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

Good morning, everyone. We're going to get started here. I'm going to turn it over to Jackie. For our sell-side friends, if you have not e-mailed myself or Holly and would like to get in the lineup for the Q&A, will you just shoot us an e-mail now and we'll take questions as folks have e-mailed us and then queued up. So with that, Jackie, why don't I turn it over to you? Jackie, we can't hear you just make sure you're unmuted.

Can you hear me?

Part of it. Thank you. Yes, go ahead.

Everybody. Can I get some thumbs up that you can hear me. Okay. Perfect. Thank you. Good morning, everybody. Why don't I to start off our e virtual investor webcast this morning. So thanks for getting up early and joining us for today. I also want to especially thank the 2 investigators that we have with us Dr. Swee Lay Thein and Dr. Kevin Kuo. So we really look forward to hearing from those guys today. I was just going to open with a couple of minutes of quick remarks as somebody can turn the slides for me, please. So we have our forward-looking statements letting those what those means. For those of you, here's the agenda that we have today, as I said, I have some brief opening remarks I'll turn it over to Chris, going to talk about mitapivat and give an introduction to the rest of the agenda. Then we have Dr. Kuo, who's going to go through our thalassemia data that he presented in an Oral EX presentation at EHA earlier. And we also have Dr. Swee Lay Thein from NIH, who is going to go through our sickle cell data with you. We're very excited about the development of both these indications for mitapivat, and we're extremely pleased to have them with us to present the data to you today. And then we'll go into the Q&A. And those of us who are listed on this slide here will be on the panel ready to answer your questions. So I just wanted to take a quick minute and remind everybody about our Agios 2025 vision, which is very much intact despite the coronavirus pandemic and things that are going on in the world related to that today. But our teams have continued to execute extremely well over the course of 2020, very proud of them. You saw some of those results back in our first quarter results call about 6 weeks ago, and we continue to do well. As everybody knows, we have 2 marketed products today for AML. We expect to have 4 by 2025, and the other items that are set out for you there in our 2025 vision. Mitapivat is an important part of this vision that is 1 of the 4 medicines that we list on this slide as we are expecting to have an approval well ahead of 2025. We hope to have multiple indications from mitapivat approved by 2025 and something that plays into the A plus indications. And it's a drug that we think has tremendous commercial potential, and we hope that you will start to see an update at a mention of that as well. So on the next slide, I just want to talk a little bit about why today is so important for us. It -- you saw 3 press releases from us so our data for thalassemia from mitapivat. In both alpha as well as beta thalassemia, we're the first company to show this type of data for alpha thalassemia, and we're very proud about that, and we look forward to hearing from Dr. Kuo on that one. We've also now established proof-of-concept for sickle cell disease. And Dr. Thein will talk to you about that. We have seen enough data on mitapivat in sickle cell disease to be ready to move the drug forward in the next steps of development. And we'll be looking to move both of these indications forward as quickly as we possibly can on behalf of patients and do that while maintaining a very high-quality clinical program for both of them. We also announced today something that we're very excited about, which is we've raised $255 million of a nonequity capital through a transaction with Royalty Pharma, where we have sold our IDHIFA royalty stream to them. And this is capital that we are now able to add to our financial resources, and it's supporting us starting the clinical development for the pivotal programs for both thalassemia and sickle cell disease for mitapivat. So we've said for a while that we were going to pursue nonequity forms of funding. So this is a step in that direction, and we're happy to share that with you today. So with that, I'm going to turn things over to Chris and our other presenters. Thank you very much. I'll be back for Q&A.

Thanks, Jackie. Can you hear me all right? Okay. Great. Well, good morning and good afternoon, everybody, from virtual Frankfurt. Too bad, we can't be there in person this year. But I think we're doing the right thing by staying home and frankly, we didn't have a choice, did we? It's really exciting to be on the call this morning and to share some of those new data and developments with you. And I'm going to give a few background comments to -- before we get to the main event, which is for you to hear from our 2 physician hematologists. We wanted to start with this slide because I think it's really foundational to the PKR story overall. And if you think back a number of years ago, we started talking about the target in terms of activating pyruvate kinase with the potential to improve red cell health, and we started out by addressing a specific disease pyruvate kinase deficiency. So on the top left, you see the schematic, which really gauges the overarching hypothesis that we're pursuing in the clinic, and that is you activate the glycolytic pathway through this enzyme PKR and increase ATP in cells and may be able to improve outcomes initially, in pyruvate kinase deficiency because these patients have mutated pyruvate kinase. And in the panel in the middle, one of our early investigations was done by taking red cells out of patients with the disease of pyruvate kinase deficiency and