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

Okay. We'll go ahead and get started. I want to welcome everyone to the 2020 JPMorgan Health Care Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. Tessa Romero and Matt Bannon from the team are here as well. We're kicking off the conference with Agios, and presenting on behalf of the company is CEO, Jackie Fouse. Jackie?

Thank you, Anupam. Good morning, everybody. Thanks for -- happy New Year, first of all. Thanks for joining us this morning. We're quite honored to kick off this presentation stream for the 2020 JPM meeting this year. And we're pretty excited about where we are as a company. After being around for 10-plus years, we see some clear inflection points coming for us in terms of where we can take our science and we look forward to sharing that with you today. That's why we want to put some stakes in the ground around our 2025 vision, and we'll also talk about some significant catalysts that we have coming in 2020. And I hope by the end of the presentation, you have an appreciation for the fact that we're going to have clear catalysts and significant data readouts every single year from now out to 2025. These are our forward-looking statements. At Agios, we've kept patients at the center of what we do since our founding as a company in late 2008, and we continue to do that. We -- or the company whose scientists brought biology of IDH inhibition into the treatment of diseases in the cancer area. And now we're on the brink of bringing products forward for the treatment of serious blood disorders coming from the same scientific platform that generated the IDH inhibitors, and we have some significant catalysts around our pyruvate kinase reaction activation program that will occur in 2020. I'll talk a little bit more about those in a minute. But we look forward to our scientific expertise, taking our products into these patients that typically are living with the serious diseases over the entire course of their lifetime with quite significant health implications over the course of their disease. Our strategy is quite clear, patient-focus, deep and broad expertise in cellular metabolism. We've elucidated the biology of metabolic pathways for longer and better than anybody else that I can think of, and we are taking ourselves into adjacent areas of biology with those deep scientific routes in metabolism. We are focused on bringing first-in-class or best-in-class medicines to market for patients. And we're focused on the 3 areas that you see on the slide up here. In terms of broad therapeutic categories, we already have our IDH inhibitors in malignant hematology indications and are moving those into solid tumors. And as I mentioned, in the nonmalignant hematology area of rare genetic diseases, we're on the brink of some significant catalysts this year. And we'll talk a bit more about that in just a moment. We have a 10-year-plus track record of delivering from internal discovery of medicines all the way through to approval in getting those medicines to patients. We've lived through what some definition of the cycle in biotech would be a complete cycle that is allowing us to bring more integrated thinking to how we bring medicines through our pipelines, including translational support to our programs. And we're very proud of the achievements. We've put up there some metrics here around that. We have terrific teams of people delivering on these enviable accomplishments, and we have an open, transparent, innovative culture that will allow us to continue to do this for a long period of time. So we feel like we have a very credible track record. 7 INDs in a 10-year period of time is a pretty notable achievement. So we're going to leverage this expertise and track record and sets of experiences into the next 10 years. Many of you probably know where we are today. As we start 2020, we have 2 medicines on the market, TIBSOVO for IDH1 mutant cancers and IDHIFA for IDH2 mutant AML. Those are 2 indications that we have for those 2 marketed products. And we have 4 other molecules, all internally developed and discovered in the clinic in those programs in human trials. And we'll look a bit more at the details of that in just a minute. For the first time this year, we are giving annual TIBSOVO net revenue guidance, and that will be $105 million to $115 million. We're moving into our second full year on the market with TIBSOVO, and we feel quite confident in giving that guidance. You will see our Q4 performance in our earnings call in the second week of February, so stay tuned for that. But we feel confident in how we ended the year and our ability to provide you this guidance. So where could we be in 2025? And you might say, why are you guys talking about that today. Well, we're talking about it today because we have clear line of sight to at least what we can achieve in 2025. And we want to share that with you so that we put some stakes in the ground so you have an appreciation for the potential that we see in our portfolio. We could have 4 medicines on the market by 2025, and at least 8 indications, and we will have at least 6 molecules in the clinic in 2025, with 4 of those being new molecules versus the ones that we have in the clinic today. We expect to be cash flow positive, at least by 2025, and maybe before. We want to put that stake in the ground. And we didn't put a number up here for revenues because there are a lot of assumptions that go into a 6-year financial plan. But I'm going to stand up here and tell you that we expect to have at least $1 billion of revenue and a very good chance of being in excess of $1 billion of revenue in 2025 with a very conservative business plan. And in a minute, and I'll talk a little bit more about how we get to that and where we think the upside potential is. I will cover each one of our broad therapeutic areas of focus in more detail. The message in this slide is that we have several clinical programs ongoing in each one of our therapeutic areas of focus. These are compounds that are in clinical trials in humans. The little diamonds on there, the green ones show you our forecasted approval dates for these different trials and programs. And the orange ones show you significant data readouts, where we will be making decisions about next steps with these programs. There's significant optionality across each of these and what I want you to go away with an appreciation for is the amount of catalyst flow that we are going to have starting in 2020, and we'll cover those objectives in more detail later. But every single year from now until 