Good morning, and welcome to Agios' Fourth Quarter and Full Year 2019 Conference Call. [Operator Instructions]. Please be advised that this call is being recorded at Agios' request.I would now like to turn the call over to Holly Manning, Associate Director of Investor Relations.

Thank you, Operator. Good morning, everyone, and welcome to Agios' Fourth Quarter and Full Year 2019 Conference Call. You can access slides for today's call by going to the Investors section of our website, agios.com. With me on the call today with prepared remarks are Dr. Jackie Fouse, our Chief Executive Officer; Dr. Chris Bowden, our Chief Medical Officer; Darrin Miles, our Senior Vice President of U.S. Commercial and Global Marketing; and Andrew Hirsch, our Chief Financial Officer and Head of Corporate Development.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 forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent Form 10-Q filed with the SEC and any other filings that we may make with the SEC.With that, I will turn the call over to Jackie.

Thanks, Holly. Good morning, everyone, and thanks for joining our fourth quarter 2019 results call. I took on the role as CEO at Agios a year ago, and at the time, I was excited about the work the company does and our ability to make a meaningful difference in the lives of patients. Today, I'm even more excited with where we are as we go into 2020. I've spent the last 12 months listening and learning from my colleagues, supporting the execution of several notable firsts for the company and evaluating ways to build on our past successes and further focus the business to create value for patients and all of our stakeholders. I have more confidence than ever about the quality of our science, the strength of our team and our impressive portfolio of preclinical, clinical and commercial programs that is truly differentiated.It is with this excitement and confidence that we rolled out our 2025 strategic vision in January, sharing for the first time what the company could look like as our portfolio progresses over the next 6 years. By the end of 2025, we expect the company to have four marketed medicines, all discovered and developed at Agios, generating at least $1 billion in product revenue from at least 8 indications across our three focus areas of hematologic malignancies, solid tumors and rare genetic diseases. We'll have six or more molecules in the clinic, 4 of which will be entirely new molecules generated by our internal research discovery engine, and we will be cash flow positive within the six year time frame.This long-term vision was built on the foundation of our 2019 achievements and our existing clinical and late-stage preclinical programs. Within our base case plan, I also think we have tremendous optionality and an opportunity to potentially exceed our goals. Our steps on the path to 2025 are already underway with an ambitious set of objectives we set for 2020 across our malignant hematology, solid tumor and rare genetic disease programs. In fact, this is one of the most compelling aspects of our 6-year vision. We have significant milestone events occurring every year over the next 6 years. My colleagues will discuss our programs and objectives in more detail in a moment.Before I wrap up, I'd like to publicly welcome our new Chief Scientific Officer, Dr. Bruce Car, who joined Agios last month. Bruce, together with his scientific leadership team, will be ushering the next wave of programs from research to the clinic to help us achieve our 2025 vision, and we're excited to have him on board during this pivotal time. We look forward to having Bruce join us on future results calls.With that, I now turn the call over to Chris to provide our clinical and regulatory updates.

Thanks, Jackie. Underpinning our 2025 aspirations are multiple early and late-stage clinical programs, spanning hematologic malignancies, solid tumors and rare genetic diseases, and in 2020, we aim to make meaningful progress across each of these therapeutic areas.I'll start with rare genetic diseases, where we expect to have several important milestones for our PKR activation program across 3 different hemolytic anemias in 2020. Our initial area of focus is pyruvate kinase deficiency where mitapivat activates a mutated PKR enzyme and has the potential to be the first disease-modifying therapy for this chronic anemia, which currently has no approved treatment options. We are conducting 2 pivotal studies of mitapivat in PK deficiency. The ACTIVATE-T study is in regularly transfused patients, and the ACTIVATE study is in patients who do not receive regular transfusions. Enrollment is now closed in both studies, and we plan to share top line data by the end of the year. In addition, we are moving forward with our plan to study mitapivat in pediatric PK deficiency patients. Through our regulatory interactions and advisory boards, we are confident in our ability to advance mitapivat in this patient population, and we expect to initiate a clinical trial in 2021.In 2019, we expanded the clinical application of mitapivat into thalassemia and sickle cell disease, where it has the potential to provide therapeutic benefit by activating wild-type PKR. In December, we announced achievement of proof-of-concept in the ongoing Phase II thalassemia study where we demonstrated treatment with mitapivat induced a hemoglobin response of greater than or equal to 1 gram per deciliter in 7 of 8 evaluable patients. Additional data from this study, including data from patients with alpha thalassemia, in addition to beta thalassemia, will be submitted for presentation at the European Hematology Association Congress in June. We are actively developing…