demonstrating that we could increase the activity of the enzyme, which is the columns on your left and in the column in the middle. We could decrease 2,3-DPG. And in the column in the right, we could increase ATP. So with that, we then went into the clinic initially in healthy volunteers. Because patients with pyruvate kinase deficiency are so rare, we wanted to understand the pharmacokinetics of mitapivat in an effort to streamline our clinical development program. And what you see in the plot, the bottom there that says the absolute change in ATP over time, and these are healthy volunteers that received a number of different doses of mitapivat, both twice a day and 24 hours. And what we showed was an increase in ATP, so this de-risked our program going into patients with pyruvate kinase deficiency and was also an indicator that we could think about developing this drug in patients with wild-type PKR. And that's going to be and that is develop it in patients with [ hemolysis kinase ] where you could activate wild-type PKR. And that's really the focus of today's discussion that you're going to hear from with Doctors Kuo and Thein. Proof-of-concept in pyruvate kinase deficiency was delivered with the DRIVE PK study. And there, you see in that plot, the maximum hemoglobin increase from baseline across all the patients enrolled in that study. And in this disease, we saw increases of 2, 3, 4 grams and beyond, and we learned a lot about the genetics of that disease. So if you go to take that to the next slide, that sort of established our program. And if you bring it back to what are we trying to do here, it's fundamental to understand that the main way that red cells derive energy is through glycolytic pathway, which you see on your left. Pyruvate kinase are the key enzyme here, and it's maintained -- for maintaining energy in homeostasis and renal blood cells. It's the most important energy source, the glycolytic pathway for red cells. And there you see at the bottom of the pathway on your left, the PKR catalyzes that final step in glycolysis and has the potential to change levels of 2,3-DPG, ATP and PEP. And then 2,3-DPG and ATP, in particular, are often dysregulated in hemolytic anemia. And our experts will be able to talk at length about that if there's interest in the Q&A. Next slide, please. So then taking this concept of activating PKR, we walk you through 3 scenarios. In the first column, you see the normal red cell has the ability to produce ATP that meets the overall demand of the cells, this allows it to live 120 days. It doesn't sickle, deform, it does what it's designed to do, it deliver oxygen to tissues. In pyruvate kinase deficiency, the mutated form of PKR leads to a situation where you have inadequate production of ATP to meet the demands of the cell, and therefore, you see early hemolysis and a chronic hemolysis and cells don't -- red cells don't live very long. On the farthest panel is the theory in terms of activating wild-type PKR and other hemolytic anemias. And here that underlying disease, whether it's thalassemia or sickle cell, creates an unhealthy red cell because of the genetic disorder. And by increasing the amount of ATP in that cell, which may need a greater demand of ATP in order to maintain its fitness and live longer, we can activate wild-type PKR. And so that's what we're going to get to shortly. Next slide, please. In thalassemia, again, looking at the pathway, we think the main [indiscernible] benefit is to increase ATP, increase red blood cell fitness, reduce reactive oxygen species, ameliorate other impacts, other components ineffective erythropoiesis and hopefully derive -- provide clinical benefit to patients with thalassemia, both alpha and beta. In sickle cell, on the next slide, where the same concept applies from the perspective of ATP that you see at the bottom of the slide, but now we introduce what the potential is to reduce sickling by decreasing 2,3-DPG when you activate the pathway. If you decrease sickling of red cells, there's a potential to reduce the frequency of vaso-occlusive crisis, which bring with them many, many bad clinical outcomes such as stroke, pain and many other bad outcomes for patients. Next slide, please. So with that now, we are in a position to activate trials across a number of different diseases, and we're into a broad life cycle management clinical development program. On your left, pyruvate kinase deficiency, we have Phase III trials that have completed enrollment, which you can see at the bottom of that column on your left. The top line data is expected sometime between year-end this year into mid-2021. And we expect to move forward in pediatrics. There's approximately 3,000 to 8,000 patients with pyruvate kinase deficiency. And the topic of today's discussion are really those thalassemia and sickle cell disease. You can see the patient numbers there. There are lots of patients with an unmet need. We're really excited that there are new therapies that are coming for these patients, and we're very excited to be -- have the potential to actually add to the armamentarium that physicians will have. In thalassemia, our Phase II enrollment is complete, and we're actively working toward developing our pivotal plans to get those in front of regulators and initiate those trials next year. And in sickle cell disease, our NIH trial continues with the -- with Dr. Thein, who's on today. Looking to submit data to ASH, and we're also beginning to work actively on pivotal trials that we expect to initiate next year as well. So I'm going to stop there and keep things going and turn it over to Dr. Kevin Kuo. He's been a great collaborator with us in developing mitapivat in pyruvate kinase deficiency, and now has been very instrumental in bringing our thalassemia program forward. So Kevin, I'll turn it over to you.

