Logo of jester cap with thought bubble.

Image source: The Motley Fool.

Agios Pharmaceuticals Inc (NASDAQ:AGIO)
Q4 2019 Earnings Call
Feb 13, 2020, 8:00 a.m. ET

Contents:

  • Prepared Remarks
  • Questions and Answers
  • Call Participants

Prepared Remarks:

Operator

Good morning and welcome to Agios Fourth Quarter and Full Year 2019 Conference Call. [Operator Instructions]

I would now like to turn the call over to Holly Manning, Associate Director of Investor Relations.

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 US 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.

Jacqualyn Fouse -- Chief Executive Officer

Thanks Holly. Good morning everyone and thanks for joining our fourth quarter 2019 results call. I took on the role of 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 our 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 six 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 eight 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, four 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 pre-clinical 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 under way 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 six-year vision. We have significant milestone events occurring every year over the next six 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'll now turn the call over to Chris to provide our clinical and regulatory update.

Chris Bowden -- Chief Medical Officer

Thanks, Jackie. Underpinning our 2025 aspirations are multiple early and late-stage clinical program 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 three 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 two 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 a 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 a gram per deciliter in seven of eight 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 a pivotal strategy for mitapivat in thalassemia which we plan to finalize by the end of the year. In sickle cell disease, we are collaborating with Dr. Swee Lay Thein at the National Institutes of Health for a proof of concept study under a Cooperative Research and Development Agreement. The goal of the study, which will enroll up to 25 patients is to evaluate safety and tolerability, changes in laboratory parameters, including reticulocytes and levels of hemoglobin, pharmacokinetics and pharmacodynamic markers such as levels of 2,3-DPG and ATP, as well as sickling in red blood cells. Enrollment is going well and we expect Dr. Thein to submit data from this study for presentation at EHA.

Beyond the mitapivat, we have developed the next generation PKR activator, AG-946 and plan to submit the investigational new drug application this quarter. Once the IND has cleared, we will initiate a study in healthy volunteers in the second quarter. Moving to hematologic malignancies, we've made rapid progress over the last several years, securing US approval for TIBSOVO Monotherapy an IDH1 mutant relapsed refractory and frontline AML while generating important data from the Phase 1 studies combining TIBSOVO with standard of care frontline therapies.

The next phase of TIBSOVO development is focused on global labels in the frontline combination settings, which will allow us to reach the largest number of AML patients with an IDH1 mutation. The Phase 3 AGILE study of TIBSOVO in combination with azacitidine and the HOVON 150 study of TIBSOVO and IDHIFA in combination with standard induction and consolidation chemotherapy, both continue to enroll patients.

In the EU, we have submitted our day 120 responses for our TIBSOVO filing and relapsed refractory AML. And are now waiting on THE day 180 list of outstanding items from the European Medicines Association. The EMA recently disclosed that Celgene BMS withdrew the ID for marketing authorization application because the single-arm Phase 1 trial did not fully address the major objections raised by the CHMP to support a positive benefit risk assessment in the proposed indication. Our goal remains to make TIBSOVO available to patients in Europe and we continue to move our MAA through the EMA review process.

Outside of AML, we are advancing TIBSOVO development and myelodysplastic syndrome and recently reopened the MDS arm, the Phase 1 study in IDH1 mutant hematologic malignancies. We have increased the trial size to a maximum of 25 MDS patients and expect to complete enrollment by the end of the year. TIBSOVO received Breakthrough Therapy Designation in this indication and our goal is to generate sufficient data from the expanded Phase 1 arm to pursue a potential US regulatory filing in MDS.

Lastly, the Phase I study of AG-636, our DHODH inhibitor in advanced lymphoma continues to enroll patients. We plan to have sufficient data by the end of the year to determine the next steps for this program. For solid tumors, in 2019, we established the utility of IDH inhibition in treating solid tumors with the positive readout of the ClarIDHy Phase 3 study of TIBSOVO in previously treated IDH1 mutant cholangiocarcinoma. This study showed that TIBSOVO reduced the risk of disease progression or death by 60% with significant improvement and landmark analysis for PFS at six months and 12 months. Mature overall survival data from the ClarIDHy study is expected in mid-2020 and we plan to submit a supplemental new drug application including these data by year-end.

As we shared in January, our Phase 3 INDIGO study of vorasidenib, our brain-penetrant pan-IDH inhibitor in low-grade glioma was initiated at the end of 2019. The team is currently focused on site activations for this global study. Our other solid tumor program is a MAT2A inhibitor, AG-270 and is currently being evaluated in combination with standard of care taxanes in two arms of a Phase 1 study, one in non-small cell lung cancer and the other in pancreatic cancer. Over the next two years, we aim to gather sufficient clinical data in these two patient populations to see if we can replicate the impressive synergy between AG-270 and taxanes that we demonstrated preclinically in these indications.

