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

Good morning, and welcome to Agios webcast and conference call from EHA 2024. [Operator Instructions] Please be advised that today's conference is being recorded by Agios request. I would now like to turn the conference over to Chris Taylor, VP, Investor Relations and Corporate Communications of Agios.

Thank you, Michelle. Good morning, everyone, and welcome to Agios webcast and conference call to review data from the Phase III ENERGIZE study presented this weekend at the 2024 European Hematology Association Congress in Madrid. You can access slides for today's call by going to the Investors section of our website, agios.com. On today's call, you'll hear from our Chief Executive Officer, Brian Goff; Dr. Sarah Gheuens, our Chief Medical Officer and Head of R&D. And we are delighted to be joined by Dr. Ali Taher from the American University of Beirut Medical Center; and Dr. Kevin Kuo from the University of Toronto. Agio's Chief Commercial Officer, Tsveta Milanova, will join for the Q&A. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements. Actual events and results could differ materially from those expressed or implied by any of the forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in our most recent filings with the SEC and any other future filings that we may make with the SEC. And with that, I'll turn the call over to Brian.

Well, thanks, Chris, and good morning, and good afternoon, everyone, and thank you for joining us on Father's Day. At EHA this week, we were pleased to present a total of 7 abstracts, including 2 focused on data from the positive Phase III ENERGIZE study of mitapivat in non-transfusion-dependent thalassemia. And earlier this month, we were very pleased to announce positive top line data from the complementary Phase III ENERGIZE-T study of mitapivat in transfusion-dependent thalassemia. We believe mitapivat is well positioned to become the first therapy approved for all thalassemia subtypes, which includes both alpha- and beta-thalassemia and both non-transfusion and transfusion-dependent thalassemia patients. And we plan to file a marketing application encompassing data from both ENERGIZE and ENERGIZE-T to the FDA by the end of this year, which is similar to the approach we took with PKD, which led to a supportive label. At EHA this week, data from the Phase III ENERGIZE study were presented by Dr. Ali Taher and Dr. Kevin Kuo, two leading KOLs in thalassemia who were also investigators in the study, and we are delighted to have both of these distinguished physicians joining us today. Each of them will briefly review the key data from their presentations, and then we'll open the call for questions. But first, I will turn it over to Sarah, who will contextualize these presentations within our broader Phase III program of mitapivat in thalassemia.

Thanks, Brian. Next slide. Thank you. PYRUKYND or mitapivat is an oral, small molecule allosteric activator of pyruvate kinase, with the potential to correct red blood cell metabolism through its novel mechanism of action, leading to more effective erythropoiesis, reductions in hemolysis and improvements in how patients feel and function. Next slide. Mitapivat thereby has the potential to address the underlying pathophysiology of all subtypes of thalassemia, and we have advanced 2 global Phase III studies, ENERGIZE and ENERGIZE-T that together encompass all forms of thalassemia, including alpha- and beta-thalassemia and transfusion-dependent and non-transfusion-dependent thalassemia. And it represents the most comprehensive development program in thalassemia to date. It also truly reflects a global population because patients were enrolled globally. And this is important as thalassemia can now be found globally everywhere, really in every country due to migration. Also important is that both ENERGIZE and studies ENERGIZE-T have met the respective primary endpoints as well as all key secondary endpoints. Based on the positive data we have generated in both ENERGIZE and ENERGIZE-T, we believe that mitapivat is poised to become the first therapy-approved for all thalassemia subtypes, and we look forward to submitting sNDA based on all available data for both studies to the FDA by the end of this year. On today's call, I'm very happy to be joined by Dr. Taher and Dr. Kuo, who will be walking you through the data that was presented at EHA just now. And the data, of course, gives an overview of the study that we have run in a non-transfusion-dependent thalassemia patient population. So without further ado, it's my pleasure to turn the call over to Dr. Taher.