Thank you, Chris, for the introduction and setting the stage for what I'm about to present. Next slide, please. So let's begin with what is thalassemia. It is inherited blood disorders that reduces the production of functional hemoglobin. It affects both quality and quantity in some cases of thalassemia, not only do you have a reduction in functional globin, you also have a production of dysfunctional hemoglobin. And what is hemoglobin? Hemoglobin are proteins in the red cell that carries the oxygen. So without functional hemoglobin -- and there is results in the shortage of red cells and a reduction in available oxygen into the bloodstream leading to a variety of issues. And there are 2 types of thalassemias, both alpha and beta. And alpha thalassemia is characterized by a mutation in the alpha globin leading to a lack of the alpha globin. And beta thalassemia is a mutation in the beta-globin gene, which leads to a reduction in beta. And so because hemoglobin requires both alpha and beta to perform, there's 2 alphas and 2 betas. So any lack of 1 or the other of the partner results in a excess of 1 and a deficiency of the other. And this imbalance creates a myriad of medical issues. There are approximately 18,000 to 23,000 patients in both the U.S. and in Europe. Approximately 70% of beta-thalassemia found in Europe and approximately 30% distributed in U.S.. And in alpha thalassemia, it's sort of a even split between the U.S. and the European Union. Now in terms of transfusion dependency and non-transfusion dependency, the split for beta is approximately 60-40 for transfusion-dependent versus non-transfusion dependent. And in the alphas, it's predominantly non-transfusion dependent. Next, please. So as I mentioned before, the imbalance in both -- in the alpha and beta globin results in the both ineffective erythropoiesis, which means that the body is not making enough of the red cells. And even if these red cells do escape into the circulation, they will result in hemolysis. So you have both hemolysis and ineffective erythropoiesis creating the complications in patients of thalassemia. And the phenotypic presentation of these patients varies. If you have thalassemia minor, which means that you're missing 1 gene, because chromosomes comes in pairs, right? And genes comes in pairs. And if you're missing 1 gene, there is no clinical consequence. However, if that particular gene is producing a globin that is not functional or that has reduced function or both genes are affected, you can have either thalassemia intermediate or thalassemia major. And in the cases of thalassemia major, these patients are dependent on transfusions for life. And in patients of thalassemia, often we start these patients on transfusions because they have a number of complications from the ineffective erythropoiesis and hemolysis, such as gallstone, splenomegaly, leg ulcers, pulmonary hypertension, extramedullary hematopoiesis that can compromise the spine and leading to paralysis. And with transfusion, however, these patients also have iron overload, which also threatens the different organs such as the heart, the endocrine tissues and the liver. And so what we hope, we've always wanted in the thalassemia community is to break this cycle of transfusion dependence and break the cycle of these chronic complications, progressive chronic complications. Next slide. And as I mentioned before, these are the complications that you can have, ranging from silent cerebral stroke, all the way to pulmonary hypertension. I mentioned about the extramedullary hematopoiesis. The iron overload itself can cause liver fibrosis and cirrhosis and cancers as well. I mentioned about the splenomegaly, gallstone, clots featured prominently in these patients, so they get venous thrombosis. And with the iron overload, even without transfusions, these patients will get iron overload. And with the iron overload affect the heart, leading to heart failure affects the liver leading to cirrhosis and cancer, it can cause diabetes, infertility and hypothyroidism. Next, please. And I'm just going to recapitulate the schema here, the mechanism of action. Again, the imbalance in globin ratio leads to precipitation in globin. In aggregates, it creates oxidative damage leading hemolysis and ineffective erythropoiesis and anemia. In addition, ineffective erythropoiesis also leads to dysregulated iron metabolism leading to iron overload. What we hope to do with mitapivat is to increase the glycolysis and ATP availability in these patients so that we can reduce the oxidative damage, leading to a reduction in hemolysis and ineffective erythropoiesis, therefore, ameliorating anemia. In addition, by ameliorating the ineffective erythropoiesis, we can also reduce iron overload. And in ex vivo studies for patients with thalassemia, mitapivat has shown to increase ATP levels as well as increase in PKR activity in the red cells of these patients. And also the thalassemic mouse model with mitapivat also ameliorates ineffective erythropoiesis iron overload and improves anemia. And it is based on these ex vivo and preclinical data that we move on to the Phase II study. Next, please. The study design is an open-label Phase II multicenter study, where patients during screening periods are screened for key inclusion/exclusion criteria, including patients must have beta-thalassemia with or without the globin gene mutation, hemoglobin e beta thalassemia or hemoglobin x disease, which is the form of alpha thalassemia. The hemoglobin must be less than or equal to 10 grams per deciliter and must be non transfusion dependent. Following screening, the patients where they entered the trial with mitapivat at 50 milligrams twice a day for 6 weeks. At 6 weeks, there is a safety check and efficacy check. And if these patients meet these checks, then they move on to 100 milligrams twice a day for another 18 weeks to complete the 24-week core period. This is followed by a 2 week -- 2-year extension period and a safety follow-up 28 days after the last dose. Primary endpoint is defined as a hemoglobin response of greater than or equal to 1 gram per deciliter from baseline anytime between weeks 4 and 12. Secondary and exploratory endpoints include sustained hemoglobin response, the light hemoglobin response, markers of hemolysis, hematopoietic activity as well as safety. The study has completed enrollment with 20 patients. Next, please. So here, 18 patients were enrolled as of the data cut off on March 3, 2020. The median duration and treatment currently is 26 -- 20 weeks and ranges all the way up to 50 weeks of our first patient. The median age is 43 years and 50% of Asian. 5 patients of alpha thal and 13 patients of beta thal. And the median hemoglobin at baseline is 8.4 grams per deciliter. And then of the 18 patients that were enrolled, 13 have completed week 12 by the data cut and therefore, could be evaluated for the primary response. And 9 have completed the full core in our period of 24 weeks. And 8 of these entered extensions and 1 didn't enter it because of investigator's decision. Next, please. The primary endpoint was met in 92% of patients or 12 out of 13. And amongst these -- amongst the primary endpoint, all of the alpha thalassemic patients at week 12 for the full met the primary endpoint and 8 of the 9 or 89% of the beta thalassemic patients met the primary endpoint. In respect to hemoglobin responders between weeks 12 and 24, of those who have completed 24 weeks, 8 out of 9 or 89% have responded as well as 7 out of 8 of the betas have responded and have met the sustained response criteria. Next. You can see here that the mean hemoglobin change from baseline in week 12, for those who have completed week 12, were 1.34 grams per deciliter. And amongst the alphas, it was 1.17 grams per deciliter, and the betas were 1.43. It is of note that the median time to hemoglobin increase are greater and than equal to 1 gram per deciliter amount of responders with only 3.1 weeks. So within 3 weeks, they were able to reach the primary endpoint. Next, please. In terms of hemoglobin change over time, again, you can see in this box plot that the mean and the medians, which are represented by the diamonds and the line in the box, very similar. And you can see that by week 4, majority of 75 percentile have reached the primary response or change in from hemoglobin of 1 gram per deciliter from baseline. And you can see that even with the increase of dose to 100-milligram b.i.d, the response is sustained over time. Next. Preliminary results for the markers in hemolysis and erythropoiesis shows improvement that are consistent with a hemoglobin increase. You can see here that the indirect pillar of the and as well as the LDH shows decline in both alpha and beta patients and the EPO level approach upper limit to normal for both groups by week 6. And these results are very consistent with the proposed mechanism of mitapivat in these patients. Next, please. ATP changes. As you can see here, is also consistent with previously observed data from healthy volunteers. 50 milligrams, there is an 82% mean increase in ATP from baseline. And at week 24 at 100 milligrams is at 92% increase. Next, please. In terms of safety, as of the data cut, there is no serious adverse events and no AEs that are leading to treatment discontinuation. The grade 3 events were reported in 2 patients. One was due to a BPPV or benign postural vertigo, which is not related. The other one was due to bloating and heartburn, which is thought to be related. And after the data cut, there was 1 SAE of renal dysfunction that was reported that resolved upon treatment discontinuation. Next, please. And the most common AEs -- this lists the most common adverse events that are reported in more than or equal to 2 patients. And you can see here that the safety profile is consistent with previous studies in mitapivat in healthy volunteers and also in the DRIVE PK study. All of the AEs are either grade 1 or 2 and the majority was self limiting. Next, please. So in conclusion, this is the first clinical study evaluating PKR activation as a therapeutic option in both alpha and beta thal. And I must emphasize that this is actually the first drug trial they're aiming and treating of thalassemia. So the proof-of-concept was demonstrated and graded 90% in patients meeting primary endpoint, showing a clinically significant increase in hemoglobin. All 4 thal patients and 8 of the 9 thal patients -- beta thal patients met the primary endpoint and sustained hemoglobin response was observed over time for these patients as well. And we also saw that the markers of hemolysis and erythropoiesis were responding that is consistent with mitapivat's mechanism of action. Mitapivat in this population was well tolerated, and the safety profile was consistent with previous studies. Therefore, these data indicates that the activation of wild-type PKR using mitapivat improves hemoglobin and associated markers in hemolysis and erythropoiesis in both alpha thalassemics and beta thalassemics. Therefore, further investigations are warranted. Currently, pivotal trials are being developed. Thank you for your attention.