Thanks, Chris. I'm pleased to share our fourth quarter 2019 results as well as our first full year of product revenue since launch in mid-2018. In the fourth quarter, we recorded $20 million of net sales of TIBSOVO, bringing total 2019 TIBSOVO net sales to $60 million. Fourth quarter growth was largely driven by continued uptake in both the relapsed-refractory and frontline AML settings and continued expansion of the unique prescriber base by 15% over Q3. Our market research continues to show that TIBSOVO containing regimens are the most preferred treatment for newly diagnosed and first relapse AML patients with an IDH1 mutation.Looking ahead, we've guided to 2020 U.S. TIBSOVO net sales of $105 million to $115 million, which represents an approximate 80% increase at the midpoint of our range over 2019. We expect to see continued growth in both the newly diagnosed and relapsed-refractory settings. To date, the largest driver of revenue growth is increasing treatment duration, which we're observing across both AML labels. Though not promoted by our team, roughly half of both newly diagnosed and relapsed-refractory patients treated with TIBSOVO, are treated in combination, primarily with a hypomethylating agent. We anticipate this will continue to have a positive impact on average duration, which we expect to settle close to the 5-month mark by the end of 2020.Moving to rare genetic disease. Our team is expanding our prelaunch efforts in anticipation of the potential approval of mitapivat late next year. As we shared in January, we've already identified approximately 1,000 PK deficient patients in the U.S. and EU5, and we continue to work on driving patient identification, increasing disease awareness and improving testing for this serious chronic anemia. This work is driven by our existing global medical affairs and marketing teams. And over the course of 2020, we'll begin to build a modest field team to support our market development efforts. I want to thank the tremendous team at Agios who've been the driving force behind our success in 2019 and laid the foundation to support many more patients in 2020.I'll now turn the call over to Andrew to discuss our fourth quarter financials.

Thanks, Darrin. Our fourth quarter and full year financial results can be found in the press release we issued this morning, which I will summarize. More detail will be included in our 10-K filing next week. Total revenue for the fourth quarter was $35 million, bringing total revenue for the full year 2019 to $118 million, an increase of $23.5 million compared to 2018. Product sales of TIBSOVO grew $46 million year-over-year, offset by a decline in collaboration revenue due to the recognition of a milestone from Celgene and the upfront payment from CStone totaling $27 million. Cost of sales for the fourth quarter was $287,000 and $1.3 million for the full year 2019.Turning to operating expenses. R&D for the fourth quarter was $106 million and $411 million for the full year 2019, an increase of $70 million compared to the full year 2018. The year-over-year increase in R&D was largely driven by clinical trial activity for mitapivat in PK deficiency and thalassemia, start-up costs for the vorasidenib Phase III INDIGO study in low-grade glioma as well as required clinical pharmacology studies and companion diagnostic work, ongoing recruiting efforts in the TIBSOVO Phase III AGILE and HOVON frontline AML combination studies and ongoing research efforts across our discovery platform programs.Selling, general and administrative expenses were $35 million for the fourth quarter and $132 million for the full year 2019. This represents an $18 million increase over full year 2018, driven primarily by increased investment in marketing activities in preparation for the potential launch of mitapivat and personnel costs related to increased headcount to support our growing operations.We ended the quarter with cash, cash equivalents and marketable securities of $718 million. We expect that this cash balance, in addition to expected product revenue, royalties, and anticipated expense reimbursements under our collaboration and license agreements, but excluding any additional collaboration related payments, will fund our operating plan through at least the end of 2021.With that, operator, please open the line for questions.

[Operator Instructions]. And our first question is from Mohit Bansal with Citi.

Great, and congrats on the progress. Couple of questions from my side. One is on your TIBSOVO European filing. Could you please help us understand, is there anything different with TIBSOVO versus IDHIFA, which could make -- or give us a little bit more confidence that TIBSOVO filing has enough data to satisfy EMA at this point? And then I have a commercial question on PKD.