2025, we've got significant product or indication approvals and significant data readouts across our portfolio of drugs that are already in the clinic. We have a robust discovery engine behind each one of those therapeutic categories of our areas of focus. And you can see optionality on this slide across multiple programs that we have in our discovery science area, and we're moving those along through the different stages of discovery. And we have targets to have new drug candidates, and then move those into INDs on a regular basis. So from early all the way to later stages, we've got, what I think for a company of our size, is a quite interesting pipeline with lots of optionality in it and upside potential for the future. If we turn to malignant hematology, where we've been in the market for the longest, and many of you in the room are probably familiar with our products here, these numbers are for IDH1 mutant AML and myelodysplastic syndrome only, the 2 that are on the left. We also have IDHIFA, the marketed product for IDH2 mutations, which are about 6,000 AML patients, and we co-commercialize that product with Bristol and Celgene, but we don't show those patients here. And we have the trials in the clinic ongoing to expand our label for IDHIFA across all segments of AML and to expand that label into myelodysplastic syndrome, and we'll look at that in just a moment as well. We have a significant number of patients that we could touch with our DHODH inhibitor AG-636 in diffuse large B-cell lymphoma and mantle cell lymphoma. And we have that dose escalation trial underway now, where I believe we're the only company looking at this mechanism in that indication, and we'll have data from that trial later this year. Our commercial team has delivered stellar performance over the course of the last 18 months since we launched TIBSOVO in the U.S. back in the middle of 2018. You've seen the quarterly numbers reported before. I already told you what the guidance is for 2020, and we feel very good about how we ended the year and how we're set up to achieve that guidance in 2020. The new piece of information or a new piece of information on this slide for you is the 515 unique prescribers. We had about 450 at the end of Q3. So that's about 15% growth in unique prescribers during Q4. So you can think about that in terms of the trajectory that we are ending the year with. Importantly, also, now we have the commercial infrastructure in place, where with very modest investment in that -- very modest incremental investment, we can support the launches of 2 additional TIBSOVO indications between now and 2022 in myelodysplastic syndrome and cholangiocarcinoma, which I'll talk about in just a minute. Because that commercial infrastructure is already in place. The potential for TIBSOVO in acute myeloid leukemia is very much ahead of us in terms of the largest patient segments within this disease. You can see how the market breaks down on this slide, it's showing the numbers for newly diagnosed acute myeloid leukemia patients. We know the incidence rate of IDH1 mutation is 6% to 10%. Our current approvals are in monotherapy only. And these are some data points from our Phase I updated data, and we have the trials ongoing for the Phase III programs to move into the intensive therapy eligible patient population as well as the nonintensive therapy patient population. And those numbers are going to allow us to access a much broader number of patients across the AML disease as those trials enable label expansions for the product. So we're looking forward to continuing to run those trials. In the solid tumor space, we have a very concentrated effort. We are bringing IDH inhibition to solid tumors. We have a positive Phase III trial readout already for cholangiocarcinoma, and we'll talk a little bit more about that in a moment and next steps. And we initiated our glioma trial of our pan-IDH inhibitor, that's brain penetrant, vorasidenib, before the end of last year, which was one of our 2019 corporate goals. And so you can see the patient numbers there that we will be able to access as we get label expansions for those indications. We also have our novel biology, MAT2A inhibitor for MTAP-deleted tumors, in combination trials being studied now in combination with taxanes. And I'll show you a little bit of data related to that in just a minute. But those would allow us to take that drug into more patients than we are in today, clearly, in a -- with very novel biology that we think is worth investing in and seeing where we can go with that. And you'll hear more about that in just a minute. We're showing you patient numbers here just for the U.S. because that's the data sources that we have, the best supportive information for. We expect about the same numbers of patients in Europe. With respect to the cholangiocarcinoma trial, next steps are that we are waiting for the overall survival final data readout, which we should have in the middle of this year. The primary endpoint of PFS was highly statistically significant with that result and hazard ratio of [ 0.37 ] in second line and greater cholangiocarcinoma. This is a disease for which there are no approved therapies and the patients' prognoses are not good at all. So we look forward to filing that this year and taking that forward. We think that though there are different diseases, we now have clear proof-of-concept of the mechanism of IDH inhibition and IDH mutant solid tumor cancers. So we are quite excited that our trial of vorasidenib in low-grade glioma initiated before the end of last year, and we look forward to enrolling that trial over the course of 2020 and moving it forward and bringing that solution to patients. You can see some of the earlier stage data on this slide and why we're optimistic about where this medicine may be able to go in this disease, which still has high unmet medical need. For our MAT2A inhibitor, those of you who were at the Triple Meeting back in November would have seen the presentation of our Phase I dose-escalation monotherapy data. That data, combined with some very compelling preclinical work has supported the rationale for us taking the drug forward in combinations with taxanes in both non-small cell lung cancer as well as pancreatic cancer. Here in a long preclinical model, you see very impressive tumor growth inhibition from the combination, which performs significantly better than either of the monotherapies. We are excited about this program, it's novel biology, it's also high risk. These are the kinds of things that we're trying to tackle by bringing innovative therapies