&A, and we will ask him those now. To start, Mike King, from H.C. Wainright, asks what does a 2 gram per deciliter increase in hemoglobin mean for your patients in terms of real-world benefits?

I think that's a great question. And first of all, I'm going to say some data and then I'm going to tell you what my personal experience is. To start off with, we know that there's lots of recent publications about both quality of life as well as on the number of complications that non-transfusion-dependent patients have. And we know that hemoglobin between 8 and 10 grams per deciliter is a very critical range. There's a recent publication showing that where the number of complications in thalassemic patients rises sharply when the hemoglobin shifts between 10 to 8 grams per deciliter. And then after that, a majority of patients will have some form of complications. So I feel that by improving the hemoglobin by 1 gram to 2 gram per deciliter, we are hypothesizing -- and this is why we're doing the Phase III, but we hypothesized that this will markedly improve our patients not just quality of life, but also in the long-term complications -- short-term and long-term complications. Now in terms of my personal experience on the Phase II study, I can tell you that I have a lot of patients, who have told me that their quality of life has improved. I'm just going to cite you some examples. One patient is a young mom with a 3-year-old and a 5-year-old, and she always tells me that she has to sleep in the afternoon before being on mitapivat because she just ran out of energy, and her mother-in-law or her mom has to come and help out with the kids. Now she can run around the kids, no problem. Being on mitapivat, she doesn't want to go off it. I mean this is part of the reason why we have the 10-year extension. It is actually by patient request. The patient requested that there's some form of extension and then I extended to Agios and saying, you know what, my patients are getting actual symptomatic improvement. Can you help? My patients have reduced back pain as a result of the medullary expansion, reduced medullary expansion. Also I have patients who said to me that before they weren't able to do any workout at all and now they're actually able to work out. Now most recently -- this is kind of an interesting adverse events to talk about. Most recently, my patient told me that she is gaining weight, and she has gained at least 10% of weight and she is fretting about it. And being a thalassemic, she was quite slim because of a hypermetabolism. But now because of this, you can see that the patients are actually improving much, much more as a result.

Next question comes from Mark Breidenbach from Oppenheimer. How would you position the drug like mitapivat in your practice relative to luspatercept?

Yes. So as we know mechanistically that luspatercept really focuses on late-stage erythropoiesis, where GDF, as you know -- we don't exactly know which GDF it is, right? There's lots of controversies, first of all. We don't even know what the exact target for luspatercept is. But nonetheless, we know that it works in the late-stage erythropoiesis and that it shuttles red cells out that were initially destined to die, whereas mitapivat focuses on the underlying energetics of the red cells, such that it increases not just red cells lifespan, but also essentially detoxifies the cell, if you can think about it, because of reactive oxygen species and hemichromes. And we need to remember that reactive oxygen species and hemichromes attacks both the hemolytic pathway, right, promotes hemolysis, but also promotes ineffective erythropoiesis, because what it does is that it leads to premature cell death, intramedullary cell death. And so the way I see it is that mitapivat targets both the ineffective erythropoiesis as well as the hemolysis, whereas the luspatercept is more of a sort of a limited range looking at the late-stage erythropoiesis.

Sort of as a follow-up to that, Marc, from Cowen, asks, is there a role for combining the 2 therapies?

As I said before, I wish you were here with me at ASH because there's actually an abstract that goes into it, not between mitapivat and luspatercept, but between luspatercept and [indiscernible] inhibitor. But nonetheless, the idea is pretty much the same. I think it really depends on the degree of response by the patient because if the patient can respond with a monotherapy, then there is really no need to combine the treatment. Also, we need to look at the degree of ineffective erythropoiesis versus hemolysis. Because if the person is highly hemolytic to begin with, there is really no point in giving them an erythroid maturation agent than vice versa. So I think that therapy, like anything else, needs to be tailored and personalized and that would be my take on that.

Great. And then this question comes from Alethia Young at Cantor. Can you talk about what the long-term disease modification means in treating alpha and beta thal? Also is there a benefit with targeting ATP, treating earlier?

Holly. I've got the first question, but not the second one.

Is there a benefit of targeting ATP earlier?

Earlier, as in early in life, right?

I believe so.

All right. So let's start with the second question. So targeting patients early in life certainly, absolutely, because we know that as patients age, complications accumulate. And so we would like to prevent these complications from happening, especially things like medullary expansion, extramedullary hematopoiesis, pulmonary hypertension, gallstones, leg ulcers, splenomegaly. These are the things that we want to prevent. So it makes sense we start early. And then the first question was, can you repeat that again, Holly? There's a -- it's a 2-part question.