Mohit, it's Chris Bowden here. Thank you for your question. So I think there are some pretty important differences between the enasidenib data set in our approach and what we're doing with TIBSOVO. So from the Celgene BMS perspective, they decided to withdraw after not being able to fully meet the questions from the MAA and from the EMA. They also have a Phase III study in relapsed-refractory disease in the indication they're seeking.So their view was they would withdraw the application and then reconsider what to do once they have the readout from IDHENTIFY. So that's a pretty important aspect because the frequency of the IDH1 mutation is pretty low overall. And then when you start to cut that down in the relapsed-refractory disease, one of the things that we found out pretty early on that doing a randomized trial was not feasible. So our arguments in terms of how we're framing this is that this is the best data set that we're going to get in this rare patient population. And therefore, given the unmet need and the fact that these patients have used up all, they really don't have any other treatment options. We think we have a different and strong argument there.And there are some other important aspects of the submission that we're emphasizing as well. We've been able to go in and tap real-world data outcomes from a number of European data centers, and we think that could play a pretty important role in terms of ascertaining risk benefit. And then one other aspect that we think is pretty important is that there's some data indicating that IDH1 mutations have a poor prognosis, and certainly, patients with IDH1 mutation seem to do worse than patients with IDH2 mutation in the relapsed-refractory setting overall.So that's not to say that it's not a challenge when you submit a non-randomized data set to the European, but we think there's some important differentiators. And that's why we're pushing forward and remain optimistic that we're going to have a positive outcome. But we'll see that as we move through the process. And as we've guided to previously, we don't expect the decision until the second half of the year.

Got it. And then -- this is very helpful. And then on the PKD side, I think, Darrin, you mentioned that you have about 1,000 patients identified. So one part is, can you please help us understand how much is this U.S. versus Europe? And what sort of challenges do you see to get to the 3,000 to 8,000-patient mark you are citing in your slide?

Absolutely, absolutely. So it's roughly half and half between U.S. and ex U.S., the majority of ex U.S. being in EU5. The -- I think the challenge always with disease on this end of the rare disease spectrum is getting a firm hand on the actual prevalence number. So the reason that we're increasing our field team is to focus more effort on being able to accelerate that. We've been successful over the last year plus. We expect to accelerate that quite a bit over the course of 2020 and expect then to have -- to be able to document perhaps twice the number by the time we get to approval at the end of 2021.

Our next question comes from Kennen MacKay with RBC Capital.

Congrats on the quarter and the execution. Maybe one for Chris first and then a follow-up for Jackie and Andrew. For Chris, on MDS and the breakthrough designation there for TIBSOVO, could you maybe help us a little bit on the time lines associated with the Phase I expansion and the potential for registration filing there? And also when that data could be presented?And then for Jackie and Andrew, I love the Dave Root's style pointing at the bleachers and the $1 billion guide by 2025. Can you maybe give us a little bit of background on the decision to put that aspirational figure out there and also help us with, so to speak, the contribution of components of that figure? And congrats again.

Okay. Kennen, it's Chris here. So we're in that all important phase of getting sites up and running and moving the amendment through because many of the sites that have been participating in that important 001 study for us are just going to reactivate that amendment with the MDS cohort in there. So that's a really key part of what we're doing at this point. And -- so that operational aspect as well as the kinetics of patients coming in and being identified and getting onto the trial will really determine the time line and when we can publish data. I think people are pretty comfortable with certainly using TIBSOVO in MDS, but I will remind you that the frequency of the mutation is around 1% to 3%. So we're optimistic we'll be able to accrue by the end of the year. And as we get close -- as we get more confidence around that, that -- and the year progresses, that will give us some sense of when we can publish and talk about the data, which we're really looking forward to doing.

Kennen, thanks for the question. I did play both fast pitch and slow -- I mean, yes, fast pitch and slow pitch softball. So the analogy is a good one, I guess. So the -- with the vision on the whole, including the $1 billion at least of revenue, we -- in 2025 -- by 2025, we wanted to put some stakes in the ground. It's not only around the revenue, but it's also around the indications that we could be, the number of programs that will be in the clinic. And the reason why we wanted to put that out there is because we see the potential to achieve those things with assets that we have in our hands now that are either on the market already. So talking about TIBSOVO or in the clinic. So these are de-risked assets by some definition of de-risking.When we think about the revenue number in particular, that includes substantial contribution from the ongoing evolution of TIBSOVO in AML. It would also include cholangio, and it would start to include some revenues in PKD from mitapivat. Most importantly, I think what it does not include would be thalassemia, sickle cell disease, glioma because all of those in our assumptions are very late in that 6-year time frame, and we have not assumed anything in there for the potential to negotiate something with Bristol around IDHIFA, just to make that very, very clear.