to market. And frankly, I'll look at this from an investor standpoint is almost a free call option on this program in our pipeline where we are today, but it's giving us some very interesting data around the biology of this mechanism. When we look at the rare genetic disease space, we're extremely excited about this at Agios as we move into 2020. We're excited about everything that we do, but we're particularly excited that our science is taking us into the nonmalignant hematology space with what we think is a unique mechanism of action to treat serious blood disorders in the rare genetic disease arena. Our pyruvate kinase reaction activation program, we think, represents a unique mechanism of action that can coexist in various hemolytic anemia indications with other drugs that are coming to market and will come to market over time. We like the profile of small molecule modalities for the treatment of these diseases with oral-convenient safe therapies for patients who may be on drug for a very long period of time. Our molecule mitapivat activates both our works on mutated PKR and also activates wild-type PKR, which is going to allow it to play in a broad range of hemolytic anemias. And we'll look at that a little bit more in just a minute. Our first indication we expect to be in pyruvate kinase deficiency. It's a rare blood disorder, and you can see some of the data here. We have patients with the updates from our Phase II program that have now been on drug for over 3 years and since seeing sustained increases in their hemoglobin levels and favorable responses in other markers of hemolysis. We are very encouraged by those data updates as they've happened over time from our Phase III -- II program in terms of the readout for 2 Phase III trials this year in the transfusion-dependent and nontransfusion-dependent setting of pyruvate kinase deficiency, which will be, again, our first indication. This disease brings significant comorbidities for the patients who are living with it, irrespective of their transfusion status, burdens from iron overload and there are no approved therapies for the treatment of this today. At ASH this year, we presented early proof-of-concept data from our thalassemia Phase II program. We look forward later this year, around the middle of the year, to presenting that full Phase II data set. We had a really strong response rate, 7 out of 8 evaluable patients with a mean hemoglobin increase of 1.76, where we had a target of seeing at least 1. Very excited about this. The safety profile of mitapivat has been consistent with that from previous trials, and we look forward to presenting that data to you in the middle of the year and finalizing our clinical development plan to move as quickly as we can with quality to take mitapivat into thalassemia, where we need more treatment options. The activation of wild-type PKR, also for this molecule, will allow us to move into sickle cell disease. Through a unique mechanism, we can move the oxygen saturation curve to the left. And because the mechanism is different than other products coming to market, we're confident in mitapivat's ability to co-exist in the treatment choices for this disease. We will have proof-of-concept data, working with our partner, investigator at NIH by the middle of this year, and look forward to presenting that data to you and working on our clinical development plans for the drug in this disease as well. So when we look at mitapivat's potential to play in a broad range of hemolytic anemias, you can see the patient numbers up here where we're starting in the rare category and then moving drugs -- the drug forward in thalassemia and sickle cell disease, where we can potentially address a very large number of patients with a unique mechanism of action. We're quite excited about this. The program has been ongoing for a few years, and we're on the brink of a big breakthrough with that, with the readout of our 2 Phase III trials and then moving forward to file for approval for the drug, get it on the market and then expand the label in these other indications over time. So with respect to our 2020 specific milestones. We talked about TIBSOVO U.S. revenue guidance that we're giving for the first time. You can see a number of our key milestones that we expect over the course of the year from a chronological standpoint. In the first half of the year, we expect to move our next-generation PKR activator. So we want to have a program for this mechanism that has multiple medicines in it with optionality across multiple indications. We will move that drug into the clinic in the first half of this year. I mentioned that we expect overall survival data from our cholangiocarcinoma Phase III second line trial around the middle of the year, and then we'll be moving forward to file that sNDA. We also expect to present the proof-of-concept data for thalassemia and sickle cell disease around the middle of the year. So you can see that the catalysts are spread out over the course of this year. And then the other milestones, on the slide here, will all occur around the end of the year with respect to geographic expansion for our label of TIBSOVO in Europe, completion of our AGILE trial that addresses the nonintensive therapy patient population in AML and completing enrollment in the MDS arm of our Phase I study. So lots going on. We also will move a new development candidate into -- along through our research organization. And we're, again, not only excited about 2020, we're very optimistic and we feel like we have line of sight to how with internally developed -- all internally developed molecules coming out of the Agios scientific platform, we have programs in the clinic in human trials today that will allow us to achieve these accomplishments in 2020 and over $1 billion of revenue -- sorry, in 2025 and over $1 billion of revenue, at least, by 2025. And there are some things that are not included in our estimates of that number of over $1 billion of revenue, including revenues for thalassemia, sickle cell disease, and no meaningful revenues for glioma either as we have those assumptions very late in our 6-year time frame in terms of when those would actually get approved. So we see significant upside potential to where we can be with -- our company in 2025, and we wanted to put some stakes in the ground today. This is all independent of business development activity or any of those sorts of things. So thank you very much for listening today. We look forward to seeing you in our breakout session for Q&A, and we hope you're just as excited as we are. Thank you.

