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

Good morning, everyone. Thank you for joining us this morning for our Agios ASH 2020 virtual investor event. I'm Jackie Fouse, the CEO and we have several members of the team with us today, who you will hear from and see in just a moment. Let me start by flashing our forward-looking statements across the screen. There you have those. Today, here's the agenda that we have. I have some quick opening remarks to get us started. I'll then turn it over to Chris Bowden, our Chief Medical Officer, who will talk about mitapivat, our PKR activator; AG-348 and its mechanism of action; and give you some clinical updates, including about our thalassemia pivotal trial plan. And he'll also cover the top line ACTIVATE data that we released last week. And then we'll spend the bulk of the discussion this morning with Dr. Swee Lay Thein, who will go through her slides on sickle cell disease, and we'll move into a Q&A. So thank you again for joining us. Patients have been at the core of everything that we do at Agios since our founding back in 2008. We've brought our science to the treatment of cancer patients, and we continue to be driven by a sense of urgency to help patients and now moving into the noncancer space with the first wave of potential indications in severe hemolytic anemias, This patient has pyruvate kinase deficiency, Tamara, you may have seen earlier on our PKR activation webinar a week or so ago. And we bring the same sense of urgency to helping these patients with serious hemolytic anemias as we do to cancer patients. And you'll hear from Dr. Thein and Chris, also [ narrations ] of the other diseases, thalassemia and sickle cell disease. So hematology has been the core of what we do for -- since our founding at Agios. As I said, we brought the science of cellular metabolism to the treatment of cancer indications for acute myeloid leukemia with our IDH inhibitors, and we continue to expand the number of patients that we have there. We have also been studying PKR activation for over 6 years. In fact, from a research standpoint, it's been much longer than that. We've been in humans for quite a few years. And that same science of cellular metabolism is something that we're leveraging our deep expertise in to bring forward to treat patients with nonmalignant hematology indications and the relationships and the infrastructure that we've built up over the course of our lifetime in the hematology space will serve us well as we move from cancer into nonmalignant hematology indications. So we -- I'm going to quickly just cover off on IDH mutations in cancer and our accomplishments to date, then we'll spend the time today in the nonmalignant hematology space. The first, there was an article from Nature in 2009 on the role of IDH mutations in cancer. We have the longest history of exploring and elucidating the biology of those and continue time lines here for how we initiated clinical trials. Brought the products to market fairly quickly by industry standards in terms of the first approval for the IDH2 mutation, a product for relapsed/refractory AML in IDHIFA in 2017 and the IDH1 [ approved ] in 2018, just over 2 years ago, where we have a label for relapsed/refractory AML and frontline AML. And we continue to do everything we can to optimize the benefit for patients from those IDH inhibitors. So you will see several or have seen several presentations at this year's ASH. We have updates related to our IDH programs, and those are shown on the slide here. I won't spend a lot of time on those. But our drugs are safe, convenient, oral, very effective competing in the marketplace and coexisting along other drugs where multiple product approvals over the last few years are allowing for a combination in AML. And we've got ongoing label expansion trials there with lots of opportunities still for growth. Today, again, we'll focus on PKR activation. We've been doing this for a while. There's some data on this slide that shows you some of the accomplishments in terms of where we are with our PKR activation drugs, [ we gauged ] pretty significantly to create a number of firsts across the community by building the first pyruvate kinase deficiency registry, as you know, or hopefully, there -- now there's product no approved for pyruvate kinase deficiency, so we can be the first drug approved for that severe hemolytic anemia indication. We helped establish the first international PK deficiency advocacy advisory council on behalf of these patients. And we're supporting -- have supported the first hemolytic anemia advocacy coalition building meeting, which crosses multiple indications in hemolytic anemia. So we're nicely embedded in with the community and I'm very [ happy ], and certainly, investigators who -- and the physicians who treat them. So this year, you see an expanding number of indications from us related to PK activation, both for pyruvate kinase deficiency as well as other indications. You see thalassemia, our first podium presentation, we were very happy about, proud about this year. So expanding portfolio in the nonmalignant hematology space outside of cancer, and you'll hear from Dr. Thein later in the presentation today about sickle cell disease. You can see some of the other presentations that we've had at this year's ASH on this slide. With my opening remarks, you'll hear from Chris, the top line data from the ACTIVATE trial that met its primary end point, that's the nontransfusion-dependent pyruvate kinase deficiency trial that we announced the top line positive result from last week. First, our disease-modifying therapy for patients with PK deficiency in 2021 in both the U.S. and EU. We eagerly await the readout of the transfusion-dependent ACTIVATE-T trial for PKD coming up in the first quarter of next year. We have developed a broad, a clinical pivotal plan for thalassemia. Chris will talk to you about that and reveal those for the first time today. And you'll see and you saw over the course of yesterday, our updated data in sickle cell disease, and Dr. Thein will walk us through that, and I'm sure we'll have a lot of Q&A on that. And then we plan to move into pivotal development for that indication in 2021 as well. And as we do all of this outside of the [indiscernible] also continue to lead the science behind IDH mutations in AML, and we saw some of that at ASH this year as well. So with that, I'm very happy to turn the call over to Chris Bowden, our Chief Medical Officer. Thanks, Chris.