And our next question comes from Alethia Young with Cantor.

Congrats on the progress over the past couple of months. Maybe two from me since we're following this trend. Can you maybe help us think about the differences between alpha and beta thal and like maybe -- is there any kind of rationale to believe the efficacy should be different in one versus the other? And then the other one probably is for Jackie, and I just wanted you to kind of -- since it's been a year, just kind of reflect on how you think about where Agios is like R&D organization was a year ago when you joined versus where you're taking it and sort of maybe weave a little bit of thoughts and about your potential -- your new hire of CSO as well?

Okay. Alethia, it's Chris. I'll go first. There's the genotype and some of the molecular distinctions around thalassemia that can be important in terms of clinical outcomes and potentially a molecular approach. From our perspective, given that we're activating wild-type PKR and looking to improve overall red cell health, we -- I would say that we're likely to see -- we don't think there should be discernible differences, but that's one of the reasons why we're enrolling those patients, and we have a number who have come in now because we need to answer that question.I think the key distinction for thalassemia is likely to remain in our view of transfusion-dependent versus not regularly transfused. Those are really important clinical regulatory pieces. And the alpha thalassemia part for us is, at this time, a point of differentiation because most of the data -- clinical data that's been generated from other molecules out there has been in beta thalassemia, and clinicians have told us this is an important group as well because they do fall into both of these categories on transfusion and transfusion-dependent and have a high unmet medical need given their underlying disease process.

Alethia, so thanks for the question on R&D and our new CSO. We're very excited about where we are with things. I think at a very high level, I would just like to point out that of our roughly 550 employees, about 400 of those are spread across, what we call, our RDS or research discovery sciences group and our clinical group. So that shows you what the emphasis is that we have here on both early and -- early research and late-stage clinical development, and that has not changed. I think if we go back and look at the track record of Agios in terms of bringing innovative science to the diseases that we're targeting to treat, we've brought IDH inhibition to hematologic malignancies and now into solid tumors, and now we're bringing our PKR activation science along with mitapivat and the next-generation 946 molecule that we'll file the IND on soon. And those are tremendous accomplishments.So when we talk about this platform in cellular metabolism, the company certainly has delivered on that and will continue to deliver on that. And I think we're doing that in a very focused way. We -- innovation comes in ways. Will all of you want us to move faster? Yes, you will. Do we? Yes, we do. We want to do that with quality. But I think that's, again, back to the question about the 2025 vision. One of the reasons why we want to put stakes in the ground is we've made a lot of investments up to this point and where we are with the portfolio. I think we're just in a terrific position to deliver some amazing things for patients and some great things for our business model over the next 6 years.When Scott Biller joined the company almost 10 years ago, and I think we thanked him on the last call that we had -- there were a handful of scientists here that RDS team now led by Bruce has about 160 to 170 internal Agios' employees. And I think Scott did a terrific job. One of the things that he did was institutionalize some of the ways that we prosecute the science here, and he built a great team, and now we're very much looking forward to Bruce's fresh set of eyes on things and the contributions and experience base that he is going to bring. So I think it's quite an amazing achievement to have put -- we're about to put our eighth molecule internally discovered into the IND filing and everything that we've got. And that vision out to 2025 is internally discovered at Agios, and we want to continue to build on the things that we're really good at and do that maybe a little bit more focus on a go-forward basis even.

Our next question comes from Anupam Rama with JPMorgan.

Just two quick ones from me. For AG-946, how are you thinking about the long-term PKR franchise and maybe remind us of any pharmacologic differences between 946 and mitapivat? And with thalassemia, sickle cell coming midyear, how are you thinking about the long-term development of 946? And then a quick one, just a clarification point. So the press release was very specific about thalassemia data being at EHA, but sickle cell was noted to be midyear. So should we think about the sickle cell update sort of outside of the scope of the conference at this point?