Yes. So the first question was the long-term disease modification in alpha and beta thal.

So this is part of the reasons why Agios embarked in this 10-year extension period, so that we can observe to see what the long-term effect of mitapivat is in our patients. But I hypothesize, again, I hypothesize that a lot of the hemolytic and ineffective erythropoietic complications associated with thalassemia will either stable or reduce. So what I mean by that? One is obviously, medullary expansion. I think the medullary expansion will either be stable or reduced as a result of the increased red cell lifespan. I mean where we have seen a reduction in reticulocyte count and a reduction in erythropoietin up to week 72. Other things would be like the risk of pulmonary hypertension probably go down. Iron overload is a very important mechanism that we want to explore. It'd be nice to have more longer-term data. As you know, it takes a very long time to remove iron from someone even using chelators actively. And so I think getting long-term data in iron indices would be very important, but that would be one of my hypotheses that it will reduce iron overload.

Great. And so I believe this will be the last question. So Anupam Rama from JPMorgan. So what portion of your patients have, I assume, you mean a decreased bone mineral density? Can you expand on your comfort with long-term therapy based on the bone mineral density data you highlighted?

So the patients where I was able to get the bone density certainly did not see any changes as you've seen in the graph. In terms of my comfort, I am comfortable with using it because simply, I have not seen it in my patients. I mean obviously, we're going to watch this over long term. This is why we're doing a long-term extension. We need to keep an eye on the bone density. But so far, we really don't see any signals.

So if there are no further questions, we will move on to Ahmar. Thank you, Dr. Kuo. We really appreciate you being here with us today.

Thank you. Take care. Bye.

Well. Good morning, everybody. Firstly, can you hear me, okay?

Yes. Sounds great.