Thank you, Jackie. Great to be here. Good morning, good afternoon, and good evening wherever you are according to your geographic location. Thanks for being here today. I'm going to take you through some slides and provide some information regarding our PKR activation program. And then, as Jackie said, I'll be followed by Dr. Thein. And it's that time of the year at the ASH meeting, and it's great to be here. It's been great to hear all the new data. One of the things that we've been spending years and years and years on is studying the red cell. And it's a fascinating cell that, on the one hand, doesn't have a nucleus and the mature red cell doesn't have any mitochondria. But at the same time, it has evolved to play an extremely important role. And it's got to transport oxygen to all the tissues throughout the body. Interestingly, as a function of becoming the Olympic athlete and meeting its goal of being the main cell to do that, the only cell to do that in the body, is that it generates -- it stripped out anything that it doesn't need in order to accomplish its goal. And therefore, it generates energy through the process of glycolysis. And that's not the most effective way to generate energy in the body through a cellular metabolism. And that creates some problems, and that's why PKR activation is such an attractive hypothesis. The other really important aspect that you all know, who follow this area, is that the red cell is extremely flexible, and it has to bend and squeeze its way down to the capillary level in order to do what it does, which is to release oxygen. So when we start to think about what goes wrong, the areas that we've been studying, as we've been leading in the forefront of PKR activation, some of the diseases that have come up are the chronic hemolytic anemias: pyruvate kinase deficiency, sickle cell disease, thalassemia. And in these patients, they either have an absolute deficiency of ATP or relative deficiency of ATP, regardless of what that component of their ATP deficiency is, is that what you see is increased reactive oxygen species in patients with sickle cell because of their molecular defect, there's a propensity for sickling with the clinical consequences that you're familiar with. And so this really sets up some areas from a mechanistic and biological perspective that offers itself to activating pyruvate kinase. And what we're ultimately looking to do is to improve red cell health. If you look at the panel in front of you, on your left, there's a life span for the healthy red cell, 120 days. And you can see in all 3 of these diseases where we're developing mitapivat and where we're pursuing the science in pyruvate kinase R activation, you can see that the life span -- the average life span of those cells is dramatically reduced to 20 to 30 days in pyruvate kinase deficiency and thalassemia, to 10 to 20 days in the setting of sickle cell disease. And one of the things that I also want to point out, and many of you who follow us and who have been following this field now understand, that when we're looking at pyruvate kinase deficiency and thinking about the biology of that disease, at the bottom of the slide, you can see that pyruvate kinase is mutated and thereby, mitapivat binds and activates pyruvate kinase and pushes it to perform better. The same concept of improving the dynamics of pyruvate kinase supplies in thalassemia and sickle cell, but in this case, we're activating the wild-type form of pyruvate kinase, which is, in fact, functional in contrast to pyruvate kinase deficiency. So it's been a fascinating journey and will continue to be so based on the red cell, the diseases that are associated with chronic hemolytic anemia and the potential and the promise of activating pyruvate kinase are. A little more on the biochemistry here. What you see is the glycolytic pathway on your left and you see glucose as the starting substrate, but then at the end of this multistep process, gets converted to pyruvate. And one of the key enzymes in terms of driving the pathway forward and maintaining red blood cell energy levels and maintaining antioxidants is pyruvate kinase, which converts PEP to pyruvate. On the far left, you see the 2 key -- one of the key metabolites, which is 2,3-DPG. And by increasing flux through the glycolytic pathway, you can drive down 2,3-DPG. And that's a great biomarker to understand whether you're actually -- and it's measurable in red cells. We did a lot of work to -- in terms of demonstrating that. It's also been known for decades that 2,3-DPG is elevated in a disease like sickle cell, for example, which makes it another interesting pharmacodynamic end point in that disease. So that in driving down 2,3-DPG in a disease like sickle cell has the potential to improve patient outcomes by reducing sickling. At the same time, when you convert PEP to pyruvate, you generate ATP. And that can contribute to the energy resources in the cell, limit reactive oxygen species damage and can allow those cells to live longer. And the key component of that then is to translate that into longer, healthier red cells, improving anemia, and by improving anemia, you improve the symptoms that are associated across these diseases that are chronic hemolytic anemias. Now mitapivat has the potential to be the first agent to transform a number of these hemolytic anemias by increasing red cell energy, health and longevity. And we've demonstrated in preclinical models that we reduce reactive oxygen species, which can decrease the amount of membrane damage, which can also decrease the process of hemolysis. In a number of different settings, we've demonstrated that mitapivat increases ATP production too, and that can help the red blood cell energy needs. And then starting with our first trial in healthy volunteers back in 2014, we've consistently demonstrated that mitapivat decreases 2,3-DPG, which is particularly important, as I stated earlier, in sickle cell disease because it increases oxygen and affinity for hemoglobin, reduces polymerization and may reduce sickling in sickle cell disease. So a lot of mechanisms by which activating that single pathway can improve outcomes for individuals with chronic hemolytic anemias. And this is a demonstration of how we've been invested in this. And if you start at the top, you can see our trials in adults with pyruvate kinase deficiency. The ACTIVATE study, just recently, we issued a top line press release announcing that, that study had met its primary end point. I'll touch on that in subsequent slides. And we eagerly await the data from our ACTIVATE-T study, which is in adults of pyruvate kinase deficiency who are regularly transfused. We have the thalassemia program ongoing with goals to open studies next year, and I'll get into some of the details of those study designs subsequently. And of course, in sickle cell disease, we have a study ongoing with the National Institutes of Health. Dr. Thein is here today to go through those results and discuss those with you. And we are moving forward to get pivotal trials up and running in 2021. So very busy time for mitapivat but there's more. We're developing mitapivat for pediatric indications. And we're moving towards finalizing our first pediatric plan, which will be in children with pyruvate kinase deficiency. We have a follow-on compound, AG-946, where we initiated our Phase I healthy volunteer study in the summer of this year and look forward to bringing you data on that molecule in the future. And then we have a number of other PKR activators in development as we think about activation of PKR. And as you may have heard, Bruce Car, our Chief Scientific Officer, talk about some very high-level thoughts around the activation of PKM2. So this is an area where we have lots of experience and continue to be highly invested in. So with that now, let me turn to our thalassemia program, where I want to present for you some of the high level design features of the Phase III studies that have been generated by virtue of the proof-of-concept data that we published at EHA this year. But first, a little bit of overview of thalassemia. This is an inherited blood disorder that reduces the production of functional hemoglobin. Ineffective erythropoiesis is a hallmark of this disease. You have a shortage of red blood cells. This is common across all of these chronic hemolytic anemias. And there's an estimated 18,000 to 25,000 patients in the United States, in the EU five. There are 2 main types, alpha thalassemia and beta thalassemia. Interestingly, there is -- there are no drugs approved for alpha thalassemia, which overall, may have some milder presentations of the disease, but in working with investigators and then designing our proof-of-concept study, they emphasized the unmet need in a significant number of these patients. And there, you see in the middle of the slide with the green boxes and the arrows, the number of molecular features and pathological outcomes, if you will, for -- that occurred at the red cell level in patients with thalassemia. And ultimately, what you're looking at, and this is shown -- described at the bottom of the slide, as the globin precipitates in thalassemia cause oxidative damage, leading