Anupam, it's Chris here. Thanks for the questions. We anticipate and make sure that the sickle cell data will be shown at EHA. So it's a double feature, thalassemia and sickle cell. The sickle cell trial, as we stated, is sponsored through a CRADA agreement with the NIH. So they will be -- we'll be certainly collaborating them and providing with input, but it's an investigator-sponsored study, if you will. So now then 946, a particularly interesting clinical development issue for us because we've got a drug in mitapivat now that's been in the clinic for several years, and we provided the community with updated data at ASH from DRIVE PK and looking at stability of hemoglobin and safety.So now along comes our follow-on molecule AG-946, and what decisions and how do we think about the next wave of development for that molecule should it pass muster and healthy volunteers and have a safety profile and other aspects that make it a compelling option to move forward into clinical development. So that's really looking across all 3 diseases we'll need to think about that. And then that gets into some of these pharmacological differences that you've asked me to comment on. So in pyruvate kinase deficiency, the drug has the potential to have a broader spectrum of action against some of the mutations that are missense mutations that mitapivat hasn't been active again. So it could broaden the spectrum of activity.There are some other aspects that we think it may have potential to be once-daily dosing and be a more potent activator of wild-type. So that would then daily dosing could be a convenience factor across all 3 indications and a more potent activator of wild-type could translate to some increased efficacy should we in -- whether it's in thalassemia or sickle cell if we demonstrate proof-of-concept there. What -- ultimately, what the steps are and how you develop it as a follow-on, a replacement what have you really is way too early to go there. And like we say all the time, it would be a data-driven decision combined with what does mitapivat look like in any of these indications at the given point in time when you start to make some of these decisions, how is the market evolving. So a whole slew of things.

Nice to have options.

Yes.

Our next question comes from Alexander Duncan with Piper Sandler.

Just wanted to ask a follow-up question, your thoughts on working with the EMA. Does the IDHIFA MAA situation change your thoughts on how to approach pipeline development in oncology in the way you maximize the ex U.S. opportunities?

It's Chris here. I'll take that one. I don't think so in the sense that when we put the IDH inhibitors into the clinic back in 2013 and 2014, we saw immediate evidence of clinical benefit in a very high unmet need population. And with both of those molecules, IDHIFA and TIBSOVO, we stated and we did move very quickly because our interactions with the FDA, with investigators around the world indicated this is a therapy that could change patient outcomes in the relapsed-refractory setting and that it had the potential to improve clinical benefit dramatically for 20% of patients with AML, if you combine IDHIFA and TIBSOVO IDH frequency overall. So those are the underlying drivers.Do we understand that when you take a non-randomized single-arm data set into other parts of the world that you will encounter some significant challenges, more so than the challenges we encountered in our submission in the U.S. with FDA? Of course, we do. We did way back when, take a look very carefully or should we do a randomized trial in relapsed-refractory IDH1 AML patients, and we looked at it really hard, and we said this isn't feasible. The best use of our resources and the chance to have the greatest impact for patients is in the frontline setting. So that's how we focus. And I would guess, qualitatively, we would do the same thing all over again. And when these opportunities come up, we'll continue to operate this way.

Our next question comes from Chris Shibutani with Cowen.

If I could ask two questions. One, a little bit more concretely, appreciate the guidance for TIBSOVO in 2020. Recalling last year, the first quarter, we perhaps saw a little bit more seasonality. I think you guys reported that, and we saw this across other category. We're about halfway through the quarter now. Can you comment about how we should be thinking a little bit about the quarterly trends and, in particular, was what we saw last year with that seasonality and the sort of donut hole effects, et cetera, and payer support and patient support programs a continuing trend this year? And then I'll have a follow-up.

Chris, this is Darrin. Yes. So we assume that when we set the guidance for this year, that we would see a similar trend as we saw in Q1 last year. We've actually enhanced our patient services support to be able to try to get ahead of it as much as possible, particularly emphasizing with practices that need to check in with their patients given the likelihood that the patients may experience an updated or a change in their overall benefits -- benefit design and potential cost share, patient cost burden. So yes, to answer your question, we've assumed a similar impact in 2020.

Great. And then we're naturally looking forward to the mitapivat data at EHA. Can you just remind us after the ASH debut of the data in thalassemia? I think there was about 8 patients. Give us a sense perhaps for the number of patients and potentially any kind of durability that we might be able to expect when the data is presented at EHA? And would there be any advanced sort of abstract type information that would make that result available prior to the meeting itself?

