U.S. Markets closed

Edited Transcript of AGIO earnings conference call or presentation 2-May-19 12:00pm GMT

Q1 2019 Agios Pharmaceuticals Inc Earnings Call

Cambridge May 9, 2019 (Thomson StreetEvents) -- Edited Transcript of Agios Pharmaceuticals Inc earnings conference call or presentation Thursday, May 2, 2019 at 12:00:00pm GMT

TEXT version of Transcript

================================================================================

Corporate Participants

================================================================================

* Andrew Hirsch

Agios Pharmaceuticals, Inc. - CFO & Head of Corporate Development

* Christopher J. Bowden

Agios Pharmaceuticals, Inc. - Chief Medical Officer

* Jacqualyn A. Fouse

Agios Pharmaceuticals, Inc. - CEO & Director

* Kendra Adams

Agios Pharmaceuticals, Inc. - VP of External Communications & IR

================================================================================

Conference Call Participants

================================================================================

* Alexander Daniel Duncan

Piper Jaffray Companies, Research Division - Research Analyst

* Bikramjot Singh

RBC Capital Markets, LLC, Research Division - Senior Associate

* Chris Shibutani

Cowen and Company, LLC, Research Division - MD & Senior Research Analyst

* Mark Alan Breidenbach

Oppenheimer & Co. Inc., Research Division - Executive Director & Senior Analyst

* Michael Werner Schmidt

Guggenheim Securities, LLC, Research Division - Senior Analyst & Senior MD

* Mohit Bansal

Citigroup Inc, Research Division - VP and Analyst

* Terence C. Flynn

Goldman Sachs Group Inc., Research Division - MD

================================================================================

Presentation

--------------------------------------------------------------------------------

Operator [1]

--------------------------------------------------------------------------------

Good morning, and welcome to Agios' First Quarter 2019 Conference Call. (Operator Instructions) Please be advised this call is being recorded at Agios' request.

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

--------------------------------------------------------------------------------

Kendra Adams, Agios Pharmaceuticals, Inc. - VP of External Communications & IR [2]

--------------------------------------------------------------------------------

Thank you, operator. Good morning, everyone, and welcome to Agios' First Quarter 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 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-K filed with the SEC and any other filings that we 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.

With that, I'll turn the call over to Jackie.

--------------------------------------------------------------------------------

Jacqualyn A. Fouse, Agios Pharmaceuticals, Inc. - CEO & Director [3]

--------------------------------------------------------------------------------

Thanks, Kendra. Good morning, everyone, and thanks for joining us on our Q1 2019 earnings call. I'm now 3 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 III 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 II 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 I lymphoma study on 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 a 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 will 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 forecast, 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 [first] .

Despite the slight revenue softness in Q1, we believe we are on track to deliver on our full year internal forecast 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 functions 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.

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [4]

--------------------------------------------------------------------------------

Thanks, Jackie. I'll begin with updates across our broad clinical development program for TIBSOVO and frontline AML, where we made significant progress since the beginning of the year in each of the 3 treatment categories: intensive therapy, nonintensive therapy and those patients who are not eligible for any standard treatments.

In February, the FDA accepted our supplemental new drug application for TIBSOVO in newly diagnosed IDH1 AML patients ineligible for standard therapies and gave us a PDUFA date of June 21. Our sNDA application, which is part of the FDA's new real-time oncology review pilot program and was granted Priority Review, is based on the results from the newly diagnosed arm from our Phase I study in IDH1-mutant hematologic 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, a randomized Phase III study of TIBSOVO or IDHIFA in combination with 7+3 recently initiated sites. This trial, run by the cooperative groups HOVON and AMLSG, will enroll approximately 1,000 patients and compare 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 2 years, which will enable us to evaluate longer duration in the intensive setting.

In the nonintensive therapy setting, patients are not able to tolerate aggressive chemotherapy and often receive hypomethylating agents, such as azacitidine.

In February, we presented compelling data from the Phase I study of ivosidenib and azacitidine at the leukemia meeting in Munich, demonstrating an overall response rate of 78% and increased CR rate of 57% since the prior data presentation at ASH 2018 and a 12-month survival rate of 82%.

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

From a safety perspective, results from the combination were consistent with the safety profiles of each drug used alone and cytopenias were in line with those seen for azacytidine alone and favorable compared with other emerging hypomethylating agent 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 III AGILE trial with this combination is ongoing with enrollment expected to complete in 2020.

Beyond AML, myelodysplastic syndrome is an 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 a compelling overall response rate of 92% in the 12 patients enrolled in our Phase I study.