Thank you, Dr. Kuo. Thank you very much, and thank you for collaborating with us on this trial and with the investigators, and we want to thank the patients who also participated. Dr. Thein, I'll now turn it over to you for the sickle cell disease overview.

As activity as an approach to treating sickle cell disease. So next slide, please. Next. So just a few words on the background of sickle cell disease. It is a rare blood disorder. If anything, I would say, it is a common red blood disorder, as you can see in terms of numbers compared to PKD and thalassemias. And the 2 key features that you all know sickle cell disease by that recurrent acute clinical events, which includes things like acute stroke, acute chest crisis, but the most common is acute pain. And this occur on the background of chronic cumulate anemia. So these pathological features are the direct result of the sickle red blood cells, which are not only rigid and adhesive, but they're also highly fragile. So the sticky sickle red blood cells, together with the other blood components, they caused microvascular occlusion, leading the ischemia and depletion of the oxygen blood supply to the tissues, which is the root cause of all the acute clinical events. But the sickle cells are also highly fragile with a shortened life span of about 16 to 20 days compared to 120 days for a normal red blood cell, and this is the underlying cost for the chronic hemolytic anemia. So in this estimated there are about 100,000 individuals in sickle cell disease in the U.S. and about 35,000 in the EU. But of course, these numbers pale into insignificance when we compared to the much larger patient population in the rest of the world, predominantly in Africa and India and also the Middle East. So what causes these cells to sickle. And, no -- can we stick to this previous slide, please. What causes this cells to sickle? And it arises from a single based mutation in the -- with the chain of hemoglobin, which leads to the production of an abnormal hemoglobin report the sickle hemoglobin, hemoglobin S, where in which the glutamine in position 6 is substituted for by [ bailing ]. And under low oxygen conditions, hemoglobin S polymerises, causing damage to cell membrane and this bizarrely shaped cells, typically sickle shape and hence, the term sickle cell anemia. Next slide. Next slide, please. So the root cause of sickle cell disease is polymerization of the deoxy hemoglobin S. And they lead, as I mentioned earlier, to the 2 key features, hemolytic anemia and the recurrent vaso-occlusive crisis, also known as VOCs, that can be so painful that they are commonly referred to as sickle cell crisis. These 2 features trigger a downstream cascade of inflammatory events, coronary inflammation and vasculopathy that underlines the accumulative organ damage, which is shown here, such as stroke, renal failure, and so on. But the list is by no means complete. And they have contributed to the morbidity of sickle cell adults and with profound impact on the quality of life, causing acute chronic pain and recurrent hospitalization, loss of school and also work. Next slide, please. And the accumulative organ damage contribute to a shortened life expectancy, which is about 20 to 30 years compared to -- shortened by 20, 30 years compared to that of an adult without sickle cell disease. And here, we have here the features which have -- that are commonly seen in patients with sickle cell disease. As we mentioned earlier, all patients are chronically anemic, hemoglobin of less than 10 is the norm. But the usual one is about 8 to 9, if there is no intervention. And 10% to 25% of patients are regularly transfused. And of late, we've also recognized that more than 50% of adults have a silent cerebral infarction, which contributes a lot to the cognitive damage in these patients. Also without intervention, more than 25%, maybe about 30% of the patient who have had a stroke by the age of 45 years. So next slide. So before we go to the study itself, I just thought -- can we go the next slide, please, that I would recap the scientific rationale for enhancing pyruvate kinase activity in patients with sickle cell disease. So we know that the red cell longevity is highly dependent on ATP. And glycolysis is the only source of ATP production in the red blood cells. And on the left side of the slide here, you see a cartoon of the glycolytic pathway. So pyruvate kinase, as you know, is a key enzyme in the final step of glycolysis. And it generates 50% of the total red cell ATP. In patients which are -- who have PK deficiency, they have increased levels of 2,3-DPG, which is one of the upstream glycolytic intermediates, and they also have less intracellular ATP, which leads to the shortened red blood cell life span of the patients and hence the increased hemolysis. So in enhancing pyruvate kinase activity, we have 2 angles in which you can try to address the pathology of sickle cell disease because we not only increased ATP, but we also reduce 2,3-DPG, which is one of the key factors that affect the oxygen dissociation in sickle cell disease and the oxygen affinity. Because if you recall, only the oxygenated hemoglobin S can polymerize. So next slide. And so when I saw how the mitapivat could actually activates or enhances wild-type PKR, I thought that this was a very good molecule that we could use in sickle cell disease. And I can only share with you the study design of -- that is ongoing in the NIH. And this is to, phase I, to test the safety, tolerability, looking at the pharmacokinetics, pharmacodynamics of escalating multiple oral doses of mitapivat in subjects with stable sickle cell disease. Initially, so the eligible criteria is subjects of 18 years over with a confirmed diagnosis of sickle cell disease, hemoglobin SS, adequate organ function, baseline hemoglobin of more than 7 grams with no transfusion of EPO therapy in the prior 3 months. Concomitant hydroxy or a glutamine therapy were permitted on the study. So initially, the subjects received 3 escalating doses of mitapivat of 5 milligrams b.i.d, 20 milligrams b.i.d, 50 milligrams b.i.d. of 2 weeks duration each. And then we have drug taper over 12 days. And just before the COVID-19 pandemic lockdown, we managed to get our -- restarted protocol amended, introducing a fourth dose of 100-milligram b.i.d. And 2 days ago, the second of the 2 patients have now completed rnd of study. So we now have -- 9 patients have enrolled into this Phase I study. The primary endpoints were safety, of course, and how well the patients tolerate the agent as assessed by frequency and severity of adverse events. Changes in the laboratory parameters, which include reticulocyte counts, levels of hemoglobin, bilirubin and [ LDH ] hydrogenous. And the secondary endpoints are the PK and PD of mitapivat levels of the metabolite of the 2 TTBG, PKR, the ATP and also in this patient population, looking at the oxygen dissociation sickling of red blood cells. And we also like to look at the relationship between mitapivat, pharmacokinetics and safety. So next slide. So we've shown that impact so far, 8 of the available patients actually experience hemoglobin increase. And 5 of the 8 actually achieved a hemoglobin increase of more than 1 gram from baseline. The ranges from 1 to 2.7 and doses of 50 milligrams twice daily or lower. Because this is only -- we evaluated them up to those patients have taken 50 milligrams b.i.d. dose. And the concomitantly, with the increase in hemoglobin, we also saw a decrease in the hemolytic markers, such as bilirubin, [ LDH ] hydrogenous levels in reticulocyte. And at the same time, we saw decreases in 2,3-DPG, increases in ATP, which were consistent with the dose increase. And these were also paralleled by changes in the sickling fractions and oxygen dissociation curves. The AEs that were observed were generally consistent with the previously reported data with mitapivat treatment for PKD and all to be expected in the context of sickle cell disease. Remember, this is a different patient population. We did see an SAE, a vaso-occlusive crisis, which occurred during drug taper, which is possibly attributed to the mitapivat. And based on this, we have extended the drug taper from 9 to 12 days. And since then, we have not seen any VOC during drug taper. Next slide, please. And this is just to share 1 illustrative single case of patients, which is a male of 39 years old. And as you can see, the panel on the left of the 2 endpoints that we look at the laboratory parameters. The top one is hemoglobin. As you can see, in fact, we already observed an increase in hemoglobin at 5 milligrams b.i.d. and consistently increased and if the hemogram response was maintained during taper and we then went back to baseline at the end of this study. And this was also followed by a decrease in reticulocyte. Unfortunately, this patient did had a VOC when he was off the study drug for almost 40 days. It was just 1 day before end of study and the VOC was due to extraneous environmental factors. And on the right, you can see that these changes were accompanied by a dose-dependent increase in the ATP levels. And below that, also there were shifts supporting by changes in the shifts in the oxygen dissociation curve with the dose increase. So with this, I would like to thank you for your attention. And happy to answer any questions.

Thank you very much, Dr. Thein. And before we open this up for Q&A, and Kendra will be opening the queue shortly, what are the key takeaways, what are the important things that you've just seen and heard. Dr. Kuo walked you through the mitapivat data in thalassemia, and this underpins our move toward full development and registration trials. Dr. Thein, just walked you through some of the study design, the concept and provided some high-level data for the use of mitapivat in patients with sickle cell disease. At the same time, we also announced today an IDIFHA royalty that provides $255 million of [indiscernible] capital. And that additional capital can support our ongoing development related to that in these 2 diseases. So thank you again to our presenters. Thank you to your collaborator teams as well as to the patients who participated in these trials. If we don't have there -- they don't take the risk, then we're not able to move things forward and very brave. So thank you. Kendra?

Thank you. First question is going to be from Tyler Van Buren from Piper Jaffray.

Can you hear me?

Yes, we can. Go ahead.