Perfect. Well, my name is Ahmar Zaidi and I too am coming to you from Sunny, Atlanta, as Dr. Kuo just said, I am the Medical Director for the RISE UP Program at Agios Pharmaceuticals. And I'm happy to be here with you today to talk about the updated NIH Phase I mitapivat sickle cell disease study results. Moving over to the next slide, Holly. Perfect. So shown here is the study design of an open-label extension study of mitapivat in 17 adults with sickle cell anemia, who had not had a recent blood transfusion or changes to doses in their disease-modifying therapies within the 3 months prior. Following screening, subjects were escalated, their dose was escalated every 2 weeks from 5 milligrams twice daily, up to 50 milligrams twice daily in the original protocol and up to 100 milligrams twice daily in an amended protocol followed by a drug taper and a follow-up safety visit 4 weeks after their last dosing. You'll see 2 sets of arrows here. The orange arrows represent time points at which blood samples were collected and the blue arrows show time points presented in the analysis of the laboratory endpoints that we'll talk about. The primary endpoint was safety and tolerability in conjunction with changes in hemoglobin level and hemolytic markers. Secondary endpoints included both pharmacokinetic and pharmacodynamic parameters. You've seen previously presented data on 2,3-DPG and ATP. In this analysis, you'll also see data on p50 and t50, which are measures of oxygen affinity and hemoglobin S polymerization respectively. We can go to the next slide. So out of the 17 enrolled subjects, one subject was withdrawn on day 4 of treatment because of the investigator's decision and is included in the demographic and adverse event reporting, but it's not evaluable for laboratory data. The 16 evaluable subjects, who completed the 50-milligram dose level, of those 10 were escalated to and 9 completed that 100-milligram dose level. One of the 10 patients self-discontinued treatment 3 days after starting the 100-milligram dose level and was withdrawn after completing safety follow-up, but remained evaluable up to the 50-milligram dose level. The baseline characteristics of this cohort is shown here with a mean age of 39 years, the majority of subjects being male, the majority of subjects being on stable hydroxyurea, and 1 subject on both hydroxyurea and L-glutamine. Their mean hemoglobin was at 9.2, and you can see that their hemolytic markers were elevated above the normal range at baseline. We can go to the next slide. So the most common treatment-related adverse events are shown in the first column, with the second column showing the incidence of AEs of all grades that occurred in 10% or more of subjects. In the third column, you see all events grade 3 and above. Overall, the AE profile in sickle cell disease was consistent with what we've previously seen in our PKD and thalassemia programs, of course, with the exception of vaso-occlusive crisis. And I'm happy to say that none required dose drug discontinuation. There were a total of 6 serious adverse events, with only 2 being possibly related to treatment. I'd like to talk about those a little bit. So there were 4 VOCs that occurred during the study period. And importantly, none were during the dose escalation period. Two occur during drug taper, which were deemed maybe or possibly drug-related. The first VOC triggered a protocol amendment to extend the length of drug taper, and the second occurred in the setting of well-known VOC triggers for that particular patient. Two other VOCs occurred during the 28-day safety follow-up period post drug exposure in the setting again of known VOC triggers, per the patient's report and were deemed unlikely to be related to study drug. There was an SAE of shoulder pain that was not typical of a VOC and one subject was discovered to have a pre-existing PE, for which that patient was withdrawn from the study shortly after starting the drug. In terms of grade 3s AE, there's one more to point out and that is Grade 3 hypertension AE that occurred in a patient with baseline Grade 2 hypertension. We can go to the next slide, Holly. So in terms of the laboratory response, we can see shown here the mean change in hemoglobin level from baseline. And, we can see that the x-axis is reflecting hemoglobin response after 2 weeks of treatment at each particular dose level at the end of drug taper, and finally, at the end of study. Of course, the error bars here correspond to standard deviations. We see that 9 out of 16 evaluable patients achieved a hemoglobin response of at least 1 gram per deciliter. And then using this linear mixed effects model with age and gender and each time point as covariates, we see a statistically significant increase in hemoglobin level after 2 weeks of treatment at the 20, 50 and 100-milligram dose levels compared to baseline. We can go to the next slide. Looking at markers of hemolysis, we see a mean decrease in the markers of hemolysis as hypothesized. We see -- this includes Lactate dehydrogenase, this includes total bilirubin, and this also includes absolute reticulocyte count and AST, or aspartate aminotransferase. This is similar to previously presented data. Next slide, please. For pharmacodynamic measures, the mean percent change from baseline is shown here over the same time points. And we observe again a dose-dependent decrease in 2,3-DPG and increase in ATP levels with return to near baseline by the end of study. In line with the anticipated effects of reducing 2,3-DPG and increasing or optimizing red blood cell energetics, we observe with treatment, there's a mean decrease in P-50 that is defined as the partial pressure of oxygen, at which 50% of hemes have oxygen bound. The signals increased hemoglobin oxygen affinity, and there's also a mean increase in T-50, which signals a delay in hemoglobin as polymerization. Next slide, please. So in summary, mitapivat is an oral PKR activator that is appears -- that appears to be safe and well tolerated at several dose levels in individuals with sickle cell disease. Mitapivat reduced not only 2,3 DPG, but also increased ATP with an expected increase in oxygen affinity and a decrease in the rate of sickling, signaling its potential to reduce sickling and improve clinically meaningful outcomes in this patient population. The study serves then as a proof of concept that mitapivat improves anemia, decreases hemolysis and that long-term disease-modifying effects of mitapivat treatment in sickle cell disease should continue to be evaluated and will be evaluated not only in an ongoing extension study, but also in the RISE UP trial, which is actively enrolling and is our Phase II/III trial evaluating against safety and efficacy of mitapivat in sickle cell disease, looking at both hemoglobin response and frequency of sickle cell pain crises. I'm going to stop there. I'm going to hand it over to my colleague, Mike Callaghan.

