Good morning, and welcome to Agios’ First Quarter 2019 Conference Call. At this time, all participants are in a listen-only mode. There will be a question-and-answer session at the end. Please be advised that this call is being recorded at Agios’ request.

I would now like to turn the call over to Kendra Adams, Vice President, External Communication and Investor Relations..

Thank you, operator. Good morning, everyone, and welcome to Agios’ first quarter 2019 conference call. You can access slides for today’s by going to the Investors section of our website, agios.com. With me on the call today are Dr.

Jackie Fouse, our Chief Executive Officer, who will review key business updates including TIBSOVO commercial performance; Dr. Chris Bowden, our Chief Medical Officer, who will highlight our clinical development progress, and Andrew Hirsch, our Chief Financial Officer who will summarize our first quarter 2019 financial results. Dr.

Scott Biller, our Chief Scientific Officer, will also be available for Q&A. Before we get started, I would like to remind everyone that 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.

In addition, any forward-looking statements made on this call represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements. And with that, I’ll turn the call over to Jackie..

Thanks, Kendra. Good morning, everyone, and thanks for joining us on our Q1, 2019 earnings call.

I’m now three months into my role as CEO here at Agios and I’ve been meeting with employees across the organization, learning more about our research platform and discovery portfolio and digging into our commercial strategy to maximize the value of our clinical assets.

I believe that for our size we have one of the best pipelines in the industry with significant optionality across multiple compounds and indications in oncology and rare genetic diseases. In the first quarter, our teams produced achievements that move us closer to realizing those opportunities.

We've made progress across our IDH development programs where we continue to drive frontline AML and solid tumor label expansions and broaden access for patients worldwide.

For our most advanced rare genetic disease program, mitapivat, in addition to enrolling patients in the Phase 3 pyruvate kinase deficiency program we have expanded clinical development to other diseases where PKR activation may play a critical role in treating the underlying disease.

We’ve started dosing patients in the Phase 2 thalassemia study and later this year a new study in sickle cell anemia is on track to initiate.

For our earlier-stage programs at AACR we presented compelling preclinical data demonstrating the rationale for synergistic activity of our MAT2A inhibitor, AG 270 with Standard of Care therapies for the treatment of certain solid tumors. In addition, trial sites are now open and screening for the Phase 1 lymphoma study of our DHODH inhibitor AG 636.

Within our research organization our teams remain dedicated to the pursuit of terrific science and are focused on making smart decisions to advance compounds through our robust drug discovery engine.

Before I hand the call over to Chris to provide more detailed updates on all of our clinical and regulatory activities, I will provide the commercial update this quarter. In April, we announced the new commercial organizational structure that will allow our commercial teams to focus on the ongoing market success of TIBSOVO in the U.S.

while we also build a lean effective organization in Europe where our MAA for TIBSOVO in relapsed or refractory AML remains under active review with EMA. Darrin Miles has assumed the new role of SVP and Head of Commercial for the U.S. as well as Global Marketing.

Darrin is transitioning from his prior role as IDH program lead and you'll hear from him on future calls. With respect to U.S. sales of TIBSOVO, net revenue for the first quarter of 2019 was $9.1 million. Underlying commercial unit growth continued, but the rate of that growth was a little slower than we expected.

This was mainly due to an increase in patients receiving free drug as part of our patient assistance program, likely related to the typical Q1 seasonality seen in oncology that results from rollovers of benefit coverages and pressure on patient out-of-pocket costs.

Though we were short on revenues for the quarter compared to our internal forecasts we saw several positive trends during Q1 and moving into Q2 including continued growth in the number of unique TIBSOVO prescribers especially in the community setting and increase in testing with close to 90% of academic and community physicians now testing their patients for the IDH mutation at diagnosis and positive volume trends starting in late March and continuing through April.

Despite the slight revenue softness in Q1 we believe we are on track to deliver on our full year internal forecasts and drive solid performance for our first full year of TIBSOVO on the market.

In addition, I was in the field in April and heard enthusiastic feedback from the AML physician community regarding the potential approval in the newly diagnosed patient population reflected in our TIBSOVO sNDA and for which our commercial team is launch ready, many thanks to our commercial team and our teams across all fronts for their hard work on behalf of our patients.