Congratulations. Really impressive set of updates this morning at EHA and great to see the royalty financing as well. So the first question is, I know the data are early, but are there any notable differences between the mitapivat sickle cell data compared to Oxbryta and hemoglobin increases markers of erythropoiesis or sickling, especially in the context of the differentiated mechanism of action and improving red blood cell health by increasing ATP and decreasing 2,3-DPG versus finding hemoglobin. And the second question is, your PKR competitor presented single ascending dose sickle cell data this morning. It showed a transient increase of 0.5 gram per deciliter. So can you just comment on the clinical significance of that?

Yes, Tyler, let me -- this is Chris here. Let me answer the second question around format, and then I'll turn it over to Dr. Thein to talk -- give her if she see the form of data as well as how she sees mitapivat's potential in the context of voxelotor, which has been approved in patients with sickle cell. So with our view, obviously when a data is, as expected, it's a PKR activator. And we would expect to see some of the changes in terms of pharmacodynamics. The thing I would point out is it's single dose data, and we're going to -- in order to develop these drugs, we know that we're going to be giving them for long periods of time. And I think the overall piece is that if you're a patient with sickle cell disease that the fact that there are 2 companies now working on this target may give some hope that there's another drug that may be able to improve outcomes for those patients. Swee Lay, why don't I turn it over to you for some further color, whether it's for voxelotor, and how you think of that with mitapivat and then you think [indiscernible] form a single-dose data in patients with sickle cell.

Well, I can say that as far as voxelotor or oxbryta, we have not treated any of our patients on voxelotor. And I have only 1 experienced with single patient who could not be transfused. And -- but this is an exception. So it didn't make any difference in hemoglobin. But the 2 agents, actually, in terms of mechanism or action are quite different. Voxelotor occupies about 1/3 of the hemoglobin in an oxidated state, whereas mitapivat in enhancing PKR activity, actually have addresses the underlying sickling, which is the root cause of the thing from 2 angles. It reduces 2,3-DPG and it increases ATP at the same time. And in fact, I've already seen from our limited data that it can probably be used in combination with hydroxyurea quite comfortably, which is again, a different sort of mechanism. And like it or not hydroxyurea works more than 30 years. And so far, it's going to be a benchmark of this point to sickle cell disease -- in sickle cell therapeutics. Have I answered your question?

Next to Anupam Rama with JPMorgan. Kennen MacKay from -- Kennen, are you there?

So I had two questions really directed for both of our KOLs this morning. First, I wanted to understand really how you view mitapivat in terms of how it relates to some of the drugs that have recently been approved in both beta-thalassemia, maybe referring to luspatercept. And then also in sickle cell disease, we've seen 2 recent approvals there. As you sort of return to your practices and your academic colleagues after this virtual meeting, how are you going to be advising around the next steps for mitapivat in clinical development and enrolling patients into these trials. And then subsequent to that, I had certainly not missed the statement in the press release that mitapivat could be moved into a potentially registrational trial as soon as next year, thank you very much for that, Chris. Wanted to understand if there's potential for an accelerated approval pathway there and what endpoint do you see really as sort of the most important for potentially pursuing that. We have recently seen an accelerated approval pathway there. So would love, Chris, your thoughts as well as thoughts from the team there and our KOLs.

Okay. So why don't we let Kevin, you take Kennen's first question, and then we'll go to Swee Lay on that same theme in terms of given approved drugs in both the sickle cell and thalassemia space, how do you see, is there a need for another drug, how might you be thinking about it at this early juncture? And then I can take the -- what we're thinking in terms of the pivotal trial after that. So go ahead, Kevin.

So I know it's very early for you there. So very good question. I think we have to understand that luspatercept mainly acts on ineffective erythropoiesis or only a small portion of that pathway. And even then, the mechanism of action is unclear at this moment. There were 2 publications in Blood in September of 2019. That points out that luspatercept actually does not work on GDF11. So while we did see an improvement in hemoglobin because of the unclear mechanism of action, it is actually very difficult to deploy it in clinical environments because we know what our patients have. We know what the underlying issues are, but we don't know what the drug is targeting, and it's really hard to apply it. And also, we must not forget that -- and people really didn't understand this in the past is that hemolytic anemia hemolysis itself features a lot in thalassemia, especially in its genesis of the anemia as well as the complications arising from the anemia and also from the hemolysis. In fact, a lot of times when you're transfusing thalassemic patients, especially the nontransfusion-dependent thalassemia. When we start transfusions is because we want to suppress the complications that are resulting from the hemolysis, for example, like [ luspatercept ].

Kevin, before we go over to Swee Lay to give perspective on the sickle cell side, how do you think about the alpha-thalassemia data?

Well, I'm still glad that Agios has actually picked the boat step in having faith in the investigators when we suggested that we should attempt this in alpha thalassemia. I mean, let's put it this way, there was no treatment in the past. I mean we didn't even dare to think that we can actually treat alpha thal. The fact that we actually have a small molecule for it, I mean, it's just blows my mind that we are actually able to do this. So while -- yes, while we only have 4 patients so far as evaluable as of March 3, I believe that moving forward as we accumulate more data, that we'll continue to see the same trend.

Yes. Thanks. Swee Lay, over to you.

Yes. So you're quite right. I mean, [ formerly ], from no having only one kind of FDA-approved agent for more than 30 years, we saw nothing. And then in the last few years, it's like waiting for a bus and suddenly everyone comes along. So the uptick [ or down ] , as far as I know, is still not that high. There's a lot of interest in voxelotor, of course, because there are about 1/3 of patients who don't respond to hydroxyurea. And -- but even then, there is still a huge unmet need. And as I said earlier, I'm attracted by the enhancing pyruvate kinase because the 2 angles in which you can -- for this patient population, there is the ATP aspect, and there's also shifting the oxygen disassociation curve. And these 2 mechanisms complement that of hydroxyurea. So -- and then the other thing, the mechanisms of [ indiscernible ] are still not entirely clear. And voxelotor is still in the early stages. But whatever it is, I feel there is still a great unmet medical need. Remember, compared to thalassemia, we have about 100,000 patients in the U.S. and the huge population in Europe. And this is increasing. So from what I've seen in just a limited time, I'm really excited by the results. I have to admit.

And Dr. Thein, maybe you could just offer your perspective on what a regulatory pathway could look like. We have seen recent accelerated approval on single-arm and [ that about ] on maybe your response on what would be needed from what you know about the FDA's process, to gain approval? And what endpoints really you are most focused on as you think about a regulatory approval here.

Right. So with that in mind, also, we are now embarking on an extension study for where the patients can be treated for a much longer period. And the quality of life, of course, is very important. Because you observe an increase in hemoglobin, but if they don't feel better, and we don't have endpoints in measuring things which introduced like 6 minutes walk tests, which are more objective measures. And we have questionnaires that regarding the quality of life that asked me and the promise questionnaire. And then also, you look at the markers like the echo. So these are already maybe ready to be rolled out as soon as the pandemic leaves and we can start enrolling. And in the meantime, we are also in discussion, listen, NIH to go into Phase II clinical study. Put it this way, I've not had patients who have been on the study to ask, please, can I continue to say on the agent? That's why I'm very encouraged by the [ antigen ].