It's in the Olympic Room.

Olympic Room because we're Olympians. [Break]

[Audio Gap] Sure. So to my far left we have Darrin Miles, who is our Senior Vice President of sales and marketing, the whole commercial organization globally and specifically for the U.S. market; Chris Bowden is our Chief Medical Officer; Andrew Hirsch is our Chief Financial Officer. And I think I'm going to moderate the questions a little bit and hopefully people know who I am.

Jackie, towards the end of the presentation you talked about Vision 2025 and kind of what's included and what's not included in the base case. So can you just go over that again on what's included in the base case scenario?

And you're talking about what I said about revenues? Or...

Yes.

So again, we didn't -- when you look at -- if you go back and have time to look at the high level pipeline slide that shows the programs that are ongoing in the clinic for each 1 of the 3 areas of focus, we have little green diamonds on there for when we expect approvals at the latest. And -- so the notable things that I would highlight there with respect to how you then dovetail that to a revenue model are related to thalassemia, where we just -- we put the diamond in 2025 simply because we haven't finalized the pivotal clinical development plan for it. We think already, based on what we've seen with our program, and we can let Chris elaborate on that if we'd like, that 2025 would be the latest that we would have an approval in thalassemia for mitapivat. And then also on that slide we also have the glioma approval in 2025, which is the latest we would expect that. And you would see the sickle cell milestone that we have on that slide is around having the proof-of-concept data the middle of this year and then working to finalize that clinical development plan. So the only thing we showed on the slide was the milestone for this year of having the proof-of-concept data in sickle cell disease and then we'll figure out what the clinical development plan looks like. So from a revenue forecast standpoint, and that's why we haven't put a specific number on it yet, but we think that we can be north of a $1 billion in 2025 with what we know today without revenues from thalassemia, sickle cell disease, or any meaningful revenues from glioma given our assumptions around the approval timeline. So we would -- we're going to have significant growth in revenues when you look at CAGRs from here to 2025 and then potentially a very steep inflection point after that as we get approvals in those other indications where the patient populations are quite significant. Did I miss anything?