With that, I will turn the call over to Chris to update you on our clinical and regulatory progress..

Thanks Jackie. I’ll begin with updates across on our broad clinical development program for TIBSOVO and frontline AML, where we’ve made significant progress since the progress since the beginning of the year in each of the three treatment categories; intensive therapy, non-intensive therapy, and those patients not eligible for any standard treatment.

In February the FDA accepted our supplemental new drug application for TIBSOVO and newly diagnosed IDH1 mutant AML patients ineligible for standard therapies, and gave us PDUFA date of June 21.

Our sNDA application which part of the FDA's new real-time oncology review pilot program and was granted priority review is based on results from the newly diagnosed arm from our Phase 1 study and IDH1 mutant hematological malignancies. Updated data from this arm have been accepted for presentation at the ASCO Annual Meeting in June.

The presentation will include updated data since it was last shared at the ASH Annual Meeting in December 2018. In the intensive therapy setting where Standard of Care is a combination of chemotherapy known as 7+3, the randomize Phase 3 study of TIBSOVO or IDHIFA in combination with 7+3 recently initiated sites.

This trial run by the cooperative HOVON and AMLSG will enroll approximately 1000 patients in compared event free survival between our IDH inhibitors in combination with induction and consolidation therapy versus induction and consolidation therapy alone.

Importantly, this trial allows for IDH maintenance therapy for up to two years which will enable us to evaluate longer duration in the intensive setting. In the non-intensive therapy setting patients are not able to tolerate aggressive chemotherapy and often receive hypomethylating agent agents such as azacitidine.

In February, we presented compelling data from the Phase 1 study of vorasidenib and azacitidine at the leukemia meeting in Munich demonstrating an overall response rate of 78% and increasing CR rate of 57% since the prior data presentation at ASH 2018 and A 12 months survival rate of 82%.

In addition the majority of CR patients achieved IDH1 mutation clearance. The median duration of CR and CR plus CRH has not been reached with a lower bound range of 7.7 months.

From the safety perspective results from the combination were consistent with the safety profile of each drug use alone and cytopenias were in line with those seen for azacitidine level and favorable compared with other emerging hypomethylating agent agents combinations. We will present updated results with longer follow-up at ASCO.

These data support FDA’s decision to grant us Breakthrough Therapy Designation in March which will allow us to interact with the agency on a broader level around this program moving forward. Our Phase 3 agile trial with this combination is ongoing with enrolment expected to complete in 2020.

Beyond AML myelodysplastic syndrome is important patient population for which we’ve actively explored development opportunities. As a reminder, we last presented data at the ASH Annual Meeting in December where we demonstrated the compelling overall response rate of 92% and the 12 patients enrolled in a Phase I study.

In order to further evaluate the utility of TIBSOVO and the approximately 3% of MDS patients with an IDH1 mutation, we’ve decided to reopen the MDS arm of the Phase 1 study to enroll approximately 30 additional patients.

This will allow us to further understand the role that TIBSOVO can play in this disease and determine the path forward with regulators. We expect the arm to be open later this year and look forward to providing updates on subsequent calls.

Moving to solid tumors; we’re on track to share topline data this quarter from our Phase 3 CLARITY trial TIBSOVO and previously treated IDH1 mutant calendula carcinoma with a more complete clinical update at the medical meeting in the second half of 2019.

TIBSOVO has the potential to be the first targeted therapy approved in calendula carcinoma, and we are prepared to file a supplemental NDA at the end of the year assuming a positive trial result.

In low-grade glioma, we announced in January that we selected vorasidenib also known as AG-881 as the go forward molecule in this indication were approximately 80% of patients have an IDH1 mutation. Molecule selection was based partially on data from the perioperative window study of TIBSOVO and vorasidenib.

As a reminder this study was designed with the following objectives; to determine the amount of drug exposure in the brain, to confirm the magnitude of IDH target engagement as it measured by 2HG levels in brain tumor tissue, to assess the impact of IDH inhibition on exploratory biomarkers of response and to assess the safety of both molecules.

Status in the first cohort of the study has been accepted for presentation at ASCO. I’ll now move to Mitapivat. Our PKR activator that is our most advanced rare genetic disease program and has the potential to be our first approved medicine in this field.