Okay. Thanks, Swee Lay. And then, Kennen, the last piece on accelerated approval would follow the path laid by Global Blood. And so that's one way to go about, which is hemoglobin as an increase for accelerated approvals into [indiscernible]. I would point out that's in the context of randomized trial. So it doesn't have the same flavor as a small and single-arm Phase II, for example, in acute myelogenous leukemia with an IDH1 mutation. Just to use that example from a company that want to try to go as fast as they can. Having said that, we're working with, whether it's Swee Lay, Kevin and others that think other patient populations that we could look at that could go that where we could approach that. And we do have some ideas. And as we develop that and get some feedback then we may be able to go into that. So we'd like to get it going. We'd like to -- we're going to get things going as quickly as possible, and we'd like to complete our trials in the most efficient way possible, and that depends on a number of factors, including what the regulators think. So next question, Ken?

All right. Let's try to go back to Anupam. And then after Anupam, we're going to go to John Newman. Anupam?

So first of all, congrats on the data. Chris, maybe a question just on the mean hemoglobin change and the thalassemia update. When we think about it from an apples-to-apples comparison here relative to ASH, because now you've got some alphas in there as well as a nonresponder. And then a second question on the competitive update here from Forma. Maybe for you, Chris, as well as the physicians on the line. Any thoughts on the palpitations that I think they observed in the study, I think they've seen that in healthy volunteers as well and the dosing that's required from that compound.

Okay. Thank you, Anupam. Good to hear your voice and I like your hat. So I think with regards to the mean hemoglobin responder, what we talked about in our ASH press release was the mean hemoglobin increase in responders. And so we anticipated we might get this question, and this is an analysis that wasn't in the presentation that -- well, look, goes after your question. And it's 1, 2, 3, 4 rows down. So this is the slide that Kevin Kuo just showed you, and we added these 2 columns so that you could see the responders change from baseline. So the closest comparison would be 1, 2, 3, 4 rows down beta-thalassemia responders as we talked about 7 out of 8. And now it's [indiscernible] 8 out of 9. And the mean hemoglobin change from baseline you see in responders is 10.6 grams. So that addresses that and connects the dots from how we presented the data at ASH versus to what we see now. The reason why we're presenting all patients that you saw in the primary analysis is that in an intent to treat, you need to consider everybody. But it is important to understand in patients who respond, who meet the definition of respond, what's their response. So in Forma, as far as the safety goes, yes, the clinical capitation signal has pulled through now into giving it with a single dose to at least 1 patient with sickle cell disease. I don't think there's much to make of it at this point other than what I've said previously as these drugs are going to be given for years. And so the important thing that we've published on and received a lot of questions about is around the safety profile of -- with a payback over the short, intermediate and long term. And I think that's a really key component that will differentiate these drugs as they come through. And because I think the chronic dosing, and our experts can speak to that and the safety and the tolerability is a really key part of that. As far as the dose goes, I think it's the same thing on upon. This is a single dose. There's a lot of data there. And I'd say our company position is that we think that they have a PKR activator. They've certainly learned from what we've done. We've been leading the science here as well as in the clinic. And I would come back, I think if you're -- I'm hoping that if you're a patient with sickle cell disease, the companies work in this direction. And you can see here about the data that Kevin and Swee Lay showed you and talked about that maybe there's some real hope here, which is why we're all working so hard. And Swee Lay or Kevin, I don't know if you -- how much you've seen that Forma data, any comments since I think Anupam asked if he could get a little color from you as well.

I just saw the abstract, and it's very difficult to make from this abstract, as you pointed out, Chris, only 1 sickle cell patients has been dosed, and is on a single dose. So they did show a picture of the locker, which is a [indiscernible], but it's only 1 dose as the shift in the [indiscernible]. But it's difficult to judge from that. I've not shared our data with you, but I can say that we do have very stringent measures, and we are considering sickling fractions of the observed are consistent with the metabolites that you see. The changes in the metabolites.

Kevin, any comments? I don't know if you've seen the data.

No. I saw also the abstract. And I echo Swee Lay's comments. 1 patient really doesn't make a [ hand cloth ]. But I think what it does is that the fact that Forma is also pursuing in the direction of our deals and in pyruvate kinase activation in sickle cell means that there's strong preclinical evidence to move this forward into the clinical arena.

There's a large population of older adults who cannot meet the criteria of bone marrow transplant. Gene therapy is a very good proof-of-concept, but we need an oral medication in addition to hydroxyurea, the others. I think plenty of room because there are so many patients. And not every drug fits everybody.

Exactly Swee Lay. I mean gene therapy and bone marrow transplant is so boutique right now, and the risk is so high, especially there's a 15-year FDA mandate is still monitoring, tells you that off-target editing is something to be concerned.

And plus that the anemia is in [indiscernible]. I mean I deal with adults. And now we see a growing population of older adults where many of them, we have to put them on regular blood transfusion simply because the bone marrow is not going to -- I think if 2 companies are working towards this direction, it shows that there's a lot of from it, and there's a good scientific basis behind this strategy.

Okay. Great. All right. Kendra?

I think Justin is on the line from Canaccord. Justin are you there?

Hi. Can you hear me?

Yes.

Yes. Go ahead.

Great. This is Justin Zelin on for John Newman. First, congrats on the exciting data. I had a question for Chris and Swee Lay on the sickle cell program. Given the different mechanism of the actions here, would you envision administering mitapivat in combination with recently approved Oxbryta? Or would there be any concerns of hyper-viscosity issues by boosting hemoglobin too high with both agents?

I think I'll go -- Swee Lay, what do you think about that?

Well, you're quite right because we do -- even in our next phase, we have a ceiling of hemoglobin. Because clearly, with sickle hemoglobin, we do not want the viscosity increase so much. It can cause problems. But the -- this has kind of been shown in studies with people when you assimilate the exogenous into [indiscernible]. But even then, this all anecdotal approach, whether the dual cost increased problems with VOC. But we are taking a caution of addressing that, that we do not recommend a ceiling of 12.5. And accompanying that, we do test other to address the mechanistic basis of the increased viscosity such as looking the [ indiscernible ] meter, the blood flow and so on. So we are aware of this.

Justin, it's Chris here. Certainly, as these drugs [indiscernible] the therapy [indiscernible] sequence, sequential approaches, combination of approaches come into play. Our -- we don't have any plans at this moment to do that. And our main focus is to drive forward and register the drug, develop pivotal trials as a single agent. But it's certainly something that's very interesting and that we might -- I wouldn't be surprised at all if it all comes into the development plan, but not right at this time.

All right. Thank you. Let's go to Peter Lawson from Barclays. Go ahead, Peter. Peter? All right. How about -- let's try to go to Mohit Bansal from Citi, and then we'll come back to Peter. Mohit, are you there? Mohit? All right. We're going to move on to -- sorry, Mohit, try that one more time?