Thank you, Sarah. Next. ENERGIZE is a Phase III double-blind randomized placebo-controlled global study of mitapivat in adults with alpha and beta non-transfusion-dependent thalassemia. The study is conducted in 70 sites across 18 countries. Eligible patients were randomized in a 2:1 ratio to oral treatment with mitapivat 100-milligram twice daily or matched placebo for 24 weeks double-blind period. Patients who completed the 24-week double-blind period could receive mitapivat and for an additional 5 years in an open-label extension period, which is currently ongoing. The study, as said enrolled adults with alpha and beta non-transfusion-dependent thalassemia with a hemoglobin of less or equal to 10 grams per deciliter. You could see also that randomization was stratified by baseline hemoglobin and thalassemia genotype. Next, these are the endpoints. I will stress only on the primary endpoint and the key secondary endpoint. The primary endpoint is hemoglobin response defined as an increase of equal or more than 1 gram per deciliter and average hemoglobin concentration from week 12 to 24 compared with the baseline. The key secondary endpoint is a change from the baseline in an average, fatigue scale, FACIT-Fatigue score from week 12 through 24 and we will see this in the second presentation with my colleague Kevin Kuo. Next. This is the patient flow chart. We started with 235 patients assessed for eligibility, 194 patients randomized between 2:1, 41 did not meet the eligibility criteria on screening. And we've ended with 130 patients included in the mitapivat arm versus 64 included for full analysis in the placebo arm. Next. The baseline demographics and disease characteristics are clearly seen on this slide, and they were balanced. For example, the mean age was around 40 years. There were slightly more female than male. The medium baseline hemoglobin was 8.4 gram per deciliter, approximately 1/3, as you see of the patient had alpha and around 40% was splenectomized. And what is important that most had received no transfusion during the 24 weeks prior to randomization. Next. This is our primary endpoint that was met. Most patients in the mitapivat arm -- as you could see on this waterfall plot, most patients in the mitapivat arm experienced an increase in hemoglobin as shown on this plot. 42% met the threshold of hemoglobin response as defined in the endpoint versus 1.6% in the placebo arm. Among -- no, back. Among patients who achieved the clinical response or the hemoglobin response in the mitapivat arm, mean change from baseline in average hemoglobin concentration from week 12 through 24 was around 1.6 grams per deciliter. Hemoglobin response rates were higher, as you could see in the mitapivat versus placebo across all prespecified subgroups. I will not go through the details, but it was higher, the mitapivat versus placebo. Next. Now the key secondary endpoint, which was a very important part of this study also demonstrated a statistically significant improvement in this key secondary endpoint, change from the baseline average FACIT-Fatigue score from week 12 through week 24 compared to the placebo. The FACIT-Fatigue questioner is a validated PRO tool used to assess the impact of fatigue on individuals with chronic illnesses, higher scores, less fatigue and my colleague, Kevin Kuo will be discussing this in his second presentation. Next? This is an interesting slide that shows that the hemoglobin levels improved early in the mitapivat. Which you could see at week 4 and were sustained all through the 24 weeks. Next. Also, the -- as you know, the pathophysiology or the pathology and the disease relates on hemolysis as well as ineffective erythropoiesis. So improvement in the markers of hemolysis were observed in the mitapivat by a reduction in indirect bilirubin and a reduction in LDH versus the placebo. Next. Similarly, improvements in markers of erythropoietic activity were observed in the mitapivat arm versus the placebo arm with an increase in reticulocytes count. Next. Now that was the efficacy. And if we look into the safety, the mitapivat was generally well tolerated. The proportion of patients with adverse events of any grade was similar between the two treatment arms, the mitapivat versus the placebo. Eight patients in the mitapivat arm had serious adverse events and were considered not to be treatment related. No serious adverse events or adverse events leading to treatment or discontinuation in the placebo arm. However, four patients had adverse events leading to discontinuation in the mitapivat arm. Next. If you look at the most frequently reported more than 10% adverse event, you see that they were headache, insomnia, nausea similar to most of the studies, and they were mostly transient and did not affect neither the quality of the life of outpatient nor necessitating stopping the drug. Next. So in summary, this global study was the first to enroll patients with alpha-thalassemia in addition to beta-thalassemia. The primary outcome endpoints were met. The key secondary endpoints were met with statistically significant improvement in hemoglobin and fatigue with mitapivat versus placebo. And when we looked at the prespecified subgroup analysis, it all favored mitapivat versus placebo. Improvement, as I've shown you in the markers of hemolysis and the erythropoietic activity were observed, consistent with the mechanism of the drug itself or mitapivat. Mitapivat was generally well tolerated in the study with low treatment discontinuation rate and the safety profile consistent with other studies. Thank you. I would like to ask my colleague, Dr. Kevin Kuo to move into the patient-reported outcome measures.