Good morning. I'm Mike Callaghan. I was until recently Sickle Cell Director in Detroit and Academic Medicine. But I'm now the Medical Director for the AG-946 Phase I study. I'm so excited to be back at ASH in person. It was really great to make connections with old colleagues, our site investigators and new friends. And I think at Agios, we're fueled by connections. And after this ASH, I really feel fueled. I think we got a lot of great feedback and really a lot of enthusiasm for our program, including the data I'm going to share with you now, which is from the ESTIMATE study, which is a Phase I study of mitapivat in sickle cell disease, which was done at the site in Utrecht. The objective of the study was to assess safety and provide proof of concept for mitapivat in subjects with sickle cell disease. The primary endpoints were a biomarker point of sickling and serious as well as other adverse events. These secondary endpoints included changes in hemoglobin, 2,3-DPG and ATP levels as well as hemolytic markers and surrogate markers of mortality and organ damage in sickle cell disease. The eligibility criteria were aged greater than 16, diagnosis of hemoglobin SS, S beta 0 or S beta plus thalassemia and prior sickle cell disease-related complications. Subjects had to have a hemoglobin between 6.1 grams per deciliter and 11.1 grams per deciliter. They could be on hydroxyurea, but had to be at a stable dose for 3 months, and could not be on chronic transfusion therapy. This is a schema of the ESTIMATE study. And you can see after the screening period, there was a dose-finding period of 8 weeks, which included the dose escalation, the first 2 weeks at 20 milligrams, and then an increase to 50 and 100 milligrams if the dose was safe. I'm going to report today the results from the 8-week dose finding period, Dutch Phase II open-label, single-center study. So 6 subjects were enrolled as of September 2020 and have completed the dose-finding period on mitapivat, all reaching the 100-milligram BID dosing. The baseline characteristics of the subjects were, 5 of 6 subjects had hemoglobin SS disease, 1 S-beta thalassemia 0. The median age was 36 years, with a range of 20 to 59 years. 4 of 6 subjects were female, and 5 of 6 subjects had concomitant use of hydroxyurea. No serious, adverse events have occurred during this trial. All of the adverse events were mild grade 1 events and transient. The most common occurring in more than 1 subject where increases in transaminase, gastrointestinal events and headaches. There was 1 vaso-occlusive crisis that occurred without hospital admission and did not require a dose reduction or discontinuation of mitapivat. So the efficacy results, all 6 subjects had significant improvement in their point of sickling. 5 of 6 subjects had achieved an increase in hemoglobin of greater than 1 gram per deciliter. And in the bottom left panel, you can see oxygen-gradient ektacytometry or [ lower curve ] results, and this was the primary endpoint of the study. The point of sickling. So this is the oxygen tension, at which the hemoglobin polymerizes in the cell sickle. And the red is the untreated at day 0 sample and the green is the day 56 sample. And you can see the shift up to the left, which indicates that sickle cell -- red blood cells need to get to a lower oxygen tension before they'll sickle, which has been associated in other studies with improvement in sickle cell outcomes. These graphs depict improvements in hemoglobin, ATP-2,3-DPG ratio and hemolytic markers, which are in tabular form on the next page. So point of sickling and p50, the partial pressure at which 50% of the hemes are occupied, shifted significantly, hemoglobin increased by a mean of 1.2 grams, which was also significant. There was a significant reduction in reticulocytes and hemolytic markers. 2,3-DPG, as expected, decreased and the ATP-2,3-DPG ratio has significantly increased as well. There were a panel of exploratory biomarkers looking at end-organ function in markers of mortality, with only 6 patients and 2 months of study. We were excited to see a change in albumin-creatinine ratio, and we'll continue to follow the other markers as well. So in conclusion, mitapivat is an oral PKR activator that demonstrates an adequate safety profile during the 8-week dose finding period in sickle cell subjects. Mitapivat increased hemoglobin level and decreased hemolysis and sickling parameters. The observed changes in 2,3-DPG and ATP are consistent with the proposed mechanism of the drug. And we were excited to see early improvements in albumin-to-creatinine ratio. And this study continues now in the ongoing follow-up for 52 weeks, which will be reported at a later stage.