Hello. Can you hear me now?

Yes. Yes, perfect.

Great. Congrats on the progress. Just wanted to get the thoughts from experts here. In sickle cell disease, we hear a lot about the compliance. And then from that point of view, some people often say that gene therapy or maybe injections, injectables are may be a better option here. In that context, how do you think an oral drug like mitapivat could fit in this paradigm? Would be curious to get your thoughts there. And then second question for the company. Now that you have probably multiple indications for mitapivat, and you would be launching with PKU -- sorry, PKD in the first launch, how would you think about the pricing? Do you think about the broader opportunity here? Or do you think you would use a second-generation program for sickle cell or beta thalassemia eventually?

Okay. Thank a lot, Mohit. So Swee Lay, perhaps you could make a couple of comments or help us a little bit about your thinking around compliance or just some of those other relative administration. And Jackie, I'll turn it over to you for the company question on how we're thinking about price. So go ahead, Swee Lay.

So Mohit, it's a very good question. I mean, certainly, the curative therapy is just the bone marrow transplant. We are actually -- are very, very getting better each time as we come to understand better about reducing the [indiscernible] treatment. But you can't take away from the fact that less than 15% of the patients have HOE-compatible siblings, okay? And people are working on alternative sources, and I have a colleague in our -- the institute here. And he's working on half matches. But this is too risky. But, at the end of the day, these are still limited for younger adults or [indiscernible] population where they have not so much organ damage. But gene therapy is just from our proof-of-concept. But I speak from a place where I used to work before in the U.K. and bone marrow transplant, we have a very good infrastructure. Bone marrow transplant, we care for [indiscernible], so many other medical disorders. And yet, when I left 5 years ago, not even in an adult sickle cell patient has been given bone marrow transplant except for other reasons, simply because of the costs involved. Then right now, an immediate problem is that we have a growing population of adults who do not qualify for bone marrow transplant or gene therapy. These are kind of pie in the sky for these patients. We have an immediate problem that we need to be able to face. And I think if you can have an agent which they can take, then -- and ideally, oral, because who wants to be poked every day to have an injection? And even with EPO, we have problems even though it's subcutaneous. And I think in terms of compliance, it actually is a testimony to how well the drug does for you. If I feel there's something -- I feel good on the agent, then I would be more inclined to be compliant, right?

Got it. Great. Thanks, Swee Lay. Jackie, do you want to take the question around multiple indications and what we're thinking around from a price perspective? Or...

Sure. I'm going to start and then ask Darrin, [indiscernible] expert on the call. So I would just start by saying when you come to market with the first indication being the more rare indication of the multiple indication, you start from a position of having maximum flexibility in terms of how you price that first indication and then deal with the others as they come along. The second thing I would say and even elaborate is we make our pricing decisions based on the totality of the data that we generate for our drugs and our assessment of what the benefit to cost profile of the drug is for our patients. Darrin, do you want to add anything?

Sure, Jackie. Thanks. So I think to directly answer the question, we have to certainly take into account the full life cycle options for the -- or life cycle development plan for the program. But we have to price for the first indication, right? So the first indication with PKD. And what we've seen from our research and our discussions with payers is that a rare disease pricing in PKD can -- is feasible also or can carry over into thalassemia. And then we'll see what data looks like for sickle cell overtime. So right now, we'll price for PKD. We believe that will work for thalassemia. And to Jackie's point, the price has to reflect -- at least our philosophy is that the pricing will reflect the total clinical value. Then also take into consideration the health care system cost impact, right, potential offsets associated with the treatment. So hopefully, that answers your question.

Can I also talk about compliance to Mohit's question? Compliance, of course, is a well-known thing among physicians. I mean we all know that -- even studies have shown that even for cancers, when you take the kind of continuous therapy, when they actually come to compliance, huge numbers are not compliance. So this is a perpetual problem. I think you just have to engage the patient better.

So Peter, let's try this 1 more time. If not, I'm going to read your question that you submitted through the Q&A function.

Can you hear me?

Yes.

Perfect. I apologize if this has been asked before, I probably spent more time than I care to admit, trying to get technology to work. But I guess the delta that we've seen in the response rates and the hemoglobin levels, would you expect that for the alpha and beta thal patients?

Can you clarify the question again?

Yes. I think, Kevin, what he's asking, when you and I and our team started talking about doing this trial, was -- what were your expectations in terms of what we would see from an efficacy standpoint? And are you surprised by a 92% hemoglobin response rate has sustained overtime in both alpha and betas?

Not at all. I mean I only bet on the betting plan and winning horse. What I'm trying to say is...

He's one of the earliest proponents of doing this trial. So...

Yes, I am. I mean we clearly see it in clinic. I mean these patients are so hemolytic, you measure the LDH, you measure the indirect bilirubin, you measure the [indiscernible] cell. You do a bone marrow biopsy on them. All you see is hemolysis. And then same as a clinical consequence, all you see are the classical complications of hemolysis. There is really no reason why it shouldn't work. Is it sort of the either -- I would put it either way around. There's no reason why it should not work.

Okay. And then VOC, you suffer the 1 sickle cell patient, is that more than you would expect versus natural [Audio Gap]

Someone muted me. I lost you. I lost you.

I didn't.

Go ahead. We can hear you right.

No. I couldn't hear the last bit of Peter's question because...

Yes. He was asking if the VOC that you saw upon drug taper was surprising or any comments you can share regarding that particular event.

Right. We kind of anticipated this, so that's why we're building a taper as it was seen in, I think, 2 cases in the PKD patients. But what -- this patient did have very good [indiscernible] response. And by adjusting, making -- it does softer landing, we not -- have not seen any other VOCs during this taper phase in the subsequent patients. So perhaps a big drop -- there was a bigger drop from the 50 to the 20, and we're building an extra step for that. It's something which we learned, but it was a very good clean view, we see that resolved very quickly.

Let's try to get through 2 more questions. Alethia, we're ready for you.

Can you hear me now?

Yes.

Yes. Go ahead.

All right. So just 2 questions. One, again, do you think the drug might have activity on VOCs? Over the long run, if you think about what the baseline is doing sort of that? And then the second question is just I guess, for Dr. Swee Lay, like what are your outstanding cost of the [indiscernible] program, like things that you kind of want to know, I mean, especially around like the profile with taper with the VOC, which is something that obviously Oxbryta had to deal with a great deal to derisk?

Okay. So you're asking me about the VOC kind of continuing during -- the take on the sustained long-term treatment of mitapivat. Is that right?

Yes. The first question was on an efficacy basis. Do you think that the drug can have activity on like reducing VOCs? That's the first one.

Yes. Well, given the scientific rationale, it should reduce the VOC. But I mean, to be honest, VOC is such a complicated event and the triggers, we still don't even really know what they are. There are some triggers that we know. But then a lot of other triggers are like stress, changes in environmental factors. These contribute to VOC. We see the -- in patients on hydroxyurea, it reduces the VOC frequency, and it also reduces the length of the VOC. But it does not take it away altogether. And this is what I always tell the patients because when you have extraneous factors, you can trigger the VOC. So I would say that it will not completely remove the VOC, this is something I have to make clear to the patients before I start them on the treatment, because we know that a change in personal stress conditions can cause VOC. So what was your second question?