I will now turn the call over to Darrin to discuss our commercial performance.

Darrin Miles -- Senior Vice President, US Commercial and Global Marketing

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 or 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 relapsed AML patients with an IDH1 mutation.

Looking ahead, we've guided to 2020 US 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 agents.

We anticipate this will continue to have a positive impact on average duration, which we expect to settle close to the five-month mark by the end of 2020.

Moving to rare genetic disease, our team is expanding our pre-launch 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 deficiency patients in the US and EU-5. 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.

Andrew Hirsch -- Chief Financial Officer and Head of Corporate Development

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 of 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 of 2019. Turning to operating expenses, R&D for the fourth quarter was $106 million and $411 million for the full year of 2019. An increase of $70 million compared to the full year of 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 3 INDIGO study in low-grade glioma as well as required clinical pharmacology studies and companion diagnostic work. Ongoing recruiting efforts in the TIBSOVO Phase 3 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 of 2019. This represents an $18 million increase over a full year of 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.

Questions and Answers:

Operator

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

Mohit Bansal -- Citi -- Analyst

Great, thanks for taking my questions and congrats on the progress. A 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 would make, or give us 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. Thank you.

Chris Bowden -- Chief Medical Officer

Hi, Mohit, it's Chris Bowden here. Thanks for your question. So I think there are some pretty important differences between the enasidenib data set and our approach and what we're doing with TIBSOVO. So from the Celgene BMS perspective, they decided to withdraw after the -- not being able to fully meet the questions from the MAA, from the EMA, they also have a Phase 3 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 identify.

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 relapse 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.

There are some other important aspects of this submission that we're emphasizing as well. And 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 is some data indicating that IDH1 mutations have a poor prognosis and certainly patients with IDH1 mutation seem to do worse in patients with IDH2 mutations 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 is some important differentiators and that's why we're pushing forward and remain optimistic that we're going to have a positive outcome. 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.

Mohit Bansal -- Citi -- Analyst

Got it. And then, this is very helpful. And then on the PKD side, I think, Darrin you mentioned that you have about thousand patients identified. So one part is, can you please help us understand how much is this US 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 slides. Thank you very much.

Darrin Miles -- Senior Vice President, US Commercial and Global Marketing

Absolutely, absolutely. So it's roughly half and half between US and ex-US. The majority of ex-US being in EU-5. I think the challenge always with diseases 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 -- our field team is to focus more effort on being able to accelerate that. And we've been successful over the last, over the last year plus and 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.

Mohit Bansal -- Citi -- Analyst

Great, helpful. Thank you.

Operator

Thank you. Our next question comes from Kennen MacKay with RBC Capital.

Kennen MacKay -- RBC Capital Markets -- Analyst

Hi, thanks for taking the questions and congrats on the quarter and the execution. Maybe one for Chris first and then a follow up for Jackie and Andrew. Chris, on MDS and the breakthrough designation there for TIBSOVO, could you maybe help us a little bit on the timelines associated with the Phase 1 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 Babe Ruth 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. Thanks and congrats again.

Chris Bowden -- Chief Medical Officer

Okay. Hey, Kennen, it's Chris here. So we are 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 on to trial will really determine the timeline 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 -- as we get more confidence around that, that will 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.

Jacqualyn Fouse -- Chief Executive Officer

Hi Kennen, thanks for the question. I did play both fast pitch and slow, I mean, yeah, 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 in 2025 -- by 2025, we're wanting 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 in, 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 derisked assets by some definition of derisking. When we think about the revenue, a 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 of all of those in our assumptions are very late in that six-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.

Kennen MacKay -- RBC Capital Markets -- Analyst

Thank you very much.

Operator

Thank you. And our next question comes from Alethia Young with Cantor.

Alethia Young -- Cantor -- Analyst

Hey guys, thanks for taking my question and 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 one versus the other. And then, the other one probably is for Jackie, and I just want you to kind of since its 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 are taking it and sort of maybe weave a little bit of thoughts and about your potential -- your new hire of CSO as well. Thank you.

Chris Bowden -- Chief Medical Officer

Okay, Alethia, it's Chris, I'll go first. There is the genotype in 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 are activating wild-type PKR and looking to improve overall red cell health, we would -- 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 what is the key distinction for thalassemia is likely to remain in our view of transfusion dependent versus not regularly transfused. So 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 in both of these categories on transfusion and transfusion dependent and have a high unmet medical need, given their underlying disease process.