Our abstract, we will write in a manner that gives us the highest chance of getting a spot and getting admitted to the meeting. So I really can't comment on what details will be in there. It will certainly become forthcoming when they're released. Accrual is going well, and we anticipate that we'll get -- we'll finish accrual of 17 patients before we get to EHA. And so you'll see additional data, new data on alpha-thalassemia patients, and then we'll certainly be able to talk about the overall duration of follow-up, and that will give you some sense of how durable the hemoglobin responses are, how they evolve over time. So I think that this would be really the first time we're presenting data for mitapivat in thalassemia. So we intend on providing a pretty comprehensive overview for people from an efficacy, safety and pharmacodynamics perspective since we think those are all important readouts.

Our next question comes from Mark Breidenbach with Oppenheimer.

Maybe two quick ones. One for Chris and maybe one for Darrin as well. First, for Chris, I was wondering if you could give us a little bit more color on the patients that are being enrolled in the NIH sickle cell trial. I'm curious if there -- if -- and a pivot is being layered on top of standard of care therapies, including hydroxyurea and maybe if we'll see any potential combinations with Oxbryta in this trial? And also, what would you define as a successful proof-of-concept in sickle cell disease?

So the patient can be on Hydrea, and that's certainly an eligibility criteria. Other drugs like voxelotor and others would not be permitted because we really want to understand the effects of mitapivat and isolate that as much as we can, and while understanding that some drugs like Hydrea are real standard of care are essential for patients. I think the proof-of-concept is what data will we need to see to declare proof-of-concept really boils down to some really key aspects. One of them is how well did patients tolerate the drug over that 6-week dosing period? What differences, if any, can we discern between the lowest dose and the highest dose in terms of safety? What does exposure look like? And what happens to oxygen dissociation curves, if anything, over those 3 doses that we test? Do we see any changes in hemoglobin? And are we able to tease out that, say, dose/exposure related effect? And importantly, can we demonstrate in sickle cells some of the effects we've been able to demonstrate in red cells from patients with pyruvate kinase deficiency or healthy volunteers or that we've been to most cleanly define our 2,3-DPG and ATP profile changes.When you go into these patients that have these various diseases, things will get a little more complicated than numero because of the red cell population, and it's a little more challenging to handle than in a healthy volunteer who has a "healthy" red cell compartment. So we are thinking through additionally a lot about the criteria for demonstrating proof-of-concept, and I think the other thing that you should be thinking about and how we'll be thinking about this is what will be the next steps for development. And we had a previous question would you go -- what aspects are you thinking on when you do more Phase II work, Phase III work, et cetera. So these are all things that will be driven by the totality of data, the number of patients we have and the duration of follow-up as well.

All right. That's very helpful. And then a quick follow-up for Darrin. Going back to the 1,000 patient -- PKD patient population that you've identified. I was wondering if you could just give us the split between transfusion-dependent and transfusion-independent patients in that group. And also, if they've been rigorously genetically characterized to confirm that they all have the types of mutations that would potentially confer sensitivity to mitapivat?

Mark, so I don't have that detail at hand. I think that's something we might be able to follow-up with the -- at this point. I think the important thing here is that we've been focusing on in both in the EU and certainly in the U.S., focusing on raising the urgency around diagnosis, offering support for testing, which is the sort of the key fundamentals that we need to have in place in order to be able to fully get to the answers for the questions that you're asking here as well. But I think we might be able to follow-up afterwards with more detail.

It's Chris here. I would just -- there's a couple of fundamentals on the disease that we don't think -- that we think are fundamental. One of them is that 80% of patients have a missense mutation. So those patients are potentially addressable with mitapivat versus that 20% who have 2 non-missense mutations. So I think that's a really important aspect of how we think about it overall. There's 300 and more mutations being described. So specific genotype, genotype that is gene A and gene B versus outcomes, something we spend time looking at. But when you think about the number of mutations, there's just a lot of unknown, unknown there.

Our next question comes from John Newman with Canaccord.

And pretty bold prediction on the $1 billion. I take my hat to you on that. Just curious, I don't think that this is the case. It didn't sound like it from your prepared remarks. But does that $1 billion target allow for the possibility of any sort of M&A? It didn't seem like it, but I just wanted to ask.