We are currently enrolling two pivotal studies of mitapivat and adults of pyruvate kinase deficiency, ACTIVATE A in patients who do not receive regular transfusions and ACTIVATE T in regularly transfused patient.

For the ACTIVATE T trial we are in the process of opening trial sites and there more patients eligible and interested in participating than we initially anticipated. As a result we are increasing trial size from 20 patients to up to 40. We expect to enroll first 20 patients by the end of the third quarter.

For our Phase 2 study of mitapivat and thalassemia, we have started dosing patients with multiple trials open and expect to achieve proof-of-concept in this indication by the end of the year.

Finally, we’ve been working with the National Institutes of Health on a clinical trial of mitapivat and sickle cell disease, where we believe there is potential for a PKR activator to provide benefit for these patients. The study is in the final stages of planning and is expected to initiate later this year.

I’ll now move to our early stage oncology programs. In March 2018 we initiated the Phase 1 dose escalation trial of AG-272, our MAT2A inhibitor and MTAP Deleted tumors with the goal of establishing a recommended dose based on safety pharmacokinetics and pharmacodynamic markers of our MAT2A inhibition.

As we have previously commented we are pleased with what we have seen related to the effects on the pharmacodynamic markers of MAT2A inhibition which we continue to monitor. As we review the data from the once daily dose cohorts, we decided to explore BID dosing as a way to potentially optimize monotherapy exposure for patients.

In the most recent BID cohort we saw dose toxicities that we need to evaluate further in order to select the appropriate dose and schedule with the expansion arms in future studies. With that, we now plan to finalize the dosing regimen and initiate both the monotherapy and combination expansion arms in the third quarter.

As we’ve said before getting dose right early on in clinical development is one of the most important steps to ensure the best possible outcome for the program, shareholders and most importantly for patients.

In April, we presented compelling preclinical work at AACR demonstrating that the mechanism of action downstream of MAT2A creates a synergistic vulnerability to antimitotic including clinically applicable [Indiscernible]. Based on these data, we now plan to initiate two combination arms in areas of high end met need.

The first we’ll test AG-270 in combination with docetaxel and MTAP deleted non-small cell lung cancer. The second, we’ll test AG-270 in combination with snap nab-paclitaxel and gemcitabine in pancreatic ductal adenocarcinoma. We will share additional details about these expansion arms once they are initiated.

And we look forward to sharing this first clinical data from the Phase 1 dose escalation study later this year. For AG-636 our DHODH inhibitor we have initiated sites of the Phase 1 lymphoma study and are currently screening patients. With that, I’ll turn the call over to Andrew..

Thanks, Chris. Our first quarter results can be found in the press release we issued this morning, which I'll summarize. More detail will be included in our 10-Q filing later today. Total revenue for the first quarter was $30.2 million, which consisted of $9.1 million of net U.S.

sales of TIBSOVO, $18.9 million of collaboration revenue and $2.2 million of IDHIFA royalty revenue. The year-over-year increase in revenue was primarily driven by an $11 million increase in increase collaboration revenue due to the satisfaction of performance obligation under the Celgene collaboration. $9.1 million of net U.S.

sales of TIBSOVO and an $800,000 increase in the IDHIFA royalty. Despite an increase in TIBSOVO demand quarterly ex factory sales were impacted by lower inventory build when compared to the fourth quarter as inventory levels remain relatively flat over the quarter. As a result we saw a small decrease in sequential TIBSOVO revenue.

Cost of sales for the quarter was $300,000. During the first quarter we started to capitalize the portion of the period expense related to manufacturing resupply which is why there is a sequential decline in cost of sales from Q4 levels.

Turning to operating expenses, R&D for the first quarter was $95.6 million, an increase of $17.4 million compared to the first quarter of 2018.

The year-over-year increase in R&D was largely driven by clinical trial activity for TIBSOVO as we continue development in the frontline combination setting including the initiation of the Phase 3 combination trial with 7+3.

Clinical trial activity for mitapivat and PK deficiency and thalassemia, as well as transfer the production of registration batches; and start-up activities for AG-636, our DHODH inhibitor.

Selling, General and Administrative expenses were $31.8 million for the first quarter, representing a $7.2 million increase over first quarter 2018, driven by increased investment in our infrastructure and commercial capabilities. We ended the quarter with cash, cash equivalents and marketable securities of $708 million.