In order to further evaluate the utility of TIBSOVO in the approximately 3% of MDS patients with an IDH1 mutation, we decided to reopen the MDS on the Phase I study to enroll approximately 30 additional patients. This will allow to further understand the role that TIBSOVO can play in this disease and determine the path forward with regulators. We expect the arm to reopen later this year and look forward to providing updates on subsequent calls.

Moving to solid tumors. We're on track to share top line data this quarter from our Phase III ClarIDHy trial of TIBSOVO in previously treated IDH1-mutant cholangiocarcinoma with a more complete clinical update at a medical meeting in the second half of 2019.

TIBSOVO has the potential to be the first targeted therapy approved in cholangiocarcinoma, and we are prepared to file a supplemental NDA by 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 where 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 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. Data from 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're currently enrolling 2 pivotal studies of mitapivat in adults with pyruvate kinase deficiency: ACTIVATE in patients who do not receive regular transfusions; and ACTIVATE-T in regularly transfused patients.

For the ACTIVATE-T trial, we're in the process of opening trial sites, and there were more patients eligible and interested in participating than we initially anticipated. As a result, we're increasing the trial size from 20 patients to up to 40. We expect to enroll the first 20 patients by the end of the third quarter.

For our Phase II study of mitapivat in thalassemia, we have started dosing patients with multiple trial sites 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 Institute of Health on a clinical trial of mitapivat in 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. As you know, in March 2018, we initiated a Phase I dose-escalation trial of AG-270, our MAT2A inhibitor in MTAP-deleted tumors with a goal of establishing a recommended dose based on safety, pharmacokinetics and pharmacodynamic markers of MAT2A inhibition.

As we have previously commented, we're pleased with what we have seen related to the effects on the pharmacodynamic markers of MAT2A inhibition, which we continue to monitor.

As we reviewed 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-limiting toxicities that we need to evaluate further in order to select the appropriate dose and schedule the expansion arms in future studies. With that, we now plan to finalize a dosing regimen and initiate both the monotherapy and combination expansion arms in the third quarter.

As we 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 and shareholders and most importantly for patients.

In April, we presented compelling preclinical work at AACR, demonstrating that the mechanism of action downstream with MAT2A creates a synergistic vulnerability to antimitotics, including clinically applicable taxanes.

Based on these data, we now plan to initiate 2 combination arms in areas of high unmet need. The first will test AG-270 in combination with docetaxel in [MTAP-deleted] non-small cell lung cancer. And the second will test AG-270 in combination with 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 the first clinical data from the Phase I dose-escalation study later this year.

For AG-636, our DHODH inhibitor, we have initiated sites for the Phase I lymphoma study and are currently screening patients.

With that, I'll turn the call over to Andrew.

--------------------------------------------------------------------------------

Andrew Hirsch, Agios Pharmaceuticals, Inc. - CFO & Head of Corporate Development [5]

--------------------------------------------------------------------------------

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 $11 million increase in collaboration revenue due to the satisfaction of a performance obligation under the Celgene collaboration, $9.1 million of net U.S. sales of TIBSOVO and $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 remained 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 a 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 III combination trial with 7+3, clinical trial activity from mitapivat in PK deficiency and thalassemia as well as [indiscernible] tech transfer for 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 the 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 to at least the end of 2020.

With that operator, please open the line for questions.

================================================================================

Questions and Answers

--------------------------------------------------------------------------------

Operator [1]

--------------------------------------------------------------------------------

(Operator Instructions) Our first question comes from Anupam Rama with JPMorgan.

(technical difficulty)

quantify the impact of TIBSOVO seasonality here in 1Q and maybe the time frame in which patients kind of work through the donut hole and plan changes and other seasonal headwinds. And then a second question on ClarIDHy. With top line results here on the horizon, maybe you could help us understand what you're hearing from the physician community about a minimal threshold for like a clinically meaningful effect and what's kind of that win scenario for you guys?

--------------------------------------------------------------------------------

Jacqualyn A. Fouse, Agios Pharmaceuticals, Inc. - CEO & Director [2]

--------------------------------------------------------------------------------

Thanks for the question. It's Jackie here. I have to say that you were cutting out during the first 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 very 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 moved 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. As we made our way through the quarter, we saw we were very happy with the volume growth that we saw and we have had strong volume growth in the month of April as well. So I think that gives us a lot of confidence in how we're going to round out the year here.

I would remind everybody, you know this, but it's the first time that we've gone through a Q1 for TIBSOVO and -- because we launched last July. So we're learning a little bit about some of the patterns here. We're talking about relatively small numbers in the grand scheme of things compared to some other drugs. So you can have some [relatively] small changes make a little bit more of an impact than you might think. But we feel like 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 continued increases in testing rights, so that base gives strong growth over the course of the year. Then we think that the impact of the seasonal things will be a little bit relatively maybe less in the future, but we're learning something about these trends. But the underlying trends are quite good. We're very happy with where we are.