to this hemolytic anemia and the hallmark of ineffective erythropoiesis. As per my previous slides, activation of wild-type PKR has some significant promise here. We first demonstrated that with preclinical studies and then moved on to a Phase II single-arm open-label study that we published at EHA in 2020 of this year. And that study demonstrated that greater than 90% of patients met the primary end point of an increase in hemoglobin. All 4 of the alpha thalassemia patients and 8 of 9 beta thalassemia patients were responders. Those responses were sustained over time, And we saw improvements in markers of hemolysis and erythropoiesis. Overall, mitapivat was well tolerated and that safety profile was consistent with what we had observed in our pyruvate kinase deficiency clinical program, which has been going on for several years. I want to update you and let you know that 17 of the 20 patients who were enrolled in this study have moved into the extension portion. That extension portion goes on for several years. And data on all 20 patients will be submitted for presentation to EHA at 2021. And as we stated at EHA that this provided proof-of-concept and gave us confidence to move to initiation of pivotal studies next year. So our team is working very hard as they put these 2 trials together. And then so our 2 global Phase III randomized trials of mitapivat and thalassemia, and you'll notice that the name for the trials are ENERGIZE and ENERGIZE-T, the T standing for patients who are thalassemia patients who are regularly transfused. Starting with the top trial, ENERGIZE, you can see that we have 171 patients for the sample size with a 2:1 randomization of the active agent, mitapivat, at 100 milligrams BID versus placebo. And patients are treated for a 24-week core period. It's a primary end point as a percentage of patients with a mean hemoglobin increase of 1 gram per deciliter from baseline. The key exclusion criteria are shown on the right, and I'm not going to read through them, other than to point out this trial will include beta and alpha thalassemia patients. And also that you can see the definition for nontransfusion-dependents is less than or equal to 5 units of red cells during the 24-week period preceding randomization. The second trial in patients who are regularly transfused also has a 2:1 randomization, a slightly larger sample size of 240 patients. And mitapivat is -- where patients are randomized to mitapivat versus placebo. In here, as per any transfusion reduction trial, the primary end point is a 50% reduction in the transfusion burden over any 12-week growing period across that 48-week core period. This trial has an open-label extension period, which is up to 5 years, similar to the ENERGIZE trial. It will include both alpha and beta-thalassemia patients. And you can see the transfusion requirements are described as 6 to 20 units transfused with a minimum -- a transfusion-free period of less than or equal to 6 weeks. So these 2 trials, we're actively at work putting together. And we really look forward to being able to share more details with you around the statistical assumptions when we get closer to when we anticipate they will launch, time lines, all of the things that you're very interested in, but it's very exciting to share the first communication around these trials with you today and look forward to your questions. Now let me change gears and provide a little bit of information around mitapivat in individual adults with pyruvate kinase deficiency. And as you saw in my pipeline slide, the clinical development portfolio for mitapivat, pyruvate kinase deficiency was the first disease that we approached and developed mitapivat in. And we shared top line results of the ACTIVATE study that I will refresh in a few slides. But let's just go back a little bit and think about where the ACTIVATE trials came from, and they came from our first study, the first study that studied the small molecule, the first study that looked at a PKR activator in the clinic, and this is in the DRIVE PK study. And what you're looking at are results that come from the New England Journal of Medicine publication as well as some follow-on -- follow-up data. The top left panel shows the improvement in hemoglobin for patients who responded. And one important aspect of mitapivat has been the fact that those responding patients have been followed out now for more than 3 years. And what you see in the panel on the far left is the stable hemoglobin response that's associated with mitapivat treatment in patients who respond. Markers of hemolysis are very important as our markers have ineffective erythropoiesis. And in the panel on the right shows the decrease in reticulocytes. So hemoglobin is going up because we're activating pyruvate kinase, we're increasing ATP, the cells live longer, they're healthier, and therefore, the marrow doesn't have to work as hard and pump out as many red cells to meet -- to try to meet the demand from the body in responding patients. On the right, you see the plot, which shows the change in hemoglobin, the 42 patients -- sorry, for all the patients who were enrolled in DRIVE PK. And one of the things that we learned from the DRIVE PK study was the importance of having at least one missense mutation in order to have the opportunity to respond to mitapivat. We also saw, and this was important in terms of designing ACTIVATE, that the magnitude of the hemoglobin response in hemoglobin responders was 2 to 3 to 4, some patients achieving hemoglobin increases of up to 5 grams. So this -- these were important findings to then set the stage for us to design the ACTIVATE studies. Those changes in hemoglobin and hemolysis were sustained. And once again, safety, an important component of a drug that's going to be given for years -- months, years and for a very long period of time is an important aspect and a continuously evolving aspect. And we're very fortunate to have an active drug for those patients on DRIVE PK and to be able to continue to treat those patients for years and continue to study the safety profile. The ACTIVATE study design is shown here will also afford us the same opportunity because the study is positive. Here's the design where adults with pyruvate kinase deficiency who were not regularly transfused were randomized 1:1 to active drug versus control. They underwent a dose escalation component and the protocol matched to placebo. And then once that dose had been optimized, they stayed on that for an approximately 3-month period and then patients went into the extension period. The majority of patients on the trial, both on the experiment and on the placebo arm, went into the extension phase. And so as I emphasized with DRIVE PK, we're going to be able to study durability of hemoglobin response, safety, what happens with iron, many things over the course of years to come now. The primary end point you see at the bottom, the proportion of patients who achieved at least a 1.5 gram per deciliter increase in hemoglobin that was sustained over multiple visits. The trial is positive, as I said, and here are some of the top line data that we shared in our press release. 40% of patients randomized to mitapivat achieved a hemoglobin response defined as a sustained greater than or equal to 1.5 gram per deciliter increase in hemoglobin from baseline in contrast to the placebo arm where there were 0 patients who raised their hemoglobin over 1.5 grams for any sustained period of time. Treatment with mitapivat demonstrated statistically significant improvements across a number of prespecified key secondary end points, including: the average change from baseline in hemoglobin; markers of hemolysis; markers of hematopoietic activity, that is reticulocyte percentage; the safety profile was generally consistent with what we previously reported; there were no adverse events leading to discontinuation in either arm of the study; and full analysis of the ACTIVATE data -- we're very excited to say, including the patient-reported outcomes, will be submitted to EHA in June of 2021. And of course, we're looking forward to the results from ACTIVATE-T. And we're also planning for U.S. and EU regulatory filings in 2021, with the potential commercial launch in those regions in 2022. So very exciting times and I want to congratulate our team. I want to thank the patients and investigators who participated in these programs. It's really been a great journey so far. Okay. So with that, hopefully, you've gotten a sense of the number of exciting activities that have started and are ongoing and are starting to deliver since we started working on this target, as Jackie said, many years ago. Let me now turn the podium over to Dr. Swee Lay Thein. Dr. Thein is Head of the Sickle Cell Branch at NIH. We've had a great partnership and collaboration with the NIH. We're very grateful for them establishing a [ creative ] for us and taking mitapivat into the clinic to study outcomes in patients with sickle cell disease. And Dr. Thein is here today, and she's going to walk you through the presentation that was given last night, and then we can get to the question and answers. So thank you again, Swee Lay, and I'll turn it over to you.