We expect that this cash balance in addition to expected product revenue and royalties, but excluding anticipated program specific milestone payments will fund our current operating plan through at least the end of 2020. With that operator, please open the lines for questions..

[Operator Instructions] Our first question comes from Anupam Rama with JPMorgan. One moment..

[audio gap] quantify the impact of TIBSOVO, so seasonality here in 1Q and maybe the timeframe in which patients kind of work through doughnut hole and plan changes and other seasonal headwinds. And then the second question on CLARITY, with topline results here on the horizon.

Maybe can help us understand what you're hearing from the physician community about a minimal threshold or like a clinically meaningful effect and what kind of that win scenario for you guys? Thanks so much..

Thanks for the question. It’s Jackie. I have say that you were cutting out during the part of your first question, so I’m going to answer what I think you wanted to ask, because I heard the last half of it. So, as we said in the prepared remarks we saw a good strong commercial growth on the demand side for TIBSOVO.

And as we moved through Q1 we saw a fair increase in the number of patients that move from having been on commercial drug back in Q4 to going on to free drug in Q1 and that had an impact there on the net revenues as we talked about.

And we may await through the quarter we saw, we were very happy with the volume growth that we saw and we have had good strong volume growth in the month of April as well. So, I think that gives us lot of confidence in how we’re going to round out the year here.

I would remind everybody you know this, but it’s a first time that we go through Q1 for TIBSOVO and because we launched last July, so we’re learning a little bit about some of the patterns here and we’re talking about relatively small numbers in the grand scheme of things compared to some other drugs, so you can have some kind of small changes might give little bit more of an impact than you might think about.

We thought this is going to all settle out the base of the demand keeps building, We’ve seen an increase in the number of unique prescribers that continues – continued increases in testing rights, so that base gets strong growth over the course of the year than we think that impact of these seasonal things will be a little bit relatively maybe less in the future, but we’re learning something about these trends.

But underlying trends are quite good. We’re very happy with where we are..

Anupam, it’s Chris here. I’ll take the CLARITY question. So we design CLARITY with a group of investigators who is specialized in achievement of cholangiocarcinoma. So the statistical assumptions around that -- the PFS in the second line setting based on literature and discussion with them is around two to three months.

And the study we’ve assumed that PFS will be about three months and the sample size overall the study has a 96 power to – for some power to detect the hazard ratio of 0.5, so that’s essentially a doubling of PFS. I’ll remind you that the trial can be positive based on the shape of the curve and being statistically superior to the control arm.

So when – to get to your question of do clinicians think a meaningful clinical benefit would be is that a statistically positive study they think has the potential to be clinically beneficial and you can see – and if you think about Kaplan-Meier curve which is the way we look at these things from a statistical perspective you can see curve that are steadily in front.

You can see curves that have a tail at the back and are statistically positive. And in this case TIBSOVO which is a drug that’s taken orally once daily in a setting where there’s really very little treatment options in a high unmet need, we think any number of scenarios with a positive study would be clinical beneficial for these patients..

Great. Thanks so much for taking our questions..

Our next question comes from Kennen MacKay with RBC Capital Markets..

Hi. This is Vikram on Kennen. He's on a flight right now and so I'll fill in for him.

So quick two questions for us on AML, so with frontline AML expansion in June, can you help us understand the size of the patient population you looking at versus the current label? And what will be the anticipated treatment duration there versus the currently labeled last-line IDH mutation patients?.

Thanks for the question. It’s Jackie. I’m going to start. And I think until we have the exact wording for the label we would hesitate to give you too much of a range on the number of patients that would potentially be there.

We’ve shown you some information in the past about the percentage of patients that we think are in the different buckets between untreated and treated.

And so, we needed to just get that final label and then we’ll be able to give you a little bit better idea what the range or the number of patients associated with that particular label indication would be. We’re really looking forward to and it’s going to be a great moment for us to get into that frontline setting in any patient population..

Thank you. If I can squeeze in one more in terms of AML landscape, how is it evolving with VENCLEXTA I think there are number of clinical trials which are academic centers are pursuing.

Is that something you are thinking about to pursue in combination with TIBSOVO or any potential synergies there in the regions you can comment on?.