Great. Thank you. So last but not least, we're going to cover pyruvate kinase deficiency and some long-term clinical data that we have presented here at ASH. So just a reminder that pyruvate kinase deficiency is another rare lifelong hereditary anemia and similarly to the other 2 that we've discussed, there are several very serious complications and end organ damage. And there are no approved disease modifying pharmacotherapies, and all available supportive therapies are associated as well with the long-term complications. Just a reminder of the studies that we'll be talking about today. So ACTIVATE was our Phase III study in non-regularly transfused patients, with hemoglobin endpoint as a primary endpoint, and then patients had the opportunity to move over into a long-term extension study, in which the placebo patients did a very similar dose escalation to get to the optimized mitapivat dose, and then we continue to follow those patients by now, then all on mitapivat. And then ACTIVATE-T was the open-label design in regularly transfused patients, in which patients were basically used as our own controls to measure transfusion reduction, and those patients also have the opportunity to roll over in the same long-term extension study as the other trial population. Of course, we were very pleased both Phase III studies were positive with their primary and secondary endpoints achieved, both on the hemoglobin endpoint and on the transfusion reduction endpoint, with changes in the secondary endpoints, highlighting improvement on hemolysis and the prespecified patient reported outcomes as well. And then across both studies, the safety profile was generally consistent with what we've observed through in the previous trials as well. And so these data are currently under review both in U.S. and in Europe. And now we're very excited because the patients did go on into the long-term extension study that we can present some long-term extension data that will highlight that there is an impact on very significant complications for these patients as well. And so Dr. Van Beers presented the iron overload and the ineffective erythropoiesis data yesterday. And so I'll be walking you through that today. So if you can just move on to the next slide, Holly. So we studied several markers of erythropoietic activity as highlighted here and also markers of iron metabolism and indicators of iron overload as well. And then we studied both patient populations. So the ACTIVATE and long-term extension study was assessed, in which we followed patients who were on mitapivat from the beginning and continued on mitapivat in the long-term extension, and so that is the M/M group. And then the other group was the patients assigned to placebo, who then rolled over into the extension on mitapivat, and that's the P/M Group. And so we will be highlighting an analysis on both those groups. And then for ACTIVATE-T and long-term extension study, we did a descriptive analysis, and we limited the analysis to the patients who achieved transfusion-free status in the fixed-dose period of ACTIVATE-T because transfusions actually impact these markers of erythropoietic activity, iron metabolism and iron overload. So that was the clean population that we could study. This is a little bit of a complicated slide with the color scheme, but it is very interesting. So we did observe decreases in markers of erythropoietic activity in the -- in both treatment arms. So you'll see the different markers here presented in table format. The light blue is the baseline value. The darker blue is when patients are on mitapivat. And the gray is when patients are on placebo. And what you see is that in the mitapivat, mitapivat group, at week 24, we actually observe what we want to observe. And then when the placebo patients get to mitapivat, they follow the same pattern as their counterparts. And we saw a decrease from baseline in EPO, the decrease in reticulocyte from baseline at the 2 time points, a decrease in erythroferrone and decrease in the soluble transferrin receptor as well. So highlighting that all of the erythropoiesis actually was decreased and better because we are impacting this hemolysis. We can move on to the next slide, and this is the graphical presentation, in which you can clearly see that the lines are separated when patients are on mitapivat versus placebo. And then once the placebo patients switch over, they start following the same pattern as their counter cohort. And then we're very excited about the data in iron metabolism and overload. So the table is set up in a very similar way. What you see here is the markers are doing what they need to do in the context of an improvement on iron overload. So over time, we saw an increase in Hepcidin, we saw a decrease in iron, and then I am going to highlight the data that we're most excited about is the liver iron concentration, which is considered the gold standard for measuring iron overload. And we saw a decrease over time there as well, actually relatively early and then continued on week 48 for those patients. So that is very exciting, and we believe a very meaningful improvement in the context of impacting the hemolysis here. And now for ACTIVATE-T, as I highlighted, is a descriptive analysis. We saw in the patients that transfusions-free responders that they experienced improvements in those same markers of erythropoietic activity and iron overload. And then we also, of course, looked at iron chelation therapy for those patients. So none of the patients actually had a dose increase One patient had an iron chelation dose reduction and 2 patients were able to discontinue iron chelation completely. And then 1 additional patient, who was a transfusion reduction responder in ACTIVATE-T, did no longer received transfusions in the extension study and that patient was also able to reduce the iron chelation therapy. So data from ACTIVATE, ACTIVATE-T and the long-term extension show that activation of PKR with mitapivat improved markers of ineffective erythropoiesis and iron metabolism in patients with PK deficiency, regardless of transfusion status. And through this mechanism, mitapivat improves in effective erythropoiesis and may have the potential to improve iron homeostasis, thereby reducing iron overload. At the same time, we also highlighted the maintenance of efficacy data at ASH. Dr. Grace presented that yesterday as well. We can go on to the next slide. So it's the same studies. The same studies ACTIVATE and ACTIVATE-T and their long-term extension data that will be presented here. And so we had -- at the time of the data cut at the bottom of the slide, you see that we had 35 patients that were in the mitapivat cohort that continued into the mitapivat, to take mitapivat in the long-term extension, and there were 36 who went from placebo to mitapivat in the long-term extension. Graphically here, you can see the first -- the greener color highlights what will happen in the core period, in which you can clearly see that mitapivat improved the hemoglobin and that the placebo patients actually remains stable. And then in the gray part of the graph, when patients start taking a mitapivat -- the placebo patients start taking mitapivat, you see the gray line coming up and merging with the blue line. And then you also see that over time, up to 72 weeks, people that have a hemoglobin response were able to maintain a hemoglobin response in the long-term extension study. So it's very nice because you basically see maintenance of effect on this graph and you also see consistency when patients are exposed to mitapivat for the first time in the extension study to what happened in the core study. And then these are individual treatment responses that are presented here for the patients who were on mitapivat in the core period, and then we followed out the hemoglobin response over time. And you can see that the majority of the patients really remained above the 1.5 grams per deciliter, so 13 out of 15 patients maintained their status at every single time point up to 19.5 months. And this is the placebo group that is actually showing a very similar pattern again. So again, consistency in the results. So for ACTIVATE-T very similarly, people continued on into the extension study. So we had 17 patients continue in the long-term extension as of November 12, 2020. So focusing specifically on the transfusion reduction response. So 9 patients in the long-term extension study met the criteria for transfusion reduction response. And then the transfusion-free duration is presented here on the graph. So those are the patients that were transfusion-free in the core period. Black triangle presents the time point at which they become or considered transfusion-free. And then the lines extend, as you can see for some patients for a very long time at this point without the need of having transfusions. So in conclusion, PK deficiency is a lifelong serious hemolytic anemia with no approved pharmacotherapies. Non-regularly transfused patients randomized to mitapivat in ACTIVATE showed maintenance of hemoglobin response through the long-term extension study for up to almost 20 months. Similarly, 35% of the ACTIVATE patients who switched from placebo to mitapivat in the long-term extension study achieved the hemoglobin response, which then was continued to be maintained. And then all regularly transfused patients who achieved transfusion-free status in ACTIVATE-T with mitapivat maintains their transfusion-free status through the long-term extension study for up to 22 months. So the totality of these data actually show that there is consistency and long-term durability of responses in those patients with PK deficiency, independent of the transfusion needs. It continues to support the potential of mitapivat to become the first approved disease-modifying pharmacotherapy for PK deficiency. And then the iron overload really starts showing that we have the potential to impact long-term complications of this disease as well.