Thank you, Professor Taher. And now I'll be talking about the quality of life as well as patient-reported outcome measures in the ENERGIZE study. So to recap, patients with thalassemia have serious long-term multi-organ complications. And anemia is associated with increased symptom burden, such as fatigue and poor health-related quality of life. And this is especially true in patients with non-transfusion-dependent thalassemia. This, of course, impacts on daily activities, physical functioning as well as emotional and mental state. Now this is, of course, regardless of transfusion status and it's for patients with both alpha- or beta-thalassemia. Now some domains within the health-related quality of life are worse or comparable in adult patients with NTDT versus those who are transfusion-dependent. And remember that for alpha-thalassemia patients, there is no approved therapies. And for beta thalassemia patients, there is no approved oral disease-modifying therapies as well. More importantly, there is no oral disease-modifying therapies for thalassemia that's been shown to improve aspects of health-rated quality of life. Next slide, please. So as you can see in this slide here, Professor Taher has already described to you the primary endpoint and key secondary endpoint. Now I'm going to expand upon our key secondary endpoints here, which includes the FACIT-Fatigue score and also the 6-minute walk test as well as the Patient Global Impression of change in fatigue as well as the PGIC in thalassemia symptoms and PGIC in walking capacity. Next, please. And here -- next, please. So let's have a look at the top table here. Patients, as you can see in both mitapivat and placebo arm, the fatigue baseline with a mean baseline FACIT-Fatigue score that are lower than the general population. For reference, the FACIT-Fatigue score in the general population is 43.6. And mitapivat -- and on the second row here, you can see mitapivat has demonstrated a statistically significant change from baseline in average FACIT-Fatigue score from week 12 through week 24 versus placebo with an LSM difference of 3.4. So the next question is, how much of a change in the FACIT-Fatigue is considered to be clinically meaningful for a patient? And that's 4.5 points or higher. And we will call this MWPC or meaningful within person change. Now let's turn our attention to the waterfall plot below that. In here, we see a higher proportion of those on the mitapivat arm, specifically 36.2% met or exceeded the MWPC threshold compared with the placebo arm, which is 21.9%. Next, please. And on Figure 4, you can see that mitapivat led to an early and sustained improvement in the FACIT-Fatigue score. Next, please. Now let's turn our attention to 6-minute walk test, which is the litmus test for function. In healthy individuals that aged 20 to 50 years, and which is a similar age range to our ENERGIZE cohort and mean 6-minute walk test distance reported in literature is 593 meters for females and 638 meters for males. And as you can see here, in the table below, the baseline 6-minute walk test is substantially lower in both the mitapivat as well as the placebo arm. Now when we look at patients in the mitapivat arm, they had a greater improvement in their 6-minute walk test compared to those in the placebo arm at week 24. And again, you can see here in table 2, the least squares mean change from baseline at week 22 -- week 24 is 30.48 meters in mitapivat arm and 7.11 meters in the placebo arm with a LSM difference of 23 meters between the treatment arms. So let's contextualize this. What does this really mean, right? What we're looking at here is that in the literature, the reported MCID threshold, the minimum change important differences -- clinically important difference, is 20 meters. Mitapivat has clearly cleared that bar at 30.48 meters. Next, please. And in Figure 5, we see that there is consistent reportment of greater improvement in the mitapivat arm, as shown in the blue bar versus the placebo in the gray bar from week 12 all the way to week 24. Next, please. In Figure 6, in terms of the Patient Global Impression of Change in the thalassemia symptoms on the left-hand graph, and in the PGIC of the walking capacity on the right-hand side, you can -- at 24 weeks, you can see that in both of these measures that there's substantially higher proportion of patients with mitapivat versus placebo that reports a much better or a little better improvement. So in conclusion, in this 24-week double-blind period of ENERGIZE, there's significant improvements in fatigue as measured by the FACIT-Fatigue, and this was demonstrated in the mitapivat arm compared to the placebo arm. A higher proportion of patients reported clinically meaningful improvements within mitapivat versus placebo. Furthermore, functional improvements in patients with mitapivat as measured by the 6-minute walk test has exceeded a previously reported meaningful change threshold from the literature, which was 20 meters. A higher proportion of patients with mitapivat reported improved fatigue, disease symptoms, as well as walking capacity as was shown in the Patient Global Impression of Change with mitapivat versus placebo. So in conclusion, mitapivat is the first oral, disease-modifying investigational therapy to show an improvement in fatigue as well as walking capacity in patients with both alpha- or beta-NTDT. Now I'm going to turn it to Brian Goff for the closing remarks.