Good morning or good afternoon, good evening wherever you are. And thank you, Chris. I'm delighted to update you on the interim results of this study of mitapivat in sickle cell disease. So as Chris mentioned, this was actually presented by my clinical fellow yesterday at the ASH meeting. So let me just take you through. So as a kind of -- to reiterate what Chris has already mentioned earlier and also to provide -- my angle has changed, he says, I'm sorry. Let me go back to the -- I'm sorry about this. I'm going to try to -- well, thinking about it. Anyway, so to reiterate what Chris mentioned earlier and also to provide the scientific rationale for why we think mitapivat would be a good treatment option for patients with sickle cell disease. Well, just to remind you, sickle cell disease is caused by a single-based mutation in a single gene, the [ beta globulin ] of hemoglobin. And this results in the production of hemoglobin S, which is a normal and actually polymerizes the form fibers when deoxygenated. And this leads to the production of bizarrely-shaped cells, which are typically sickle-shaped, hence the name, and the cells themselves would trigger because they have a very [ steep ] trigger base of occlusion. And at the same time, because of the reduced life span, causes a chronic hemolytic anemia. This recurring -- these are the 2 key features, recurring acute microvascular occlusion and chronic anemia, 2 key features of sickle cell disease. And the pain resulting from this vaso-occlusion is so severe that it's often referred to as vaso-occlusive crisis. The chronic hypoxia caused by vaso-occlusion and the hemolytic anemia, there underlies the systemic complications that we associate with sickle cell disease, impacting the quality of life and also shortens the life span of patients with sickle cell disease by as much as 20 to 30 years compared to patients without. So one of the key factors that -- as you know that the hemoglobin S can only polymerize when deoxygenated. And one of the key factors that regulates the oxygenation of hemoglobin is 2,3-DPG. And 2,3-DPG levels are elevated in patients with sickle cell disease. This reduces the affinity of hemoglobin for oxygen. So it maintains the hemoglobin S in a polymerized or [indiscernible] state. And 2,3-DPG, you've heard earlier, is actually a key metabolite in the glycolytic pathway. And PKR is a key enzyme in the final part of this glycolytic cycle. So when we enhance the pyruvate kinase activity, this will drive glycolytic cycle forward, reducing the upstream intermediates, including 2,3-DPG. So enhancing 2,3-DPG -- PKR by using mitapivat or also called AG-348, will actually reduce 2,3-DPG and this will destabilize the hemoglobin S fiber. At the same time, in halting PKR, it will also generate more ATP molecules, and ATP is only depleted in sickle red blood cells. These will replenish the ATP levels and reduce the potassium loss to the [indiscernible] channel, increases the MCV red blood cell and improving dehydration. So activating the -- or enhancing PKR activity actually provides a very attractive anti-sickling strategy from 2 angles because it reduces 2,3-DPG, and at the same time, increases ATP. And mitapivat is a -- activates not only just mutant pyruvate kinase but also [indiscernible] type or normal pyruvate kinase. And we've already seen that it improves anemia in thalassemia. So -- I don't know. Can we advance the slides now? Hello? Hello? So okay. I'm sorry, but there's a hiccup here. If you bear in mind, so this is the design of our Phase I study for escalating the dose of mitapivat in sickle cell disease. This is a nonrandomized, open-label study, and we plan to enroll 15 to 25 patients, including adults aged 18 years or more with stable hemoglobin SS disease. And the patients should not have any blood transfusion or changes in the hydroxyurea dose and no L-glutamine within the last 90 days. So because the mitapivat was not tried in the different patient population such as sickle cell disease, we started with a small dose of 5 milligrams, escalating to 20, 50 each for 2 weeks initially. And then, later on, with a protocol amendment, we escalated up to 100 milligrams twice daily for 2 weeks. After which, the patients undergo a dose taper over about 2 weeks period, and they're followed up for 4 weeks and then after which, that's the end of study. And then -- sorry, at each points here indicated by the arrows, you can see blood samples were collected for assessment of the hemolytic and pharmacodynamic markers. As the primary end points, of course, of safety and how well the patients tolerate the mitapivat as assessed clinically and by changes in hemoglobin and hemolytic markers. Secondly, end points with the pharmacokinetics and also levels of 2,3-DPG and ATP levels. We also did oxygen dissociation studies and the sickling tendencies. These data will not be reported here because they were not completed due to the COVID-19 pandemic lockdown. So this is just the -- so far, by October 6 this year, we have enrolled 12 patients. Patient 4 was withdrawn on day 4 into the study because we discovered that she had primary embolism prior to enrollment. So only 11 patients then completed the 50 milligrams dose level, of which 6 completed the study per protocol, i.e., they escalated up to 50 milligrams twice daily in the original protocol. Then, of these, 5 escalated to 100 and one withdrew, patient 10, on day 76 of the 3 days of 100 milligrams. I can go into the details later if you want to know. Subject 12 is ongoing, and in fact, subject 12 and 13 have now completed end of study. So we could assess 3 patients who have been on the 100 milligrams dose level. So on the left panel here, these are the demographics of the patient that have been enrolled, assessing 12 patients with a mean age of 40 years, 8 of whom were male and all of African-American or African origin, 8 were also on hydroxyurea, of which, one was also taking L-glutamine. This was the baseline hemoglobin measures. Hemoglobin mean level of 9.5, with the hemolytic markers increased as one would expect in patients with sickle cell disease. And many of them -- or 8 of them were actually on hydroxyurea, and this was the mean hemoglobin F levels, 18.3%. And the patients demonstrated a safety profile which is consistent with that seen in those on the pyruvate kinase deficiency -- with pyruvate kinase deficiency and thalassemia. And just to reiterate that the dose related to the drug were considered insomnia, headaches. We also encountered serious adverse events, of which there were 5. One, as I mentioned earlier, had primary embolism, but this was actually discovered that she had it prior to enrollment for about 2 weeks before. And one patient who's hospitalized for shoulder pain, which is unrelated to the drug. She had recurring chronic pain in the shoulder. And we had 3 patients with vaso-occlusive crisis. One occurred during the drug taper. And although we could not state for sure that it is related to the taper because of the contemporaneous origin, we then went on to extend the period of drug taper, and this has improved with the extended taper period. 2 VOCs were encountered during the follow-up 28-day period when they've already finished the taper. One occurred, in fact, just a day before end of study and the other, 2 weeks after drug exposure. And for these 2 patients, we could identify VOC triggers, and we do not consider them to be related to the mitapivat. And you could see that there was a consistent dose decrease in 2,3-DPG, which is measured after 2 weeks of each drug. And here, on the y axis here, is the main change from baseline. And on the right panel, in conjunction, the decrease in 2,3-DPG, there was also a consistent dose increase of ATP, which then reduces at the end of taper and to the -- at the end of the study to the baseline levels. We forgot to mention that the linear pharmacokinetic was observed up to 50 milligrams twice daily. And after 100 milligrams twice daily, there was a 20% reduction in exposure, which we think is due to a CYP3A auto-induction effect. And although this study was not set out to measure the efficacy, we do see hemoglobin increase. And on the left here, you see that those increase in hemoglobin, which is measured by mean change from baseline from 5, 20 and 50. And although there was a slight reduction, in 100. And at the end of taper, they went back to the baseline. Note, however, that only 3 patients had -- were taking -- we could only assess 3 patients who are taking 100 milligrams twice daily. And on the right here, we know that of the 11 patients, their mean increase was 0.8. The maximum increase is 1.3. And 6 patients achieved a hemoglobin increase of more than 1 gram. And of those who achieved an increase of more than 1 gram, the maximum hemoglobin increase was 1.9. In parallel with the increase in hemoglobin, we also see a concomitant decrease of the hemolytic markers, including bilirubin, lactate dehydrogenase and absolute reticulocyte count. And at the end of taper, going back to the baseline; and by the end of taper, back to the baseline for each of these hemolytic marker. So in summary, I could say that mitapivat was well tolerated in the subjects with sickle cell disease. The pharmacokinetics and the safety profile resemble those from the studies in pyruvate kinase deficiency and thalassemia. And this study provides proof-of-concept that enhancing pyruvate kinase using mitapivat reduces 2,3-DPG and increases the ATP in patients with sickle cell disease. And despite this short period of exposure, we could see a hemoglobin increase by more than 1 gram in 6 of the 11 evaluable subjects, in parallel with a decreased hemolytic markers, which signals its potential to improve the clinical outcomes. And in fact, going forward, we have now started an extension study, and I'm pleased to say that the first patient was enrolled 3 days ago and today will come for some follow-up. And the second patient will enroll next week, with a third in December, before the end of the year. Thank you very much. And I'll be very happy to take any questions related to this study.