Great. Thank you, Sarah, and to our presenters. We'll kick off Q&A now. [Operator Instructions]. And I will start asking them now. Question from Alethia Young. In the VOC case that was possibly drug-related, it sounded like the person had a history of them. So can you explain why it was deemed possibly related to drug?

I'm going to hand that question over to Ahmar.

Sure. So what I'd like to do, I guess, is talk a little bit more in depth about the VOCs we've seen to date. So of course, there's 2 VOCs that we've previously discussed, one near the end of drug taper, which led to the extension of the tapering time, and then another patient who had VOC while not on drug. Now the 2 new VOCs understanding that sickle cell disease is this catastrophic entirely unpredictable disease, particularly as it relates to how patients feel pain. I think it's important to keep that framework in mind. But the 2 new VOCs in the first patient, we see VOC happening 12 days after starting the drug taper at the lowest dose, 5 milligrams q. daily. And again, in the context of very well-known VOC triggers, travel, temperature, physical exertion. And then the second new VOC is a patient who had VOC while not on drug, again, very, very near the end of their safety follow-up period. I think just remembering that VOCs are expected. This is sickle cell disease. This is the most common manifestation of sickle cell disease. And we're going to continue to see VOCs through our clinical studies as this is just the nature of how this disease unfolds.

I think also in the context of safety reporting, the way investigators get the choice around related, unrelated, there is this gradient in which they have to pick many, many physicians in between categories because it's not a binary choice, and it's almost like it's in a way easier to choose that. This is where we always look for safety data at the totality of the data rather than specific single events, and we're very excited to rise up -- continue to deliver on efficacy and safety data moving forward.

So I have sort of a 2-part question, 1 in sickle cell and 1 for PKD from Greg Harrison at Bank of America. So maybe sticking to sickle cell first. What was the timeline of the 2 VOCs seen in taper? Could this safety be seen in a noncompliant patient? And is there a threshold of mitapivat concentration you found as a threshold to reduce or avoid VOC?

I think this one goes back to Ahmar.

Yes. So thanks for the question. I can say that the VOCs that occurred during taper occurred in both individuals very much at the -- near the end of the taper period. And remember that, that taper period is roughly 2 weeks. And the second part of that question relating to compliance. Compliance is a tricky thing always in chronic disease, particularly in sickle cell disease. But I can tell you that it seems that missing doses here and there is not triggering a VOC. It really does seem like based on these 2 instances of these taper-related VOCs that takes some time before we get into a position where VOCs are occurring during sort of the period of being off drug or being sort of at a lower dose of the drug.

Great. And the second question in PKD. With PDUFA approaching, how do the long-term updates today support the potential to use mitapivat as a chronic treatment for PKD.

Well, I think they clearly support the use of long-term treatment. The responses are clearly maintained over time now for a very long period of time that we're following these patients. The safety continues to support that as well. And we haven't spoken about it, but we did present bone mineral density data and PK deficiency as well with up to 5 years of follow-up. So the long-term safety data continues to support us as well. And then like I mentioned, we are very excited about the iron overload data because we know that, that really is driving a lot of the long-term complications together with the hemolysis. So it's very important to understand that this is an interplay of different factors. The fact that we continue to impact hemolysis, thereby probably also reducing inflammatory situation in the body, it continues to support it. So very exciting to continue to drive this process forward. And yes.