Well, thanks a lot, Dr. Kuo and thank you very much, Dr. Taher. This is really a special opportunity for us to hear directly from both of you. We really appreciate your perspectives, your insights on the data from this important study, and we're very thankful for your time. So with the positive data, we've generated with mitapivat in thalassemia as well as in PK deficiency, in sickle cell disease as well, we have great conviction in the potential for mitapivat to become a first-in-class and best-in-class treatment option for multiple indications and to become a multibillion-dollar franchise. Now as a reminder, in addition to the two positive Phase III studies in thalassemia that we've already reported this year, we're anticipating multiple additional catalysts over the next 12 to 18 months, specifically by the end of this year, we expect to submit an sNDA for mitapivat in thalassemia, report top line data from the Phase III ACTIVATE-Kids T study of mitapivat in regularly transfused pediatric patients with PK deficiency and complete enrollment in the Phase III portion of the RISE UP study of mitapivat in sickle cell disease. And next year, we expect to report top line data from the Phase III portion of the RISE UP study in sickle cell disease as well as the Phase III ACTIVATE-Kids study of mitapivat in pediatric PKD patients who are not regularly transfused and to launch mitapivat for thalassemia in the U.S. Finally, I'll note that through the divestiture of our oncology business to Servier and the recently announced royalty agreement with Royalty Pharma, we have the potential to receive an additional $1.1 billion in payments upon FDA approval of vorasidenib, which has a PDUFA action date of August 20 of this year. We believe this additional cash will provide us with financial independence to prepare for back-to-back potential launches in thalassemia and sickle cell disease, as we build a PK activation franchise with multibillion dollar potential. Before we transition to Q&A, I'd like to take a moment to thank the entire Agios team, and again, express my sincere gratitude to Doctors Taher and Kuo for joining us today. And with that, we will now open the call for questions.

[Operator Instructions] And our first question is going to come from the line of Gregory Renza with RBC Capital Markets.

Great. Brian and team, congrats again on the updates today and certainly over the course of this year. Brian, maybe for you, Sarah, of course, and for the doctors on the line. Just curious if you could comment a bit on how the health-related quality of life measures in the FACIT-Fatigue, of course, correlate to hemoglobin improvement? And do we think that those quality of life improvements are driven by the hemoglobin increase? Or are there other aspects of maybe mitapivat's biology that could also contribute?

Sure. Thanks, Greg. And first off, happy Father's Day.

Yes. Happy Father's Day to you as well. Yes, it's Kevin here. That's a very interesting question. Definitely, we need to look at that, but we have not looked at that yet.

And so if I can add to that, it's -- we're -- right now, we have done the intent-to-treat analysis just as prespecified in our protocol. And we were very pleased with the results that we have obtained via our prespecified statistical analysis and are now really focused on moving the program forward towards regulatory submission.

Got it. Got it. And maybe just -- I'll use -- my follow-up. And just with respect to the primary endpoint and the secondary endpoint results, including that quality of life data, maybe for the doctors, what percentage of thalassemia patients would you believe could benefit from mitapivat in light of these data?

Yes, Dr. Taher?

And this data, you mean in non-transfusion-dependent thalassemia. These are a group of patients that do not require transfusion regularly, and they might require transfusion every now and then maybe not all their life, maybe a few times through their life. But the major issue that we have clearly shown that if they have a low hemoglobin, they will develop most -- at least 3 morbidities and more during their life from adolescent to adulthood. So increasing the hemoglobin is really something which is very important, not only to improve the quality of life, which you could see directly as a key secondary endpoint, but waiting for a few more years, you would see maybe that older morbidities will decrease and will not be there anymore. So I'm sure that the majority of the NTDT patients were requiring increasing their hemoglobin. This is not for sure, not those that have a hemoglobin of 10, we're talking about those that with hemoglobin less than 10. But it remains to be that treating these patients should be a personalized treatment. Each patient is a different patient.

And our next question is going to come from the line of Eric Schmidt with Cantor Fitzgerald.