Jacqualyn Fouse -- Chief Executive Officer

Hi, 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 PK, our activation science along with mitapivat in 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 and cellular metabolism, the Company certainly has delivered on that, we'll continue to deliver on that.

And I think we're doing that in a very focused way. Innovation comes in ways, will all of you want us to move faster? Yes, we 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 some 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 six 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 in to the IND filing. And everything that we've got in 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 with a little bit more focus on a go forward basis even.

Alethia Young -- Cantor -- Analyst

Thank you.

Operator

Thank you. Our next question comes from Anupam Rama with J.P. Morgan.

Anupam Rama -- J.P. Morgan -- Analyst

Hey guys, thanks for taking the question. Just two quick ones for me. From -- for AG-946, how you're 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 mid-year, how are you thinking about the long term development of 946? And then a quick one, just a clarification point. So the press release is very specific about thalassemia data being at EHA, but sickle cell was noted to be mid-year. So should we think about the sickle cell update sort of outside the scope of the conference at this point? Thanks so much.

Chris Bowden -- Chief Medical Officer

Hey, Anupam, it's Chris here. Thanks for the questions. We anticipate and share [Phonetic] 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 that 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 in the clinical development.

So that's really looking across all three 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 against. 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 three 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, we demonstrate proof-of-concept there.

What -- ultimately what the steps are and how you develop it as a follow on replacement, what have you, really is way too early to go there. And like we say all the time, it would be data-driven decision combined with what does mitapivat look like in any of these indications at a given point in time when you start to make some of these decisions, how is the market evolving -- whole slew of things.

Jacqualyn Fouse -- Chief Executive Officer

Nice to have options.

Chris Bowden -- Chief Medical Officer

Yeah.

Anupam Rama -- J.P. Morgan -- Analyst

Great. Thanks for taking our questions.

Operator

Thank you. Our next question comes from Alexander Duncan with Piper Sandler.

Alexander Duncan -- Piper Sandler -- Analyst

Hi, thanks for the question. Just wanted to ask a follow-up questions, your thoughts on working with the EMA. So does the IDHIFA MAA situation change your thoughts on how to approach pipeline development in oncology in the way you maximize the ex-US opportunities?

Chris Bowden -- Chief Medical Officer

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 dataset 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 US 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, that we would do at the same thing, all over again. And when these opportunities come up, we'll continue to operate this way.

Alexander Duncan -- Piper Sandler -- Analyst

Great, thank you.

Operator

Thank you. Our next question comes from Chris Shibutani with Cowen.

Chris Shibutani -- Cowen and Company -- Analyst

Thanks very much. Good morning. If I could ask two questions, one, a little bit more concretely. I 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 categories. 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 etc. and payer support and patient support programs a continuing trend this year. And then I'll have a follow-up.

Darrin Miles -- Senior Vice President, US Commercial and Global Marketing

Hi, Chris. This is Darrin. Yeah, so we assume that when we set the guidance for this year that we would see a similar, 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 the need to check in with their patients, given the likelihood that the patients may experience an updated or a change in their overall benefit design and potential cost share, our patient cost burden. So yes, to answer your question, we've assumed a similar impact in 2020.

Chris Shibutani -- Cowen and Company -- Analyst

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 that was about eight 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. Thank you.

Chris Bowden -- Chief Medical Officer

Our abstract we will write in a manner that gives us the highest chance of getting a slot and getting admitted to the meetings. 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 17 patients before we get to EHA. And so you'll see additional data, new data on thalassemia -- 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.

Chris Shibutani -- Cowen and Company -- Analyst

Great. Thank you. Looking forward to the updates, especially with that program. Thank you.

Operator

Thank you. Our next question comes from Mark Breidenbach with Oppenheimer.

Mark Breidenbach -- Oppenheimer -- Analyst

Hey, good morning guys. Thanks for taking the questions. 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 -- it's been a pivot, it's been layered on top of standard of care therapies, including hydroxyurea and maybe it will 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?

Chris Bowden -- Chief Medical Officer

So the patient can be on Hydrea, and that's certainly an eligibility criteria. Other drugs like voxelotor and others that 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 a 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 do patients tolerate the drug over that six-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 three doses that we test. Do we see any changes in hemoglobin and are we able to tease out that that's a 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 patient 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 get a little more complicated than numero because of the red cell population. And it's a little more challenging to handle then 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 you should be thinking about and how we'll be thinking about this is that, what will be the next steps for development. And we had a previous question, would you go -- how -- what aspects are you thinking on when you do more Phase 2 work, Phase 3 work, etc. 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.