No.

Can you speak to...

Do you guys want him to use the mic or no? I don't know how you're set up. I'll repeat the question.

All right. Is there any interest in going outside of hemolytic anemias for a minute? It could be for myelofibrosis or MDS?

So I think in the first wave of this, we know where we want to go with the mechanism. What we like about our PKR activation program across both mitapivat and the follow-on molecule 946 is we have a lot of optionality for how we potentially take those things forward. Now we're also going to let Chris jump in maybe, but we're also mindful of being efficient with our capital utilization and being able to be differentiated first, best, and think about the appropriate way to do that and whether we would partner on any indications or not. And so I think it's early days because we are just now on the brink of having more significant data to support the drug's utility in a variety of indications we are going to figure out how to best prioritize those.

And the think I would add to that is just to reiterate the point that Jackie made in her presentation, which is that thalassemia trial provides clinical proof-of-concept that activating wild type PKR has the potential to convey clinical benefit. So the answer to your question is we definitely want to think much more broadly and what we're talking about today are that strategy of any wild type PKR, but what we're talking about now are how that translates into some real tactics that you can hang on to in terms of how we're thinking about the next wave of clinical development. But certainly our research folks are thinking through other mechanisms and the way we might apply this drug even more broadly.

We're excited about it.

A question on the $105 million to $115 million to sort of a guidance for the year. Maybe you can help us understand what are sort of the levers in there that you are considering in terms of scripts rather than terms of consumption around duration of therapy. Trends there [indiscernible]?

Sure. So the number -- we expect to end what we have disclosed is just what Q4 is, yes -- is. If you assume that consensus is accurate, it represents about 85% growth going into 2020. The majority of that growth still coming from the AML indications and largely out of the immunorefractory setting. But it also will be our first full year in the frontline setting. And we've seen some nice adoption over the course of the year. And the biggest driver for revenue is duration, as you would expect, the multiple over that of share. And we're continuing to see nice quarter-over-quarter growth in duration. What's important to note and why we're very optimistic about how things will play out for the program over the course of 2020 is that in the frontline setting, even though we focus our promotions on the monotherapy treatment, we're also seeing nice adoption or nice utilization of IVO in combination with HMA based on the Phase I combination data, the report out of MD Anderson. About half of the frontline use is in combination, which then appeals to a larger patient population and those patients will have substantially higher -- or longer duration as compared to the number of patients would be on monotherapy alone. We're also seeing combination use in the relapse setting. Again, not a focus of promotion, but the market is -- physicians are responding to the data that are being presented at Congress. So again, the largest contributor here AML, mostly relapse refractory, expect a nice bump in duration, both the frontline and the relapse setting. That's what gives us confidence in the $105 million to $115 million number.

I think in that 3Q call, you noted that the duration had improved a little bit from our 4-month to 5-month setting. So are we talking about going to the [indiscernible] duration?

Well, the additional duration hasn't reached 5 months just yet. It continues to move in that direction. There is the possibility that it could certainly exceed 5 months as you get -- as you move into the larger patient population in the frontline setting in combination use.

For those on the webcast, if you couldn't hear the question, we were talking about the commercial drivers underlying our expectations for 2020 revenue guidance and momentum coming out of Q3.

Could you set the stage for the sickle cell data set in terms of read through mechanistically from beta thal to sickle cell? And to the extent that once it works -- and let's say it works, and you can define what's a good data in terms of if it works in both of those, what does that tell you more about the mechanism that we're still learning today? What more would that teach you about the mechanism?

Can you repeat the question?