Yes. It’s Chris here. And in the time when we took our IDH inhibitors into the clinic till now and especially in the last 18 to 24 months there are now 11 drugs that have been approved in the space. So that’s after decades of really not having much in the way of clinical investigation to improve outcomes for patients.

So it create challenges, but opportunities and to your point we’ve talked about an investigator sponsored study that Dr, DiNardo, Courtney DiNardo at MD Anderson is running with TIBSOVO plus VENCLEXTA and in fact that’s getting ready to expand to look at a triplet which is adding azacitidine to that combination and she’s in fact getting ready to expand that with additional centers.

So we’re looking forward to that being initiated because we think that’s going to be important data for us and for patients and of course we’re looking at and talking about with investigators about other combinations whether it’s with three inhibitors, [Indiscernible] number of drugs.

So, there’s going to be a lot of activity here not just to newly diagnosed patients, but in patients who relapse, looking at how do you sequence these drugs given that there are oral agents, they can be given in combination, they can be given in sequence and they’re rather sensitive tools that we have around looking at changes at the molecular level whether it's through MRD or variant allele frequency which we talk a lot about with IDH1.

So lots of opportunity and we’re really happy with Dr. DiNardo’s progress on the trial. She’s in control of that. When it’s going to published and looking forward to getting that data out there as well as with the expansion that I just talk to..

Thank you so much..

Our next question comes from Michael Schmidt with Guggenheim..

Hey. Thanks for taking my questions and congrats on the all the progress. I had a few follow-up questions on your comments around AG-270.

Can you maybe help us walk through the implications of the recent preclinical data presentation from AACR on the potential development in monotherapy and combination? What was the bases for specifically selection of lung cancer and pancreatic for the initial expansion, cohort for example.

And then you did talk about some DLTs and the need to optimize dosing of AG-270 on monotherapy. Can you just help us understand that a little bit better? Thanks..

Okay, great. It’s Chris here. Let me do the dose piece first and then I’ll finish with the some other things we’re thinking around combination therapy, because that’s predicated on some of the interesting data that our teams are working and was presented at AACR.

So we – when we wrote the study we specified upfront that we were going to investigate both daily and BID dosing. Here in Phase 1 as you’re increasing your dose and investigating your dose, with an oral agent especially that's one of the schedule manipulations that you can do.

Given that work that we've done with biomarkers and pharmacodynamic markers that is looking at same levels in the finding, it’s really important for us to understand how that will change at all. With our daily dosing we’ve seen nice impacts on the pharmacodynamic output. So we had pre-specify that we look at BID which is what we did.

And that’s when we’ve encountered these dose limiting toxicities. So, the important thing for us now is to look at all the data that’s come out from those cohorts, so we’ve recently dosed.

And take a look at that exposure data and that PD data, reference that back to what we seen so far with our once daily dosing data, in order to really make sure we’ve looked at everything as we make our decision to go forward. And that's why there’s a slight delayed the program.

With regards to the combination is that what our research team presented at AACR demonstrated that when you inhibit MAT2A your downstream effects – that can affect splicing and DNA repair and cell cycle defects that can be address by combining a MAT2A inhibitor AG-270 with taxanes and taxanes are ubiquitous in the treatment of patients predominantly with solid tumors.

And two areas if you think about the frequency of MAT – of MTAP deletions with high unmet need, non-small cell lung cancer and pancreatic cancer come to the floor, its two important indications because taxanes can be cornerstone therapy depending on the setting et cetera.

So that’s why we’ve select them as our first two combination indication that we want to look at..

Okay. Thank you.

Maybe one follow-up, I mean, do you feel you are getting too high enough exposure levels based on your dosing schemes and the PD data that you have in hand?.

Overall, we are very satisfied with the progress of trial in terms of information we’ve got in terms of the exposure, exposure related to pharmacodynamic effects understanding the toxicity profile. And now as we want to – we’ve got some more data coming in, we want to look at this in the BID settings, so yes..

Okay, great. Thank you..

Our next question comes from Chris Shibutani with Cowen..

Thanks very much. If I can ask you a commercial question. In the past you've talked a little bit about some of the underlying patterns of use, the types of patients in terms of severity initially and the duration of use.

As the launch continues to progress can you comment about how those patterns are continuing to shape? And then secondly with the decision that you've made, I realize it's still early to go it alone so to speak in Europe, can you comment about what you're learning there? How that's progressing? Maybe the cadence of news flow that we can expect there? Thank you..