Thank you, Swee Lay, very much. Jackie, I'll hand it over to you to moderate here.

Whatever makes sense. So yes, we're going to let the operator tell us who has a question. So just real quickly, everybody. Darrin is joining us, our Head of the U.S. and Global Marketing, is joining us for the Q&A.

[Operator Instructions] Our first question comes from Kennen MacKay of RBC Capital Markets.

I was wondering if maybe you could elaborate a little bit on the 3 vaso-occlusive crisis events that we saw in the sickle cell presentation. Obviously, we have seen one of those previously earlier in the year at EHA. Had a little bit of concern, but really would just love to hear your perspective on how you're thinking about this as a safety event and potentially mitigating it going forward.

Sure.

Go ahead.

Yes. Sure. So as you know, these events, kind of, they recur independent environmental triggers. So one VOC occurred in the first patient, in fact, during the period of taper. And although we could not be sure that it's related to the taper, but because of the contemporaneous nature, we then decide to extend the taper and -- by 3 days. And since then, there were no VOCs that occurred during the taper. And of the other 2 VOCs, one occurred just a day before the end of study. And this patient, the subject was actually attending a conference, and it was right in the Michigan vertical, and he was quite stressed out about the flying and very cold when he arrived. And he said, I couldn't take the cold salad that was offered because we arrived really late. He couldn't sleep and he insisted on actually presenting. So these are all recognized triggers for vaso-occlusive crisis. And with that, I'm very confident that it was not related to the -- he has already returned to his baseline hematology. The second subject with VOC, he was already 2 weeks of the trial. This subject actually had a total hip replacement just 3 months before he enrolled, just 3 months before the lockdown period. So he had not been mobilizing with the total hip replacement. And when he joined the study, the activity was actually -- he found that it was aggravating his -- the pain in the hip. And by the time he went on to the 100 milligrams, he actually decided that he could not actually continue with coming in and out for the assessment. So he redo. And actually, I'm never pleased to say that I was actually worried that he would actually precipitate [ ongoing hemolysis ] in VOC. But again, the VOC that occurred was 2 weeks later when, in fact, he already returned his baseline and he presented at ER. And that was actually a particularly cold weekend. And independently, the physicians who saw him there ascribed it to the cold -- changing cold weather. So have I answered your questions about the VOC?

Maybe just a little bit -- elaborate a little bit more. How do you see that -- the competitive profile? How do you see that safety event? If this drug were to be approved and be on the market commercially, how would you think about that...

There's a lot of banging. I'm sorry. How do I say -- please repeat your question because I couldn't hear with the banging.

Sure. Was just wondering if you could talk a little bit about how you would think about that safety event, if this agent were approved and as it relates to the competitive landscape. Is this something that you've seen with other agents and treatment regimens? Or, I guess, how you would think about that?

Yes. Well, first, I would like to say this. Actually, using pain as an end point with sickle cell disease is very difficult. And many jobs -- clinical trials have actually failed. But I certainly hope that if we continue this that actually the number of VOC events might be reduced, even when we have external triggers. So -- and the other thing in my 20 years of looking after a patient with sickle cell disease, despite those being very adherent in hydroxyurea and despite the fact that hydroxyurea can reduce the frequency of pain, we still get them because we cannot control the external environmental triggers. And the mental stress is a very important trigger, which people underestimate. And cold environment is a very important trigger, too. So -- and this is a very short observational period. And all I can say is that the 2 patients who have VOC, it's kind of not unexpected. I don't think it was related to the drug.

Kennen, it's Chris here. One of the things in terms of a data perspective to also get a feel for this is if you look at the Phase I/II voxelotor published experience, you see that in the however many of the 41 patients who got treated with active drug, they reported that 22% of those patients had a sickle cell anemia crisis off-treatment and there was one of the -- in the 14 placebo patients. So that would justifiably raise some concerns. And yet, when they did their Phase III study with a control, while some are -- all are disappointed that we didn't see a reduction in VOC, we didn't see an increase. So I think that sort of underscores the clinical picture that Swee Lay outlined in terms of the numerous stressors and factors that can come in and are very difficult to predict. And that, I think you've heard us say, is the challenge in terms of thinking about how we design that component into our trial. So there is some additional data that you can look at, published data, to connect that with what Swee Lay just described as an individual -- as a physician expert who sees lots of these patients on a regular basis. Next question, please.

And actually, on that line, too, regardless of whether the patients are taking any medication or not, within the patient, they can go through cycles where 1 year, they might have recurring VOCs, maybe treated for hospitalization. And then another year, they would be better. So -- and this actually raises the real difficulty in planning pain in the [ cell ] as an end point. Obviously, we have to take that into account.

And our next question comes from Anupam Rama of JPMorgan.

There was a comment yesterday as well as in the presentation today, on the CYP3A auto-induction effect, right? Was this observed in other studies like ENERGIZE, ENERGIZE-T using 100 mg, right? And in DRIVE PK, if I remember, you also studied a 300 mg BID dose, along with the 50 mg, but you ultimately went with 50 mg. How should we be thinking about this effect?

Yes, let me take that one. The way we look at it is if you go to -- I don't know if you can see the slides, but I'm trying to show this one. So what I see on my slide is 2,3-DPG and ATP, and what you see is as you go from 5 to 100, you see increasing -- decreasing levels of 2,3-DPG, and then you see ATP increasing up to 100 as well. And when you look -- and so this is the really interesting part of the drug development here. When you go from 5 to 20, you see a qualitatively a pretty big increase. When you go from 20 to 40, you see another qualitatively noticeable increase as when you go from 50 to 100. But when you go from 20 to 50 of those proportional PK but you don't have an equal comparable increase in 2,3-DPG, and so when you look at ATP, you see that increase from 5 to 20 and slight increases from 50 to 100. So what we don't know when we look at that data is how does that translate exactly into clinical benefit. But from looking at the thalassemia data and from knowing the safety profile of the drug, it looks like we can still get some additional pharmacodynamic effect when we go from 50 to 100. So -- and you saw me present the dose for thalassemia at 100. And you've heard us say, well, is it going to be 50 or 100, what's the range in sickle cell? And so one of the things that we've heard from people who treat both of these diseases is that in sickle cell having the flexibility to start a patient at a dose and then move them around may be an advantage. So let me put that back to Swee Lay now. That's sort of the company pharmacokinetics PD look, and how do you think about that, Swee Lay?