Just any outstanding questions that you have around kind of the program and the drug itself based on what you've seen so far?

So I -- it's very limited data from the small -- some patients that we have so far enrolled. One, as we mentioned earlier, was possibly related to the taper, and we now have introduced an extra step to make the landing a bit softer. And then the second, VOC, we do not attribute it to the drug at all because the patients were off the drug 40 days already. And it clearly has triggers that could actually bring on a VOC. So just got off a flight, where you dehydrated, and then you will see the hotel environment, the room was cold, and he was all stressed out because he was going to give a major presentation and things like that. I cannot go into greater details about the patient. But we will encounter this, but we have to take it in the context of the disease, we have to take it in the context also [indiscernible] communication and whether the patient has been regular with the medication.

So Swee Lay, just having build a little bit on Alethia's question. What do you think -- what do you want to know in this next -- as you continue to accrue patients, whether it's in your data set? And you alluded to wanting to do additional development with the drug. Where do some of the -- with 1 key question that you want to see. Is it longer-term efficacy data? Do you want to explore relationships between PD and outcomes, things like that?

Yes. I think in the longer term, it's important to see how they impact the quality of life, which is the most important thing. They subjectively feel an increased amount of energy, even though this may be reflected by an increase in hemoglobin, even in those who -- hemoglobin increase is not that high. So I don't know where maybe it's a super-centurial effect, I don't know. But we will try to measure it objectively by 60 [indiscernible] test and [ the echo ] measures on the extended treatment. So in terms of VOC, obviously, we also try to be more objective about it. We'll take the background, how many they've had before the [indiscernible] and whether they also see variation in contacts when they're taking the agent. And I see the -- if mitapivat has been approved, I see this as a longer-term treatment, and I see this in -- that it can complement the treatment of our drugs here, which we see in patients as they get older, they become more sensitive to hydroxyurea. We have to reduce the dose. They become more sensitive in terms of -- they drop -- the white cell count drops very quickly and the platelet count, too. So we have to reduce the dose by hydroxyurea. And I see this agent is complementing that hydroxyurea usage. The mechanisms of action are quite different. So this, from my point of view, is also very exciting addition to the medication that we can offer our patients of sickle cell disease.

Yes. So our last question is going to come from Chris Shibutani from Cowen. For the rest of you, I know we had a few questions we couldn't get to. Holly and I will follow-up and make sure that we get time with the team with each of you later today. Chris, let's try it one more time.

Yes. Can you hear me now?

Yes. Go ahead.

Okay. Terrific. Two questions. One relating to the sense on the alpha versus beta-thalassemia patients. Can you further elaborate on why you would expect any potential difference in the kind of results? And when you do the further clinical development, do you think you'd expect to have to segregate those populations? And then on sickle cell, for the sickle cell -- for the KOLs, is there any biomarker data indicating that the benefits of ATP improvement independent of oxygen binding would be a differentiated dimension of the results that you're kind of seeing, certainly compared to other treatments for sickle cell, including Oxbryta?

So Kevin, why don't you talk about the -- what would you expect mechanistically and outcome-wise for alpha versus beta? And what are your initial thoughts if we were to run a randomized trial on how we might handle those 2 populations, and then we'll close out with -- for the Q&A with Swee Lay, a couple of comments around biomarkers and ATP and oxygen binding. Go ahead, Kevin.

So the background to the story that you're mentioning is that alpha thalassemia, the hemoglobin H patients, these are non-transfusion-dependent on alpha thalassemia, can we divide it into 2 subpopulations. And one is the dilutional and the non-dilutional. The reason I'm mentioning this is because they do make a difference phenotypically, the non-dilutionals are more hemolytic than the dilutionals. So the patients that we have enrolled so far are the dilutionals. So -- and I expect that as we enroll more patients, of course, there will be a mix of dilutional and non-dilutional or the non -- you'll see, and I expect that you will see that the non-dilutionals will respond. That's spectacularly is not -- even more spectacular than the [indiscernible], simply because when you produce a junk, so the non-dilutional is introduced with a junk, and examples we include [indiscernible], [indiscernible], [indiscernible] and so forth. And these -- when these junk are produced, they -- it places a huge oxidative stress on the red cells, one the developing red cells. And so that's why you will see -- I would expect a greater efficacy in the non-dilutional hemoglobin H in the [indiscernible].

Okay. So more to come on, why don't we -- because of time, Chris, more to come on how these impost betas can create some interesting nuances in terms of how we think about the trials because it's definitely -- nothing is approved for alpha. And so it's an interesting facet for us, but didn't -- for the sake of time, Swee Lay, can you comment a little bit on the second part of the question?

Yes. Okay. Very good. You're quite right. I mean, I think, in fact, the sustained response actually come from the improvement in ATP. And as you know, is related to the reduction in the reactive oxidation species. So in this extension study, we're going to investigate further on the mechanistic basis of these. One immediate direct biomarker, which can be actually done fairly routinely in other LEDs, is that evolving the processes [indiscernible], and we can use a flow cytometer to actually look at the levels or -- this continue to the VOC. So this is one. But then the usual biomarkers that we do hemolysis hemoglobin increase, which is easily measured in any routine lab, I can only think of the -- look at the positive and the [indiscernible] for the cytometry. With regard to the of the oxygen disassociation curve, I mean, this is a very, very [ finical ] kind of measure. Only specialized labs can do the assays reliably. And with India and Asia unfortunate to collaborate with the legend in sickle kinetics. So we measure the sickling fraction, too. And this is quite clear that they do have reduced it. But from the ATP side, I think the best biomarker is looking at the [indiscernible], which can be done in a flow cytometry.

Okay. Thank you. Thank you very much, Swee Lay. Thank you, Kevin. Over to you, Kendra.

Let's have Jackie close it out, and thank you, everyone, for staying on the line. We really appreciate it. Go ahead, Jackie.

Yes. I just want to reiterate and thank everybody. [indiscernible] this morning. I want to just thank, obviously, my team, and Dr. Kevin Kuo and his feedback on today was just amazing and terrific, and we've been proud to work with them as investigators working with our -- they definitely are making our programs efforts as the other one would be. So thank you to both of you. Thanks, everybody, for listening. We're very excited about going with mitapivat in these -- the [indiscernible]. I'll remind everyone that we've gone back to the key testing -- 3 trials that we will have data on sometime between the end of this year or first half of 2021. So -- and that's the way or [indiscernible]. And we think that's the main [indiscernible] to treat a waste range of hemolytic anemias. So thank you again. And with that, I think we're going to close out. Thanks for participating.

Thank you, everyone. Bye-bye.

Thank you, everyone.