Great. So I have one question from an investor. Can you comment on the improvement in creatinine-to-albumin ratio? How do you interpret it and the implication for demonstrating additional clinical benefit?

So I think that one goes to Mike.

Thank you for the question. So I think we were surprised to see a change in only 8 weeks in only 6 subjects. And it's encouraging, but I think it's really too early to say. So we'll have to collect additional data, but certainly exciting to see an end-organ signal in such a small study.

So a question from Marc Frahm, Cowen. How did the subset of patients in the NIH trial that reached 100 perform when they were on 50 milligram, looking across the 2 ISTs? Is there any indication of which patients are more or less likely to respond to mitapivat? And what criteria will you use to select a dose in the Phase II portion of RISE UP?

Mike, do you want to take the first part and the second?

Sure, yes. Yes. So at least for the first part of that question, I can tell you that the individuals who were escalated to that 100-milligram arm based on Dr. Schuh's data, it appears that the type of response they had at 100 milligrams was pretty close to the type of response that they had at that 50-milligram dose as well. So I think early indications are still not clear to us as to which dose is going to be the "winner." But that's exactly why we're pushing forward with RISE UP in our Phase II to really delineate which dose is best to push forward with. And as far as dose selection, there's a lot of nuance in sickle cell disease. And as we go through the 12-week treatment period in 69 patients in our Phase II, we'll make a decision based on primarily safety, but of course, also efficacy and sort of make a decision based on the totality of that data.

And related to the VOCs from Mike King, H.C. Wainwright, can you discuss what steps you might take to reduce VOCs during drug taper? And any protocol amendments you might make in terms of inclusion or exclusion of criteria?

Ahmar, do you want to start?

Absolutely. I think one thing that has sort of become clear with our over half a decade experience with these PK activators is that a taper is probably necessary for individuals, who take medicines that activate pyruvate kinase I think at this point in time, we're very confident and comfortable with the way we're approaching this, particularly from a frame of patient's safety always being top of mind in all disease spaces, but very importantly, in sickle cell disease, I think we want to ensure that we are monitoring hemoglobin rises and decreases as closely as possible, ensuring patient's safety. So at this point in time, there's no plans to change the way we've been approaching this issue. And again, at this point in time, I don't see any immediate plans to alter our inclusion and exclusion criteria.

Great. A question from Kennen MacKay RBC. So PK activation in sickle cell has been a growing focus at ASH. What differentiation do you see between PK activating agents? And where do you ultimately see these agents fitting into standard of care in sickle cell disease?

Maybe I'll start a little bit and then hand it over to Ahmar and Mike to give their perspective as well. Yes, indeed. So I think PK activation because what we've been showing across the different diseases, we see very consistently that we're impacting anemia, hemolysis. We have now these data presented as well on point of sickling. So we're very excited about our PK activation, having the potential to impact both anemia and sickle cell pain crises. And obviously, there has not been a drug that has demonstrated that clearly in a Phase III trial. So we truly believe that, that can make a huge difference for patients moving forward with this program. There are indeed many drugs being studied, and from my perspective, the more the merrier, because this is a really tough disease that needs treatment options. And we're excited to see to see all of these programs moving forward. I think there is a place for everyone to be honest, because the patients are so much in need. And what works for one patient may not be optimal for another patient, so options are needed here. Because it is an oral therapy, very easy to use, right? We think that has an advantage as well that some of the other medications may not be offering. And with that, I'm going to hand it over to my colleagues here to provide their perspective.

Oh, sorry. Mike, I see you unmuted, but here, I'm going to intro this really quickly, and then I'll pass it to you, I promise. So Mike and I have spent the last several years of our life, prior to joining Agios, working at a very high volume sickle cell center in Detroit and cared for 800 patients or so with sickle cell disease. So we've really seen the trajectory of the therapeutic space and how things have changed over the last -- certainly over the last 5 years. The renewed energy around these therapeutics is fantastic. And of course, we're super excited about the science behind activating pyruvate kinase. I think there was a part of this question that talked about where we see this fitting in. And I think the short answer there is anywhere and everywhere. The need is so large in this group of patients that any new therapy that's able to not only optimize red blood cell energetics, but also make meaningful differences potentially in the patient's ability to stay hopefully pain-free and hopefully have a better quality of life. Hopefully, we'll be able to show that by the time it's all said and done. Therapies like that will always be necessary, and there can't be enough of them. I'll pass it to Mike.