Yes. Well, thank you, Chris. I mean, as you pointed out, the readout, even though there's an auto-induction, the 20% reduction, it's still -- they saw a consistent decrease in 2,3-DPG and increase in ATP. But one of the things we forget also is the basic exposure, the red cell dynamics, they're always changing. And we get an idea, and I actually haven't got the chance to show some of the oxygenation in the sickling study, but immediate exposure show reduction. And then as the red cells health, if you like for want of a better word, improves, then the change is less remarkable. So we put a figure on this, but the truth is, we don't actually really know what actually is happening in the red cell, which is actually changing each time they get exposure. So at the end of the day, it's actually the clinically how patients feel and what we can see in terms of the hemoglobin improvement and hopefully, with time, a reduction in the vaso-occlusion process. And -- but we have still to allow for the fact that there could be external triggers that we can -- beyond our control. Maybe it's only a very short period, 8 weeks. For some patients, only 6 weeks.

And our next question comes from Mohit Bansal of Citi.

Just staying on the 100-milligram and 50-milligram delta here. So it does seem like that on biomarkers, 100-milligram dose does have a benefit, but it is not so much translating into hemoglobin benefit and the drop is now at 20%. It seems more than that. So just trying to reconcile that effect. And does this mean 100-milligram dose is a viable dose going forward? Or it could be a viable dose for some patient? I mean it could be because of low number of patients, but just wanted to get your thoughts on this.

Yes. Maybe you could move to the next slide. I do hear you, which is this one here. And you're right because we see a consistent kind of decrease. But when you come to the 100 milligrams, it seems to actually drop. But you see the N here is only 3. And also, these 3 patients did not demonstrate such a remarkable increase even when from 5 to 20 or to 50. So my take on this is that we will see some variation in patient response. Just like we have seen variation in patient response in hydroxyurea and just as we see patient variation response to any other drugs they were taking. So in these extension studies that -- what we're going to do is that we're going to start with 50 and then escalate to 100 for some, but not for others. And we're still kind of feeling our way in titrating the dose to optimize the hemoglobin level in all. I think at the end of the day, it's actually the well-being of the patients more than the numbers, actually.

So it's an important -- an important takeaway is that it seems that people look at the data and they think that a responding patient, when they get to 100, the responding patient at 5, 20 or 50, when they get escalated to 100, drops. That's not what's happening. All of the responders, all 6 responders that have been described have responded to 50 milligrams or lower. So we'll get more experience with 100 milligrams. But I think one of the really important aspects that we're emphasizing is that increasing hemoglobin and reduction in hemolysis is very important. But the reason why you hear us talk about and I'm showing you this is that this 2,3-DPG is another important potential reason to believe. And so we think that pushing 2,3-DPG down even further by going to 100 maybe help us address the issues with VOCs and red cell sickling. And we can do that because we know that safety across 50 to 100 is comparable. So this is a very important -- it's an important decision to cross multiple factors of trial development. And I just keep coming back to when Dr. Swee Lay and others who take care of patients with this disease and as she talked about an extension, understanding that flexibility could be very important. And we'll keep working on that. Next question, please.

Yes. And then actually, the -- yes, I was going to say that actually -- I'm sorry, I was going to say, the 3...

It's okay, you go ahead.

Yes, I was going to say, the 3 patients who are taking 100, actually, they didn't demonstrate such a good response even at 50 or 20 or 50. So I bring back the point, again, there will be some variation in patient response to any drugs.

And our next question comes from Alethia Young of Cantor Fitzgerald.

This is Emily on for Alethia. I was wondering if you could tell us anything about the nonresponders, particularly if there were any baseline characteristics that stood out? And also, are you seeing any evidence that taper is helping to improve VOC risk?

I think it's a bit early yet to know the nonresponders. Our sample size is openly 11. So -- but I'm really working on that because I'm very interested in the detail in itself, and I know there are a lot of variance in that. And regarding the taper, we actually did it out of caution because, like I said, I'm not sure whether it's actually related. But the fact that we extended the period to -- by another 3 days instead of taking it away. That said, the one patient who actually stopped after 3 days, the 100, actually didn't have any problem. He presented 2 weeks after he stopped taking the drug when he returned to his baseline and there was clearly, an external environmental trigger. So I do not think -- we're actually building the taper more for caution and what we've learned from the patients with pyruvate kinase deficiency.

Right. One of the other things is that, to Swee Lay's comment, Emily, is there's a number of factors that we want to look at related to both clinical factors as well as molecular factors. And hopefully, we'll have more of the story to tell around that, but we're looking at Swee Lay within her laboratory and also doing some collaborations with us, we're looking heavily into that. And if we have a story to tell, we'll certainly want to bring it forward and incorporate it into our trial design.

And our next question comes from Marc Frahm of Cowen and Company.

Congratulations [Audio Gap] trials. I'm sure it was trying times in the clinic. Maybe just one thing to clear for you and Chris is that we're making -- just want to make sure we're clear. The 3 patients who made it to 100 milligrams and had the 2 weeks of follow-up at 100 milligrams, those patients did not respond at lower doses, is that correct, from the 1 gram level?

They did not show a response as remarkable as we saw in those 6. They do not show response, even when they were on 5 or 20 or 50, unlike the other 6. I mean, on the other hand, we've got patient 13 who just completed. She went onto 100, and she did show an increase. So it just happened to have these 3 who did not respond so well, even at a smaller doses.

Okay. Great. That's helpful. Dr. Thein, your colleagues had presented at ASH. She also made it felt that there may have been some changes in hydroxyurea compliance during the course of the trial. Do you agree with that?

We think so. Yes. We think so, but I cannot be absolutely sure because also when the patients are being followed up and went under this study, like I said to them, they're under a microscope. So they've become more adherent. But I'm not -- we thought they could be but, in fact, it's similar because you saw a slight increase in the MCV. But in terms of the other parameters like hydroxyurea, they remain the same. The hemoglobin percentage is the same, the white cell count is the same. So -- and these are patients who we kind of, if you like, perfect patients because we want them to be adherent and complete the study. So I leave that open. I don't know whether it's because they've become more adherent to hydroxyurea. But in terms of the other markers, the reduced hydroxyurea, MCV, hemoglobin F, they were not changed -- they didn't change at all during the period.

It's one of the interesting [indiscernible] like from early, early drug development where you see things and you wonder what their [indiscernible] relatedness is. And so it's always a fascinating component. And you just have to be aware of that smaller number that you can get -- you have to go into these types and make these observations with your eyes wide open with regards to the caveat. It's a very interesting statement.