Mark Breidenbach -- Oppenheimer -- Analyst

All right. That's very helpful. And then a quick follow-up for Darrin, going back to the thousand 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. Thank you.

Darrin Miles -- Senior Vice President, US Commercial and Global Marketing

Hey, Mark. So I don't have that detail at hand, I think that's something we might be able to follow up with 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 US focusing on raising the urgency around diagnosis, offering support for testing, which is the sort of the key fundamentals what we need to have in place in order to be able to fully get to the answers to the questions that you're asking here as well. But I think we might be able to follow up afterwards with more detail.

Mark Breidenbach -- Oppenheimer -- Analyst

Okay, thank you.

Chris Bowden -- Chief Medical Officer

It's Chris here, I would just -- there is 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 two missense mutation.

So I think that's a really important aspect of how we think about it overall. There is 300 and more mutations being described. So specific genotype -- 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 there.

Mark Breidenbach -- Oppenheimer -- Analyst

Sure. That's helpful.

Operator

Thank you. Our next question comes from John Newman with Canaccord.

John Newman -- Canaccord Genuity -- Analyst

Hey guys, good morning. Thanks for taking the question. And it's a 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. Thanks.

Jacqualyn Fouse -- Chief Executive Officer

Hi, John, It's Jackie. No, there is 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.

John Newman -- Canaccord Genuity -- Analyst

Great. Thank you.

Operator

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

George Farmer -- BMO Capital Markets -- Analyst

Hi, good morning. Thanks for taking my question. 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've seen some increased pick up in the combo setting, how are docs thinking about cycling between TIBSOVO and venetoclax in combination with HMAs?

Darrin Miles -- Senior Vice President, US Commercial and Global Marketing

So the -- I think couple of things to it, maybe fully first established. I think the -- we continue to see in our research a firm belief in the importance of targeting the target, meaning if you got a target therapy for an 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 is also firm belief in that IDH1 -- mutated IDH1 is a driver mutation in this setting, and particularly an early driver mutation.

So that I think is what -- that along with the clinical outcomes data is driving the adoption of TIBSOVO at both single agent as well as in combination in the frontline setting that we only promote to the single agent use. The data that we've seen and it's continued to improve quarter-over-quarter, now suggests that it -- or indicates that it is the most preferred regimen, about half of the overall use, both in the frontline setting as well as in the relapsed 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 that Congress over the last two 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 focusing on those patients who have been previously exposed to an HMA.

And I think we get -- we have good resonance -- that message has good resonance with the community there. And then as they become more aware of the emerging -- of the emerging data in combination, they're finding it compelling overall clinical profile that's leading them to expand their use beyond that portion of the patient population. So 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 relapsed setting.

George Farmer -- BMO Capital Markets -- Analyst

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 a -- had been an issue in the earlier stages of development. And again does genotype matter in that setting, do you think?

Chris Bowden -- Chief Medical Officer

Yeah, so it's Chris here. Genotype matters in pyruvate kinase deficiency and because you've got to have protein in order for the drug to bind and we have found that non-missense mutations as a general rule are less stable, and there is not as much protein around or there is 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 the, 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 you're 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 is less ATP because of that mutated enzyme. Whereas in these wild-type approaches, there is a relatively -- there is, I wouldn't say, normal, but there is more ATP, that we're trying to push up the ATP levels, so that those red cells can tolerate their underlying disease process and live longer.

George Farmer -- BMO Capital Markets -- Analyst

Great. Thank you.

Operator

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

Jacqualyn Fouse -- Chief Executive Officer

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 the 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.

Operator

[Operator Closing Remarks]

Duration: 52 minutes

Call participants:

Holly Manning -- Associate Director of Investor Relations

Jacqualyn Fouse -- Chief Executive Officer

Chris Bowden -- Chief Medical Officer

Darrin Miles -- Senior Vice President, US Commercial and Global Marketing

Andrew Hirsch -- Chief Financial Officer and Head of Corporate Development

Mohit Bansal -- Citi -- Analyst

Kennen MacKay -- RBC Capital Markets -- Analyst

Alethia Young -- Cantor -- Analyst

Anupam Rama -- J.P. Morgan -- Analyst

Alexander Duncan -- Piper Sandler -- Analyst

Chris Shibutani -- Cowen and Company -- Analyst

Mark Breidenbach -- Oppenheimer -- Analyst

John Newman -- Canaccord Genuity -- Analyst

George Farmer -- BMO Capital Markets -- Analyst

More AGIO analysis

All earnings call transcripts

AlphaStreet Logo