Yes. The question is to provide some additional read through in terms of proof-of-concept for -- in mitapivat in sickle cell disease. What the implications are in terms of clinical development and next steps? So the trial that's of great interest to us is being conducted at the National Institutes of Health in the sickle cell branch. It's 25 patients. It's an open-label study. Patients start at 5 milligrams, they're on drug for 2 weeks, they escalate to 20 milligrams, then they escalate to 50 milligrams. The reason why that's important, and this gets at the heart of your question, is that across those 3 doses and exposures, we'll be able to look at oxygen dissociation curves, sickling indices as well as clinical outcomes, like do we see an improvement in hemoglobin? And overall, how do patients feel, and what does the safety look like? We'll also be able to look at that against other pharmacodynamic outputs such as 2,3-DPG and ATP, which those of you who followed us know, we have looked at carefully in pyruvate kinase deficiency. So the definition of success can be across a spectrum. I think seeing really tangible impact on those pharmacodynamic markers like 2,3-DPG in hand in partnership with changes in the oxygen dissociation curve, that is 2,3-DPG goes down and we see what we would expect to see with oxygen dissociation curves. We can also measure -- we will also measure ATP, and if we were to see ATP go up and see improvements in hemoglobin, then that would be the greatest PD efficacy readout that would really compel us to move forward. However, any combination of those factors we'll have to interpret. And that's why I will make the comment that I make frequently when we talk about early stage data, which is the totality of data. The flip side would be if we didn't see any impact on those pharmacodynamic markers -- so just flat, then that's pretty clear, right? That's the black and white scenario. In the setting where we were to see evidence of pharmacodynamic modulation and/or markers of clinical benefit like hemoglobin going up, then it becomes how you're going to approach the clinical development. And I think the way we'll approach it would be if you just step back for a minute and you look at some of the drugs -- non-gene therapy drugs that are either in development or have been approved, it really breaks down into 2 groups at this point, and there's some overlap. So in the setting of global blind, you're looking at can you raise hemoglobin and that -- because that has some important implications for clinical benefit over the long term. And then if you look at the P selected marker molecule from Novartis, for example, there they're reducing the frequency of vaso-occlusive crisis, whether it's chest syndrome, hospital admissions, can you get out of the hospital faster. So there's a number of different ways that we'll have to think about approaching it, depending on what the mechanisms look like when we look at that data. We'll get that in the middle of the year. Dr. Thein is planning on submitting that data to EHA. We'll be looking at that data in front of that presentation. We're in collaboration with the NIH people as they're running the trial now. So we'll start -- we're already thinking about how the data looks and that will certainly influence the next steps that we take. I would say for thalassemia -- because we demonstrated proof of concept and we showed that data at ASH, we're off now actively developing the drug in that disease area. And we are enrolling patients with beta and alpha thal and other genotypes if you will. So our -- how that will set up? Will it be beta thal? Will it be alpha and beta, e beta? Those are all questions that need to be answered. But the real clinical context is transfusion-dependent versus not regularly transfused. And those are the areas that we have to study and go through, including kids and other aspects. So it's early, which means we have to look at everything, but since we are guiding to having pivotal plans in place that we can execute on by the end of the year, we'll start making decisions over the next several months and then start moving forward, seeing the feedback we get from regulators and then we get in that iterative cycle and then we make some decisions based on data, risk, speed, all those things. But we're really excited about the fact that this hypothesis has been realized by virtue of thalassemia. Will it read out for sickle cell? We don't know, but certainly the thal data increases our confidence that we may have something in sickle cell.

The lights came up while you were talking, so your comments were very illuminating.

It's just a -- when I joined Agios as someone who's done mostly oncology stuff, we always look to block mutated enzymes and to get into a small molecule situation where you activate a mutated enzyme and show proof-of-concept in pyruvate kinase deficiency is a really cool thing to do. And then to now actually back up a little bit so it's not really a personalized medicine approach anymore, but it works, is sort of -- not sort of, it's really the definition of following the science, and we think it has a big opportunity for patients, which will have a big opportunity for our business. So if that has anything to do with the lights, then so be it.

Couldn't have said it better myself.

[indiscernible] this year, I think you guys executed on [indiscernible] studies and what -- can [indiscernible] evolving based on how [indiscernible] the curve [indiscernible]?

I think what we can...

Can you repeat the question? So...

Oh, yes. So the question is, can we glean anything from epidemiology as a function of how accrual and study conduct has progressed? So you want me to start or...?