Yes. But the MCV is a little bit increased, that would be very exciting because then it addresses, it validates our other principle that actually increases ATP and increases MCV, improving the hydration, and this is another kind of anti-sickling strategy advantage. So we're watching that very carefully is what I can say.

Just one question on the thalassemia trial. This is one trial that didn't get [ as much ] patients. I assume those will be stratified in a similar way. Is the end point going to be across all patients? Or will they be kind of separately evaluated across those 2 populations?

Sorry, you broke up a little bit. I heard stratification, but I'm not sure which category -- which one you're talking about. Can you say the question, again?

Yes, sorry. The -- for the thalassemia pivotal trials, they will enroll both alpha and beta thal in the same trial. I'm guessing you will be stratifying the population based on health [Audio Gap] or beta separately for the primary end point? Or will the primary end point be across all patients?

So the trial will be eligible -- the trials are eligible for patients for alpha and beta thalassemia. And your question is a very interesting one for us. It's do we need the balance for alpha thal distribution in the arms evenly? And at first glance, some of us on any given day, will say, yes. On the other hand, when we think we're activating wild type, and if they have -- they fit into the clinical characteristics and eligibility criteria for the trial, then you're looking at -- they're largely same in terms of what they're unmet need is. So it's a very interesting component. We haven't declared that yet, who will be eligible for both alpha and beta. And the primary end point would not look at alpha versus beta thal.

And our next question comes from John Newman of Canaccord.

Congrats on the data. Chris, just curious. For the pivotal studies in sickle cell disease, based on what you've learned here to date, just wondered if you're going to choose a specific dose for patients in that study? Or would you also look to do a dose escalation as you've done here? And also, how are you thinking about evaluating VOCs in terms of perhaps selecting patients that had a certain threshold of VOCs in the past? Or if there's another way to potentially look at that? I'm assuming that will be a secondary end point.

Let me answer that, and then I'm sure that Swee Lay can add some additional details. So I think from the Phase III perspective, the dose is a decision to be made. But given that what you're seeing today from a pharmacodynamic marker perspective and nice improvements across 50 to 100 milligrams, and the fact that we're seeing hemoglobin going up in that 20- to 50-milligram range, 50 milligrams is certainly a dose that would seem reasonable to be in the trial one way or another. And the question is, when do we go to 100, and that's something that we're going to work through and plan. So we're not ready to make that decision, to announce that decision today. I know we've talked to you about the design overall, but one of the things that's important about looking at these data and then looking at the totality of our experience with mitapivat in patients with thalassemia or pyruvate kinase deficiency is what we understand about the safety profile in that 50- to 100-milligram range. So we can't do that. And then that's versus, John, the other decision, which would be 50 or 100, right? And so that's something we can work through. But I would just come back to the previous comment I made that Swee Lay will probably go into. Having the flexibility to start, there's something to be said for starting at dose x and then seeing what type of response you get and then pushing that dose up a bit to see if you can max -- if you can improve it a little bit, checking in with the patient, [ how they're dealing ], et cetera. So there's some different strategy. With regards to VOCs, there's a lot of experience in -- the published clinical trial experience in terms of bringing patients in who have a minimum number of VOCs and the maximum number of VOCs in a pretreatment period when you go back and walk and then setting your trials up that way. So I think that's what you're seeing with a lot of studies these days in terms of how they're looking at it. It is one of the -- I would say one of the interesting and challenging parts of designing trials here because these 2 end points are so important to how patients feel. And then the underlying aspect too is that, that plays into both sickling and how patients feel in hemolysis. So what kind of impact do you have on hemolysis, whether they're hemoglobin is 1 gram or 2 grams. If you reduce the amount of stress on them now, that might also bring some benefits to patients. And the challenge that we see on the drug company's side is how you actually -- what tools there are to capture those types of improvements. So with that, Swee Lay, you've got some experience with mitapivat in these patients that you're talking about today. And do you see -- what's your experience then between 20, 50 and 100 to the [ safety difference ] what do you [indiscernible] data and the absolute [indiscernible]?

So yes, the patients who were going to enroll at extension, they're the ones who've taken part in the Phase I. So we already have a few how we want to respond. And we chose 50 as a kind of entry dose. We'll see how well the hemoglobin goes. And for caution, we actually have a ceiling of not more than 12.5 or if the increase by 2 grams within a short period of 4 weeks. So then you just maintain them on that dose. And with regard to the VOCs, it is very challenging because the external triggers that we cannot control. I think most studies now actually look at annualized VOCs maybe in the preceding 2 or 3 years to, at least, try to be objective rather than saying they're going through that phase. And then compare that to see is it out of the ordinary for the patient to get this period. And of course, the challenge as well, particularly in adults, where a large number will already have some chronic pain. And sometimes, it's difficult to tell whether it's an exacerbation of a chronic pain, or is it truly a VOC. And we try to use markers to help us. When the VOC usually accompanied by some drop in hemoglobin, some increase in pneumonic markers, which is indicative more red cells breaking down. But sometimes patients complain they have pain, and yet, we don't see this. So that is to kind of challenge in actually doing this -- using pain as an end point, particularly in adults with sickle cell disease. And you've heard yesterday from the rivipansel study, they could get a kind of cleaner, if you like, end points from pediatric patients in rivipansel. And their pain was used as -- of course, it was used for treating VOCs. I think I've answered your question.

And our next question comes from Alexander Duncan of Piper Sandler.

Slightly different iteration of a prior question, but could you comment on baseline hemoglobin percent hemoglobin S and F levels in hydroxyurea used in the study and how it could influence hemoglobin response to the PKR mechanism? And specifically, if there were any baseline differences in the 100-milligram patients relative to the overall group? And secondly, could you comment on whether any of the patients enrolled into this study have tried and failed Oxbryta?

Can you repeat the last part? Yes, because you're breaking a bit.

Yes. Could you comment on whether any of the patients enrolled into this study have tried and failed Oxbryta?

Okay. So let me go back to the demographics, so that we can -- right. So this one here, 8 of the patients were on maximize on hydroxyurea. And as you can see, they do have a higher than what we would see in patients with sickle cell disease. This is a high in percentage of hemoglobin F without intervention. So these patients have been taking hydroxyurea already. So with regard as to whether the mechanisms, if the hydroxyurea could actually influence the effect of mitapivat. And actually, when you -- the mechanisms, I would think will complement each other because they are different. The anti-sickling from hydroxyurea comes from the increase in hemoglobin, which will interfere in the formation of [indiscernible], whereas the enhancing pyruvate kinase actually reduces 2,3-DPG, which actually affects the sickling in a different mechanism and, at the same time, also increases ATP. So I think they complement each other. And this is why I kind of feel that this is a very good -- a complementary mechanism simply because as patients get older, they become more sensitive to hydroxyurea. And several of the older adults that I look after, we have to reduce the dose of hydroxyurea. And regarding your second question, how many patients have failed Oxbryta? I think it's too soon to tell because I'm not sure how many patients are actually taking Oxbryta. Right now, the patients you look at in the NIH, none of them actually are on Oxbryta. A couple of them are taking L-glutamine. That's all I can say really.