Yes. Thanks. And let me add my congratulations as well. It's great to see some real innovation in the field of thalassemia. Maybe the first question for Sarah or the company, it's around the open-label extension. Do you have a sense of the number of patients who enrolled and are continuing on therapy in that OLE?

So we have a lot of patients that elect to continue in open-label extension studies, which we see pretty consistently across our different programs. We have not highlighted the numbers yet or any data from the open-label extensions yet, but as we have done so for pyruvate kinase deficiency. This is something that we definitely will do at a later time point. Yes, the majority, indeed. Kevin -- Dr. Kuo was adding something too.

Just echoing Sarah's statement. I was saying that patients on my site, they are very happy to be in this program and all the other programs as well.

Yes. Similar in our side also in Lebanon, all of them are happy, and I don't think anyone is getting out of the -- most of them are going into the open label.

That's great to hear. Maybe as a follow-up for doctors Taher and Kuo. It sounds like mitapivat is probably going to get a pretty broad label for alpha- and beta-thalassemia as well as transfusion dependent and independent patients. So maybe just can you give us a sense of which of your patients are going to be offered the drug, which are kind of the best candidates? And conversely, is there a subgroup of patients who you don't think are candidates?

That's a good question. And this is personally my opinion. I'm going to tell you right now. Any patient who comes to me to clinics have clinically significant morbidities. So ergo, I would try everybody on the drug. That's the bottom line. Otherwise, they wouldn't be in my clinic to begin with, right? And if they have morbidities, it means that they need a disease-modifying therapies to alter their outcomes and also to change their function.

Thanks, Kevin. Dr. Taher?

I follow a large number of NTDT patients around, let's say, 200 patients that I've been following over a long period of time, 22 years. As Kevin said, the majority of this, especially those that are moving into adulthood, the majority have at least 3 to 4 morbidities. Some of these morbidities are really hard morbidities like pulmonary hypertension and other. So it is really my job to give such a product or such a novel therapy to most of the patients in order to reduce these morbidities or abolish them hopefully when we do a pediatric study.

And Eric, as you noted upfront, we are targeting a broad label. I mean here today, we're talking about the ENERGIZE data for the non-transfusion-dependent patients, which encompasses both alpha- and beta-thalassemia, but we were equally delighted last week to talk about the top line results from the ENERGIZE-T trial, which now gives us a firm footing for both of those cohorts as well non-transfusion-dependent as well as transfusion-dependent patients. And this is a real advantage for the thalassemia patients broadly, and we were just delighted to be able to feature that data from ENERGIZE yesterday in the plenary session.

Our next question. Our next question is going to come from the line of Salveen Richter with Goldman Sachs.

This is Lydia on for Salveen. And congrats again on the progress. Could you just help us understand the difference in hemoglobin response between alpha- and beta-thalassemia subgroups and what might be driving this?

Thanks, Lydia. Sarah, do you want to start?

Yes. I can start on that one. So we do not see that as a difference between the two subgroups, Lydia. So when you look at the prespecified subgroup analysis, you can see that for both -- and this is a standard way of doing an analysis on your stratification factors. It is each group that is tested for -- treated against placebo. They're not meant to be compared towards each other. So it is alpha mitapivat treated versus alpha placebo treated or beta mitapivat treated versus placebo mitapivat treated. And then the conclusion out of there is that in both of those subgroups, mitapivat was favored against placebo, which means that overall, in the overall primary efficacy results, there is not a single subgroup driving the overall efficacy results. And the conclusion that you can take from there is, therefore, that the drug works in alpha-thalassemia and in beta-thalassemia. And that's really -- they're not meant to be like number-wise compared to each other. Yes.

Yes. So I would echo Sarah's statement, but I also -- this is what I tell my students and my methodology class is that when we use forest plots like this and subgroup analysis is meant to look at the direction of change. that's more important than the magnitude of change. So as long as the direction of change is consistent, it means that we are seeing a consistent effect. It is only when the direction has changed that are divergent then we start to need to dig in and think about other causes as to why that is the case. But here, we see that in both alpha- or the beta-thalassemia subgroup is that the direction change is consistent.

And our next question is going to come from the line of Tess Romero with JPMorgan.

First one from us is, what were the reasons for the 4 TEAEs in the mitapivat arm that led to treatment discontinuation?