John, it's Jackie. No, there's no business development or M&A included in that. This is what we think we can deliver at least, I'll repeat at least, with what we see in our hands today with TIBSOVO and the current portfolio.

Our next question is from George Farmer with BMO Capital Markets.

I'd like to get a better understanding, maybe, Darrin, you can answer this about. TIBSOVO penetration in the AML setting in combination with HMAs and now that you're seeing some increased pickup in the combo setting. How are docs thinking about cycling between TIBSOVO and venetoclax in combination with HMA?

So I think the couple of things to maybe fully first establish. I think the -- we continue to see in our research a firm belief in the importance of targeting the target. Meaning, if you've got a targeted therapy for identifiable mutation and physicians are more inclined to want to use it. The -- I think what's important along with that is, is that there's also a firm belief in that IDH1 -- mutated IDH1 is the driver mutation in this setting and particularly in the early driver mutation. So that, I think, is what -- that, along with the clinical outcomes data are what's driving the adoption of TIBSOVO, both single agent as well as in combination in the frontline setting though we only promote to single agent use.The data that we've seen, and it's continued to improve quarter-over-quarter, suggests that it -- indicates that it is most preferred regimen about half of the overall use, both in the frontline setting as well as in the relapse setting is in combination with HMAs. Again, we don't promote it. But this -- the use is likely prompted by greater awareness of the combination data that we've updated at the congress over the last 2 years, and most recently at ASH.In terms of how they will cycle between venetoclax and TIBSOVO, I think at the end, our focus in the frontline setting for the monotherapy indication at least is in -- is focusing on those patients who have been previously exposed to an HMA. And I think we get -- we have good residents -- that message has good residents with the community there. And then as they become more aware of the emerging data in combination, they're finding it a compelling overall clinical profile that's leading them to expand their use beyond that portion of the patient population. So -- and I think at this stage, it's still sort of early days as the community begins to figure out just what are going to be their established treatment algorithms because of the influx of new treatments in the frontline as well as the relapse setting.

Great. That's very helpful. And then regarding mitapivat, how are you -- how should we think about drug activity against the mutant form of the enzyme versus the wild-type form of the enzyme? Are there any subtle differences? And are there any concerns about overshooting hemoglobin levels? I think that had been an issue in the earlier stages of development. And again, does genotype matter in that setting, do you think?

Yes. So it's Chris here. Genotype matters in pyruvate kinase deficiency. And because you've got to have protein and -- for the drug to bind and we have found that non-missense mutations as a general rule are less stable, and there's not as much protein around -- there's no place for the drug to bind because there's been a large deletion. So genotype and molecular features are really important in terms of pyruvate kinase deficiency and ability to activate the enzyme.In thalassemia and sickle cell, our approach is to activate the wild-type enzyme, the same pyruvate kinase that's in anyone's red cells if they don't have an underlying hemoglobinopathy or they don't have pyruvate kinase deficiency. Now one of the things that could be interesting is that will outcomes when you activate wild-type PKR be a function of, for instance, the type of thalassemia? Whether you have alpha or beta or the various globinopathies that can present within that disease or in sickle cell, if you're SS or your S-thal? Those will be some things that we'll be looking at.So we tend to think of these three diseases as separate. We do -- you will hear us lump somewhat thalassemia and sickle cell together because we're approaching -- we're activating wild-type PKR, whereas in pyruvate kinase deficiency we're activating the mutant form of the disease. So in pyruvate kinase deficiency, there's less ATP because of that mutated enzyme, whereas in these wild-type approaches there's a relatively -- I wouldn't say normal, but there's more ATP there we're trying to push up the ATP level so that those red cells can tolerate their underlying disease process and live longer.

And I'm not showing any further questions in the queue. I would like to turn the call to Jackie Fouse her final remarks.

Thank you, operator. 2020 is a pivotal year for Agios as we execute against important milestones across our business. We expect significant progress in our clinical pipeline for all of our three therapeutic focus areas, outstanding growth in our product revenues and continued productivity from our research engine with a new IND to be filed this quarter. I would like to thank all of the tremendous employees at Agios for their dedication and passion to making a difference for our patients. I also want to thank all of the patients, caregivers and physicians who participate in our clinical trials. Without them, we could not do what we do today. I would also like to thank all of you for joining us on our call today, and we will see you soon.

And with that, ladies and gentlemen, we thank you for participating. You may now disconnect.