So, with respect to the first question, thanks for that, Chris, it’s Jackie. I think that -- I mean what we're seeing is our Chris here on this side just was talking about we've had quite a number of drugs come into the AML market in the last 12 to 18 months. We had three alone approved in Q4 of last year. Some of those are targeted agents.

Some of them are less targeted agents and what we're starting to see, I think it's still very early days is that all of these drugs are going to settle into the marketplace and find their respective roles in treatment paradigms for patients, which is a great thing as compared to the past when there were fewer choices.

Some of you have heard me, use of analogy of how we saw the multiple myeloma play out over the past four, five years when there are bunch of new therapies that came to market here as well.

So, I think for our drugs in particular when you think about patients with IDH mutation there’s no reason why patient shouldn’t see one of our drugs over the course of their treatment paradigm and our belief that and as we have our ongoing lable expansion then we’ll be able to play across all the different patient segments in AML.

And as Chris also spoke about, we will now and physicians will have the choice of using more combination therapies than they ever have in the past and they’ll find the best ways to sequence those therapies. With respect to the EU build, we again, as you said we’re in the early days of that. We don’t have a lot of new news to report.

We’re working on starting to recruit the most senior members of that team. We’re seeing some very talented people with the lot of experience building in that geography and hopefully we’ll able to announce something in that regard soon. But things are going quite well. The regulatory process continues to move along as we would have expected to.

So you'll hear more to come from us on that in the future. Thanks..

Great. And then just a quick clarifying what Chris said AG-270, where he mentioned is slight delayed to the program, is that relative to the combination or monotherapy program? If you could just clarify what you meant there? Thank you..

Well, we had -- we were thinking at JPMorgan, we would get everything those -- that combinations as well as the expansion up in the middle of the year by the end of the first half of the year. So it's really for everything, Chris..

Okay, great. Thanks very much..

The two combination cohorts and the monotherapy expansion..

Thanks..

Our next question comes from Mohit Bansal with Citigroup..

Great. Thanks for taking my questions. I mean just to follow up on the AG-270 program. When we see the data in the latter half of the year should we be expecting any responses as there or we should be more focused on the biomarker decline? And then I have a follow-up question. Thank you..

It’s Chris here. When I look at Phase 1 data from our drugs, other drugs, I look at several things.

The mechanism of action, are you able to demonstrate that you're hitting the target or how well is the data that you're looking at able to demonstrate that you're heading the target, how well is that target developed validated is important in that, the exposures at which that is demonstrated, the variability, and then the safety that you see across the entire spectrum of dosing and efficacy.

So I think to focusing on one singular component that's not what we do and that's not our intent here. Our intent is really to understand the appropriate dose to take in the Phase 2 for further development.

I mean if you think about this trial it's solid tumors study where we see it just a variety of patients with different diagnoses, they've had varying levels of varying prior therapy.

And so to -- from your question around efficacy making conclusions on the basis of a small number of patients treated at a bunch of different doses with varying exposures is a tenuous thing to do. So that's not how we're seeing the primary endpoint of this objective of the study..

That very helpful. Thanks for clarifying. And then if I can fit one more on betathal and sickle cell disease, can you just help us remind because there's a lot of development going on in these diseases.

Where do you see mitapivat fitting in? And could you please help us understand what do you think is the internal bar for success that can make you move ahead in trials there?.

Yes. So the bar for declaring an effective drug is not something I can answer right now.

The way we design study is a pilot study, designed to see what level of clinical activity we could see based on our hypothesis where we think is a pretty good preclinical model that activating wild type PKR ameliorated some pretty significant disease associated effects in mice with thalassemia.

So you're right there's lots of things happening and an lots of good things happening in thalassemia with luspatercept or gene therapy.

And what we want to understand first is, can we validate our hypothesis that activating wild type PKR can improve in some meaningful way that we can detect outcomes for these patients and then we can decide how to go forward there, whether it’s a single agent or with some of these new drugs coming in combination.

So there's just a lot of a possibility here. But the thing that we really wanted to do first was to see if we can demonstrate proof-of-concept in a relatively small number of patients..

Got it. Very helpful. Thank you. Thank you, Chris..