I would reiterate what Sarah and Ahmar said. I think in treating patients over the last 15 years, it's clear that even with our best therapies now, there's a tremendous amount of unmet need. Our patients are suffering, and we need to bring new therapy. So I'm really excited that there are a lot of them coming. It's early days for almost all of these therapies, and we have a lot of work to do. And I see that we have a really well-designed pivotal Phase II/III trial that I think can answer important questions, about our molecule. I'm excited about our molecule and really look forward to seeing all that data and hope that multiple agents can come and really serve our patients.

A question from Andy Berens at Leerink. Can you give us an update on how many patients you've identified in the PKD registry? How many patients have been in the clinical program and how quickly they will be converted to revenue-generating patients?

I'll start with the second part. So our clinical extension trials are ongoing, and we are committed to continue to study those patients as we have designed the trial. So there is currently no plan to move those patients over to commercial drug because we do need to continue to study these patients in a clinical trial setting. In regards to the registry, I can't remember the exact number to be quite on. So I am going to see on what the last update was, but it continues to enroll patients, the -- and...

And maybe, Richa, if you want to speak to sort of the way we laid out our -- what we view as the state of play at launch for the PKD patients we've identified?

Yes. So the plan, as you guys know, we've been working a lot on identifying patients and doing disease education. So that's going to continue to be a focus at launch as well. It's really important that we lay out the disease burden so that physicians truly appreciate what it -- what the disease burden associated with PK-deficiencies, which Sarah talked a lot about, in the context of the data we presented at ASH this year. And as we've also talked about, we have the anemia ID program, which we've been using to help physicians diagnose patients with PK deficiency, and that has had a really good reception from physicians in their ability to be able to identify these patients. So that's going to continue to remain a focus between now and approval and then also post approval.

All right. So a question from Mark Breidenbach again. Last year, at ASH, Dr. Zhu suggested, CYP3A auto-induction may be coming into play at the 100-milligram BID dose in her sickle cell trial? Has this been ruled out?

So well, we know that we have 3 auto induction, but the 100-milligram dose actually falls below that line. So it's -- we do continue to see with increasing doses, increases in ATP and decreases in 2,3-DPG. So I don't see that having panned out. We do believe we have the dose ranges, like pharmacodynamic dose ranges here, that 50 milligram and 100 milligram do provide pharmacodynamics and efficacy. And of course, as Ahmar has outlined, we will be looking at this more closely in the RISE UP.

Great. A question from Danielle Brill with Raymond James. How would you explain the differences in magnitude of benefit on markers of erythropoiesis and iron metabolism at 24 weeks in the M/M cohort versus the placebo crossovers in the LTE portion of ACTIVATE?

Yes, indeed, it's pretty -- well, the erythropoietic markers, I think is more like it's very logical, right. You impact the hemolysis and you start seeing those changes pretty soon in the trials. For iron metabolism, we're very encouraged by seeing like a signal pretty early actually. It's -- but that signal continues to be seen over time. So we think this is actually one of the bigger differentiators in our data as we have presented it so far with what was presented at ASH by others that we truly continue to impact hemolysis, and we believe this is tied into that.

Great. So I'm not seeing any other questions. So just a reminder, if you had a question, please submit it to the Q&A portion of the chat. So I have a question about -- so patients who have responded initially and fell back to baseline, do you know what the reason would be for this? And is it captured in your data?

Patients who fell back to baseline, I'm not sure.

They had hemoglobin response and then if it went down after having an initial response, what would be the reason for that?

So the data basically shows the maintenance of response, right? Of course, there's always some fluctuations in hemoglobin. It's not going to be always like the same value or always going up, like always going up. Even if you have a hemoglobin response, you do see fluctuations around that response over time. So we consider that all of the patients presented in our data set have maintained their hemoglobin response. There were 2 patients in the cohort presented that hovered right around 1.5 grams per deciliter, but then they were at that point and they continue to say to maintain their response as well. And then the other thing is like I'm going to make a pitch for this as well because I do think you have hemoglobin response here that we're looking, but I think the hemolysis impact is very important too in the long run. So even if your hemoglobin would not rise 1.5 grams per deciliter, but you have some hemoglobin improvement and an impact on hemolysis, I think that is very meaningful too.

Great. Well, I'm not seeing any other questions. So thank you to all of our presenters today. Thank you to those of you who have joined. We really appreciate it.

Thank you.

Thank you.

Thanks. Bye.