I'm happy to address it. You're asking, are we learning either lesser or more patients than we originally assumed in this sort of setting. The -- what about the clinical trial setting because you have to be able to meet certain eligibility criteria and all of that. But in terms of just patient finding work, right? So a lot of what is characterized as a rare disease treatment like this is having to do -- having to literally go out, educate on the existence of the disease and help to improve the diagnosis of those patients. And so over the last couple of years, the team has had our feet on the ground, actually out connecting with customers who then have identified patients who have since been diagnosed with pyruvate kinase deficiency. To date, we've identified 800 patients between the U.S. and the EU. And I think in addition to what we have enrolled in our clinical trial setting, we have well over 1,100 patients identified. So it's important to note, I think that what we've provided in terms of our range on the [indiscernible] is between, I think, 3,000 and 8,000 patients. So we've -- on the low end, we've identified at least 1/3 of what we believe to be the prevalent population for PKD. We're going to actually increase the amount of resources that we're dedicating to that work over the course of this year as well as we ramp up towards approval. So the -- have we learned something? Yes. We've learned more about where the patients are, we've learned what's effective in terms of being able to help the community identify those patients. We've also continued to focus on our diagnostic work. If you go to knowpkdeficiency.com -- I always have to tell it to marketers, so I have to tell that website, you'll learn more about the work that team is doing in terms of supporting testing in the community and the peak registry that we'll -- so we'll continue to do that work leading up to the approval and post the approval. I would also note that -- your question is around, have you learned anything over the last year or 2. I think it was last year, the output of the International Working Group dedicated to, again, helping the community to better -- to align on a firm understanding of the disease and diagnosing and treating patients published there, I think it's a treatment consensus document, which reflected their suggested treatment algorithm or diagnosis and treatment algorithm for PKD. I think it's -- [indiscernible] published it 20 -- I think it was 2019. And so that's the sort of work that we've been supporting either directly or indirectly to help the community to get a better handle on it and to help us better understand the actual prevalence of the disease.

Yes. I think to have identified that number of patients at this stage and where we are with the program, gives us a great degree of confidence in that range that we've put out there for the epidemiology.

Yes. I've got an email question here, which is, how do you think about competitive Venclexta over the next several years?

Happy to take it on. So Venclexta is a good treatment. I'm glad there are lots of new treatments for patients with AML. The -- I think the key thing for us is to compete most effectively with Venclexta in the frontline setting is to be able to build on the combination data that we've reported thus far between IVO -- IVO in combination with azacitidine. So that's the AGILE trial, which we've targeted to fully enroll by the end of this year. So far, I think we're holding our own pretty well relative to Venclexta. Remember, our approval for monotherapy is based on response rate, duration of response and clinical benefit. And our strategy has been focused on those patients who had been previously treated with HMA or antecedent disorder like NDS/MPN or those patients who have been unwilling or unable to deal with the heme tox associated with HMA-based regimens. So -- and that's been working thus far, right? So in the IDH1 population -- newly diagnosed population, IVO -- the TIBSOVO-based regimens are the most preferred regimen for that population. So we've been holding our own. And then we'll simply build on that as the aza combination data continue to mature and be reported out.

At -- if I could just make one statement. At ASH this year, for the first time, we got to make some cross-trial comparisons of TIBSOVO plus azacitidine versus venetoclax plus HMAs. Because for the first time, the venetoclax data broke out IDH1 mutant from IDH2 mutants. So I won't go into the numbers here, but if you look at our CR rates, our duration of response, most of that data in a similar population, but yet it's a cross-trial comparison, looks better than the outcomes when you add Venclexta to azacitidine. And -- so that may be -- qualitatively one of the things that happens in the clinic, is that this combination of TIBSOVO and azacitidine has its own set of safety issues that one has to pay attention to, differentiation syndrome; QT prolongation. And on the venetoclax side, you have myelosuppression and those things you have to deal with. So then you start to ask, well, what's the clinical -- what's the therapeutic index look for these combinations. And I think our data that we've been very excited about numerically, I think, clinically is definitely holding its own. So that may be part of this as well.

There's one other thing to add to that. The -- there's also a great deal of excitement around more novel rational combinations like TIBSOVO plus Venclexta, plus or minus azacitidine. So last year, according to Nardo, disclosed -- put up some preliminary clinical data in -- for a combination and the relapse of ivosidenib plus Venclexta in the relapsed/refractory setting. She's since expanded that study to move into the newly diagnosed setting and adding the doublet on top of azacitidine as well. So as it typically plays out in oncology, you're usually going to head into the best efficacy that you can achieve for patients. Oftentimes, it's going to come in combinations and a series of combinations and it may well be this doublet or triplet in the frontline setting as well.

Any final questions? Okay.

Thank you very much.

Thank you.

Thank you.