Thrombocytopenia -- mild thrombocytopenia, increase in liver function test, abdominal distention and arthralgias. I think these are the 4. So I mean, these are 4 to me, minor events, but these were the causes or the reasons for stopping the drug.

And as we have said before, like there -- clearly, there are 4 different things. So there is not like a cluster of events that led to discontinuation within the study.

Okay. And then the second one or the follow-up from us is, you have talked about the objective for a broad label, and certainly, these were adult studies. What is your strategy in pediatrics?

Yes. So we're very excited about the benefit risk profile that we have generated in adults. So of course, pediatric development is now a top priority for us, and you can expect something very similar to how we've approached our pyruvate kinase deficiency program. However, we haven't guided yet to exact start date or the details of that program, but we -- our intent is to really expand the patient population over time.

Our next question comes from the line of Alec Stranahan with Bank of America.

I want to just offer my congrats as well on the breadth of the positive data seen to date from the thalassemia program. First question, maybe one for Dr. Taher and Dr. Kuo. How do you view the overall convenience of mitapivat in regards to currently available treatments? I guess how would a broad approval of an oral therapy change the way patients are managed from a logistical perspective in either or both transfusion dependent and independent populations? And then I've got a follow-up.

Yes. Thanks, Alec. And maybe Dr. Taher could start because actually, this was some commentary at the end of the plenary yesterday.

So you mean what's the benefit of using mitapivat over [ available ] modalities. First, as Kevin said, this is an oral drug. It's for both alpha- and beta- at least for now, non-transfusion-dependent thalassemia. The other alternative would be luspatercept, which is a subcutaneous injection every 3 weeks also to improve hemoglobin. The third alternative would be blood transfusion, if needed, which is what we are trying as much as possible to minimize or even abolish from the management of this group of patients. So whatever is available now is luspatercept versus mitapivat. I think that, as I said at the beginning, that treatment is a personalized treatment. But as also Kevin said, I would I think that each and every patient with NTDT, whether alpha or beta would benefit from such a drug. Compliance is a major issue in the management of our patients. And we have got a lot of compliance issues at the era of the deferoxamine or Desferal in our patients where subcutaneous injection that was available to each and every one, the compliance rate was 30%. So I do believe that taking an oral drug is really by far more beneficial, not for compliance, for school performance, for their daily life, for their work. I think this is the major benefit. Kevin, would you like to add something?

Yes. Yes. And as well, we need to remember that there's really nothing out there for alpha-thalassemia right now other than putting them on transfusion, which as Professor Taher has noted it is not desirable and it's sort of the last resort. So for those patients, this would be the first go-to, the first disease-modifying therapy that we ever have. And more importantly, the fact that we saw improvements in both function as well as quality of life, I think, should be a great impetus for our patients to at least try to be on this therapy first because the alternative really is nothing.

All right. Great. And one more quick follow-up, if I may. Just a regulatory question. How do you think the FDA will assess the totality of the data? Do you think, they'll look at each study ENERGIZE and ENERGIZE-T on its own? Or is there may be some read across they'll make for say biomarkers or the pro endpoints?

So well, obviously, we're not the regulator. So I can't comment on how they will look at the data, but our intent is to submit of course, both trials supporting each other. We have now two trials that highlight that we can improve anemia with a trial that measures hemoglobin response and another trial that measures transfusion reduction response. So they are complementary to each other, highlighting that we can improve anemia in this disease. And then of course, as always, it's a matter of ongoing review. There will be -- when once we submit there will be questions and answers provided back and forth. And then we are very much looking forward to start that collaborative process.

I think the -- combining the two studies, not combining them, using them both will strengthen your file that you were going to be presenting. Although it's the same disease, but there is a lot of diversity and severity of this disease. On the contrary, learning from experiences of other drugs and the way they were presented, I think this is the ideal way to present both together showing reduction in transfusion and increase in hemoglobin.

And our next question comes from the line of Divya Rao with TD Cowen.

This is Divya on for Marc. I will also add my congrats on kind of all the progress and the really great data. I just have two quick questions. One is, when can we expect a filing in the EU for thalassemia? And my second question is on the data itself. I know competitors have used like PROs of tiredness and weakness, I think, which is obviously a different endpoint from this FACIT-Fatigue score. Can you give us a little bit of color on kind of the difference in criteria and like what is [indiscernible] goes into each of those PROs?