Our next question comes from Terence Flynn with Goldman Sachs..

Hi. Good morning. Thanks for taking the questions. Maybe just two for me. First vorasidenib and low grade glioma.

Just wondering what gating to starting the Phase 3 trial there? And any more details you can share on the potential endpoint for that study? And then, secondly on AG-270, just wondering if you can give us any more details around the DLP? Was that on-target or off-target? And any potential venue in mind yet for the presentation of that data? Thanks..

Yes. So vorasidenib and moving forward with a pivotal trial now, Terrence, it’s Chris here.

We're interacting with regulators, getting feedback, defining the patient population, understanding from them how they see this patient population in this watch and wait approach where they think our outcomes that would be associated with clinical benefit whether it's from a primary endpoint to secondary endpoints.

So all those things are coming together and we're working hard to get that study designed. We're also interacting with our investigators who've been extremely helpful in putting this trial together, patient groups et cetera. As far as 270 goes, I can't share the individual details of dose limiting toxicities that we've seen.

However, some of them would be predicted from our preclinical tox and some not. That's pretty typical for a Phase 1 trial in oncology. And I can't guide on the venue yet. But certainly as we head into the second half of the year we'll be able to provide that for you..

Okay. Thanks a lot..

Our next question comes from Peter Lawson with SunTrust Robinson..

Hi guys. This is Walid [ph] on for Peter. Thanks for taking the question.

Just a quick question on the upcoming ASCO presentation, can you help some investor expectations on what we maybe in that data?.

Mostly what you're looking at on the hem side is a longer duration, understanding durability, understanding what aspects, how safety looks as we continue to go on in time. And then of course the other presentation that we're focusing lot on is our perioperative study.

And I went through what the objectives are in my remarks and so we're going to present information around that in the first cohort. So you're going to get some information in terms of how these two drugs; TIBSOVO and vorasidenib get into the brain, the effects they have on 2HG. What the overall safety looks like.

And that will then provide some further understanding in terms of our statement that we make around looking at the totality of data in terms of our molecule selection. Perioperative study has been really helpful for us in selecting vorasidenib to go forward into further considerations around pivotal development.

That's not the only dataset and you heard us referenced data for both TIBSOVO and vorasidenib in these patients with low grade glioma..

Great thanks. That's really helpful.

Just a follow up, if we're thinking about on top of that, can you talk about how you're thinking about the market opportunity for PKR efficiency given widely under diagnosed? And do you expect that to be a hurdle for patient enrollment in your clinical studies?.

With the commercial opportunity….

I can talk about that. He was asking about enrollment in the studies based on..

No. Our accrual has been well and we expect to complete by the end of the year for both studies and ACTIVATE T, we actually – we’re able to find in more patients than we initially anticipated which is why we increased the sample size..

So, and it's Jackie. I think we might be given you a couple of different sources in the past to go and have a look at the ranges right now that you would find if you go out and try to identify patient population for this indication that are pretty broad.

So, over time we'll be refining what we think about of that with our peak registry and some other things that we've done, we feel like we know how to identify these patients we're working with the physicians in that regard and we’ll again give you more information around those opportunities as we take them forward..

Yes. This is Andrew. I think what we've said previously as we think there's about 3,000 to 8,000 patients in the U.S. and EU that are addressable. We know that number is wrong and as we continue to do patient finding work that number will kind of get tighter a little bit, but it won't be perfect.

Obviously, since some under diagnosed disease you're never perfect until you're actually on the market..

Great. Thank you..

Our next question comes from Mark Breidenbach with Oppenheimer..

Hey, guys. Good morning and thanks for taking my question.

Just a quick one on the recent Breakthrough Therapy Designation in elderly patients for TIBSOVO, I'm wondering if this can lead to an acceleration in your filing plan or label expansion plans in this population or it's the plan right now is to kind of let the adults trial run its course and pile after that completes? Thanks..

I can't comment on specific interactions we have with FDA. But Breakthrough does give us the opportunity and the indication in the group of patients that you discuss to discuss to several plus azacitidine and how we're going to develop it.

Whether it's -- how we would look at the agile trial which as we've stated previously we're changing the primary endpoint to event free survival which shrinks the sample size and has us guiding to finishing accrual by the end of 2020. We also have some other activities going on.