But Swee Lay, to the best of your knowledge, none of these patients -- it's Chris here. None of these patients on this slide had received prior Oxbryta?

No, no, no. We actually put out an exclusion [ partition ] simply because it's fairly new, and we want them to be stabilized on Oxbryta.

And our next question comes from Michael Schmidt of Guggenheim.

I just had one more on the VOC topic. Chris, you mentioned in the HOPE study, Oxbryta obviously did not reduce the incidence of VOCs. And I was just wondering with PKR activators, in general, which raise hemoglobin to a similar extent, I guess, what is the mechanistic -- I guess, how do you think about potentially having an effect on VOC reduction? And mechanistically, how is that -- what's the basis for that potentially?

Well, but [indiscernible] in the beginning, we will reduce the propensity of the sickling. There's a number of mechanisms that Swee Lay can speak to. So our goal is to increase hemoglobin. And as red cells are living longer or healthier, maybe would stand the stress down, getting through a capillary because the 2,3-DPG has been reduced. And there, because ATP has gone up, their membrane is gradual. Swee Lay has been studying this her whole life, so she's better -- much better in answering this question than I am.

So Oxbryta increases oxygen affinity, hemoglobin-oxygen affinity and the [ cell ] occupies 30% of the hemoglobin. And it's actually down very avidly, okay? And this is one of the concerns that was raised that actually binding its own [ vividly ], hemoglobin actually offload the oxygen. But in terms of enhancing PK activity, it's a completely different direction. Because the enhanced PK activity, you actually then drive through the glycolytic part of it, and this will reduce the upstream metabolized, one of which is 2,3-DPG. And, at the same time, it generates ATP. So these are 2 known mechanisms that will actually influence sickling. Now I'd like to say that the reason also why enhancing PK works -- one PK patient's -- PKD, pyruvate kinase deficiency patients, some of them can compensate very well for hemoglobin because I have looked up the PKD patients too, with hemoglobin of 8, 7, 9. And one of the reasons is because with the mutant pyruvate kinase, they build up this 2,3-DPG, which actually reduces hemoglobin-oxygen affinity, allowing them to actually offload oxygen. And so they actually cope very well. But this is no good for patients with sickle cell diseases. So if you actually enhances this PK, you want to reduce 2,3-DPG, not increase it. So that is the rationale, which I found very attractive, and that's the reason why I also went to Chris and say, I would like to try this in patients with sickle cell disease.

And our next question comes from Andrew Berens of SVB Leerink.

I know you answered a lot of questions on this, but just a couple more on the auto metabolism. Is there actually a way to quantify the CYP activity?

Yes, it's Chris here. Well, we can do that through various [indiscernible] assays that we do as part of our pharmacology package. The auto induction that we see when dosing 50 to 100, we don't have the exact proportion of kinetics. So the exposure at 50, when you go to 100, isn't twice that. The other thing to know is that it's stable once we see that. And so we know that from our pharmacokinetic studies in the study. And then we also know in both thalassemia and the DRIVE PK study is that the patients who are having hemoglobin responses are stable over time. So if auto induction was occurring and was unstable or continuing to occur, we would expect that those patients would lose their response, if you will, over time. So by following drug levels over longer periods of time, we saw [ a lot ] of patients from an efficacy perspective to stable auto induction. The CYP numbers, CYP-3A4, I'd have to check with our clinical pharmacology people as to what we've got in the public domain and would we cover some on that. But we have that information.

And our next question comes from Mark Breidenbach of Oppenheimer.

Obviously, a lot of people are trying to make direct comparisons between mitapivat and FT-4202 sickle cell studies. I was wondering if you can point to any material differences in the patient populations enrolled in these 2 trials? I know it's 11 patients in one and 7 in the other. But in terms of baseline symptom severity and baseline annualized VOC incidents, things like that, that would indicate a real difference between the 2 populations.

We don't see many -- it's hard to know much from that. The one piece that you can hang your hat on is the mean age that we've got up there is 40, and the mean age on the Forma study was 29 years of age, I think. Now neither Swee Lay nor Forma have commented on the burden of disease. And so we can't comment on that part from the Forma perspective, but, Swee Lay, perhaps you could talk about their overall burden of disease and how sick these patients were on your study?

Yes. Chris, you're right because I can't go too much into what was presented in the abstract on the severity of the patients and all that. What I could actually say is outpatient patients who come to the NIH all tend to have more severe disease. So -- because we are a tertiary center and they only get referred because it hasn't worked for the other centers. And that said, also, there's a huge variability in disease severity in sickle cell. And this is why sometimes when you look at the study to say that to reduce VOC in, say, 50 patients, but actually, they're all grouped together. So you might find there may be 20 of the 50 patients could have had no VOC during that 1 year. And then another 10 might have one VOC and then maybe 5 might have 3 VOCs or 2 VOCs, and then the rest. And then at the extreme end, you might get 2 or 3 that make up for the average. And this makes it very difficult. I guess, for one, when I look at all these studies, actually like to actually look at a much higher resolution to see how the data was analyzed. So it is a very complex, challenging disease due to the trials. But I think this can be answered with larger patient numbers. And at the end of the day, patients actually, they, themselves, will would tell you how they feel with the study. It is said in hydroxyurea -- I was going to say, it is said that in hydroxyurea, when patients were taken, regardless of whether before we even see hemoglobin have increased and hemoglobin within a few days, many patients already know whether it is going to work. And there are things to do with the [ NO ] and base dilution. So I'd say it again, we tend to measure by numbers, which, of course, has helped, but it's a -- patients themselves would tell you whether they get better on the study.

I think the bottom line is the [ 2 small ] early studies and we had a slightly higher age, I think our hemoglobin is a little bit higher than their mean baseline hemoglobin across the entire population. So it's early. We've got ways to go. I think both presentations indicate that PKR activation may be the treatment that is coming. So we've got to keep working on this and we're excited about it. I think we're out of time, Jackie?

Yes. So -- and with that, I would like to thank our analysts. And I like the way, Swee Lay, that you finished with reminding us that it's all about patients first. So that's a great way to end the session today. So thanks to all our investors and analysts for -- and anybody else, for joining us during the session today. And many, many thanks, Swee Lay, for your ongoing collaboration and presentation with us this morning.

No, not at all. And, in fact, Jackie, it was the patients who actually was taking the drug that drive me to approach Chris and say, can we have an extension study for those who wants to stay. That's the reason why the extension study came about.

So that's great. Well, thank you.

Yes, thank you.

Thank you for listening to this [indiscernible].

Thank you very much.

Thank you, everybody. Take care, and we'll follow-up for anybody whose questions didn't get answered. Thank you so much.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.