Sarah, you want to start on the regulatory?

I'll start on the regulatory piece. And then I do think you might need to repeat the beginning of your second question because you broke up for a second. So let's maybe start with the regulatory path. So as you know, we try to always work as fast as we can. And so the team is in full on filing mode. We have guided towards a submission for the FDA by the end of year. But as you know, we always work with core documents with a goal to be able to submit to other regulatory authorities as well. So we haven't provided the details yet on which regulatory authority when, but we're definitely in full-on global filing mode. And maybe I can ask Tsveta to comment as well.

Absolutely. And Divya, as you know, we are in active launch preparation for the U.S. The team is progressing very, very kind of fast and steady there to make sure that we get ready, we educate the market and we prepare for launch. As Sarah said, we've looked globally, and we have actually prioritized some of the markets for regulatory submissions and Sarah and the team are working very closely with us to do that and have as quickly as possible submissions to the relevant regulators. From a commercial priority market, when you look at the prevalence of the disease, the Gulf region comes as a high priority for us. So we'll definitely make sure that we prioritize that, and we are in active conversations to select partners with strong experience in the region, so we can launch there as quickly as possible. We will look into Europe as well. Again, in Europe, a regulatory submission and approval needs to be followed up by individual pricing and reimbursement processes. So that might take some time for us, but we are looking to assess what are the next regions that will enter after the Gulf.

And Divya, do you mind just repeating the second part of the question was to get related to the PRO.

Yes, that was helpful. So your competitors have used a PRO, I think it's like tiredness and weakness, which is different from the FACIT-Fatigue score. Can you give us a little bit of color on the kind of the difference in criteria and how each of those are evaluated?

So Divya, I think you're alluding to the BEYOND trial where the PRO that was done was a so-called non-transfusion-dependent thalassemia PRO tool, the NTDT PRO. And in there, there's two different domains. There is the tiredness domain as well as the weakness domain. Is that what you're referring to?

Yes, that's correct.

Yes. Okay. And your question for that is?

Just in terms of the evaluation of how each of those are done, what are the criteria? And how are they kind of different between the FACIT-Fatigue score and that tiredness and weakness PRO?

Yes. So these PROs are constructed with certainly some domains that have overlapping themes and some domains that do not have overlapping themes. All of them have been previously validated. It's not necessarily a criteria that we look at in these constructs is what we call. So when we talk about PRO instruments as they're called, surveys are essentially instruments, within these instruments are different domains and domains map to the different aspects of the patient reported -- aspects of function as well as quality of life like fatigue, tiredness, et cetera. And so what we have chosen, in this study is specifically to look at tiredness because this is what we found our patients were focused on. This is what they talked about most. And the other thing that we chose, of course, is the 6-minute walk test. And again, that alludes to the fact that many of our patients, especially during the Phase II study, the 010, they talk to me about how they are not able to even, say, carry groceries or to do activities of daily living that we find to be simply essential or very common to us. And like one patient, for example, described how she's not able to pick up her 3- and 5-year old at that time. Before starting the medication, she always has to take a nap because she's so fatigue and she can't even walk to do any of the chores and she has to rely on her mother-in-law to do everything in the afternoon.

And from several questionnaires that we have done previously, 7 or 8 years ago, and we have published, fatigue is the most -- tiredness and weakness, fatigue is the most important -- what do you say -- fatigue is the most important symptom in this group of patients.

And this is something we have consistently heard also across all of our development programs, both for pyruvate kinase deficiency, thalassemia and sickle cell disease, which is why the fatigue has been prominently featured in all of these development programs as well. And so for PKD, we were able to highlight that improvement on fatigue, tiredness. Now we have the same type of results for thalassemia. And of course, we are still enrolling in our Phase III study for sickle cell disease, but our hope is to be able to deliver a similar result there.

And I'm showing no further questions at this time. And I'd like to hand the conference back over to CEO, Brian Goff, for any further remarks.

Well, thanks a lot, Michelle. And thanks to everybody for the questions this morning, this afternoon, depending on where you are. And I just want to thank again especially Doctors Kuo and Taher for joining us today. So again, Happy Father's Day to all the dads out there, and we look to -- look forward to speaking with all of you again soon. Thanks a lot.

This concludes today's conference call. Thank you for participating, and you may now disconnect.