We have Beat AML with where we're treating patients with TIBSOVO and azacitidine as well as our five studies. We've got a number of different datasets that we'll want to discuss with them within the setting of Breakthrough discussions.

And I think the previous questioner who brought up novel combinations as well and perhaps that triplet depending on what Dr. DiNardo’s data shows might allow us to think about another way of building onto this combination in this group of patients.

So a number of different ways we can go with it but Breakthrough Designation does as FDA states give you the opportunity to have some increased access to them to get guidance that may turn into opportunities either to expand one's label or to get there faster..

Okay. Thanks..

Our next question comes from Tyler Van Buren with Piper Jaffray..

This is Alex Duncan on for Tyler. Thanks for the question. Great to see the HOVON trial kick off and congratulations on that. When do you expect full enrollment to be completed and assuming the primary data are positive, will you be able to file the sNDAs prior to completion the maintenance phase? Thanks..

So, the trial, Alex is a big multi country international cooperative group effort. So it's in its early phases of initiation now. And in the beginning if you think about accrual curves it's relatively flat. And then we look for it to really get going. So it's too early to be able to guide to accrual and timelines.

Your question around filing on the basis of the prior to all patients had completed maintenance is a really interesting one. It's an event driven trial. So once you see the requisite number of events that are pre specified then you can unwind the study. So it's -- and that really is a very interesting question you raise.

I just can't answer now but it's really going to be dependent on when patients progress meet that that primary endpoint of event free survival is one it would be unwinded. So I guess, yes, it could be, but I can't, we can't really predict at this point when that will happen or whether that will happen..

Make sense. Thank you..

Our next question comes from Michael Schmidt with Guggenheim..

Hi, guys. Thanks for taking a follow-up. I just had a couple more. Regarding ACTIVATE T, so the addition of these 20 additional patients, I guess, can you help us understand sort of timelines to potential data release, I guess, does that impact our potential data disclosure or the endpoint itself? And then I had a second question after that..

So we’re guiding to getting the first 20 patients by the end of third quarter and we hope to get to the additional up to 40 patients. Then you have to follow them to, because this is a group of patients that are regularly transfused. So they have to be followed for a period of time up to a year in order to ascertain the primary endpoint.

So we can guide to when we have data readout. We’re thinking about ACTIVATE T in the setting of Activate A as well, but we’re encouraged by this development and it sort of ties in to all these questions about how many patients are there, how many patients are regularly transfused versus not..

Right..

But it doesn’t check the timeline that we’ve given before..

Yes..

Same timeline..

Well, the endpoint now will be based on the 40 patients or it would be assessed based on the initial 20 as before?.

Can’t say yes, I think that the way we wrote the study is that it’s really depended on a number of patients we could accrue and so that we’ll take a look at how we would do that and how many patients we need. It’s an open label study that will really depend on how things go..

Understood. And then the second question I had is just whether you could update us on the status of the European filing for TIBSOVO.

I think you should have the day 120 questions in hand now, just wondering is there any updates there?.

We were validated in January, so we expect to see the day 120 questions before – within the first half of the year and it’s May, so sometime in the next eight weeks or so. But yes, we’re right in the period and we’re expecting to receive them.

And then the next step, whether there’s a clock stop and sort of what we’re thinking in terms of potential approvals will depend on that. We have been talking about 2020, but when in 2020 really depends on some of those factors that I’ve just touched on.

The nature of the question, how long of the clock stop we take, whether there’s an oral explanation and other factors..

Understood. Great. Thanks for clarifying that and taking the follow-up question..

You’re welcome..

And I’m not showing any further questions this time. I’d like to turn the conference over back to Jackie..

Thank you, operator. 2019 is an important year for Agios as we work to execute across our broad oncology and rare genetic disease portfolios. We will also our complete our first full year of U.S. launch of our first wholly-owned commercial product, TIBSOVO and will commence our plans for commercialization outside U.S.

I would like to take this opportunity to thanks all of the tremendous employees at Agios for their dedication and passion to making a difference for patients. I also want to thank all of the patients, caregivers and physicians who participate in our clinical trials. Without them we cannot do what we do. Thank you all for joining us on the call today..

Ladies and gentlemen, this concludes today’s presentation. You may now disconnect and have a wonderful day..