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [3]

--------------------------------------------------------------------------------

Anupam, it's Chris here. I'll take the ClarIDHy question. So we designed ClarIDHy with a group of investigators who specialize in the treatment of cholangiocarcinoma. So the statistical assumptions around that, the PFS in the second-line setting based on literature and discussions with them is around 2 to 3 months. And the study, we assume that PFS will be about 3 months in the sample size. Overall, the study has a 96% power [to detect the] hazard ratio of 0.5. So that's essentially a doubling of PFS. I'll remind you, though, that the trial can be positive based on the shape of the curve and being statistically superior to the control arm. So to get your question of what do clinicians think a meaningful clinical benefit would be is that a statistically positive study they think has the potential to be clinically benefit -- beneficial. And you can see -- and if you think about Kaplan-Meier curves, which is the way we look at these things from a statistical perspective, you can see curves 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 and a high unmet need, we think any number of scenarios with a positive study would be clinically beneficial for these patients.

--------------------------------------------------------------------------------

Operator [4]

--------------------------------------------------------------------------------

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

--------------------------------------------------------------------------------

Bikramjot Singh, RBC Capital Markets, LLC, Research Division - Senior Associate [5]

--------------------------------------------------------------------------------

This is Bikram on for Kennen. He is on a flight right now. So I'll fill in for him. So quick 2 questions for us on AML. So with frontline AML expansion in June, can you help us understand the size of the patient population you're looking at versus the current label? And what will be the anticipated treatment duration there versus the currently labeled last-line IDH mutation patients?

--------------------------------------------------------------------------------

Jacqualyn A. Fouse, Agios Pharmaceuticals, Inc. - CEO & Director [6]

--------------------------------------------------------------------------------

Thanks for the question Bikram. So -- 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 yet 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 need to just get that final label and then we'll be able to give you a little bit better idea of what the range of the number of patients associated with that particular label indication would be. We're really looking forward to it. It's going to be a great moment for us to get into that frontline setting in any patient population.

--------------------------------------------------------------------------------

Bikramjot Singh, RBC Capital Markets, LLC, Research Division - Senior Associate [7]

--------------------------------------------------------------------------------

If I can squeeze in one more in terms of AML landscape, how is it evolving with [relation] to VENCLEXTA? I think there are number of clinical trials which academic centers are pursuing. Is that something you're thinking about to pursue in combination with TIBSOVO? Or any potential synergies there in the region you can comment on?

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [8]

--------------------------------------------------------------------------------

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 this space. So that's after decades of really not having much in the way of clinical investigation to improve outcomes for patients. So it creates 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 is, 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 FLT3 inhibitors, Vyxeos, a number of drugs. So there's going to be a lot of activity here, not just in newly diagnosed patients, but in patients who relapse looking at how do you sequence these drugs. Given that they're all oral agents, they can be given in combination, they can be given in sequence and the 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 her trial. She is in control of that when it's going to be published and I'm looking forward to getting that data as well as with the expansion that I just talked to.

--------------------------------------------------------------------------------

Operator [9]

--------------------------------------------------------------------------------

Our next question comes from Michael Schmidt with Guggenheim.

--------------------------------------------------------------------------------

Michael Werner Schmidt, Guggenheim Securities, LLC, Research Division - Senior Analyst & Senior MD [10]

--------------------------------------------------------------------------------

Congrats on 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 presentations from AACR on the potential development in monotherapy and combination? What was the basis for specifically selection of lung cancer and pancreatic for the initial expansion cohorts, for example? And then, could you just then talk about some DLTs and the need to optimize dosing of AG-270, particularly around monotherapy. Can you just help us understand that a little bit better?

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [11]

--------------------------------------------------------------------------------

]

Okay. Great. It's Chris here. Let me do the dose piece first and then I'll finish with some of the things we're thinking around combination therapy and -- because that's predicated on some of the interesting data that our teams have been working on 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. Because in Phase I, 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 the work that we've done with biomarkers and pharmacodynamic markers that is looking at SAM 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 have prespecified that we can look at BID, which is what we did, and that's when we have 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 that we recently dosed. We'll take a look at that exposure data and that PD data, reference that back to what we've 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 delay to the program.

With regards to the combinations is that what our research team presented at AACR demonstrated that when you inhibit MAT2A [of] downstream effects that can affect splicing and DNA repair and cell cycle defects that can be addressed by combining a MAT2A inhibitor, AG-270, with taxanes, and taxanes are ubiquitous in the treatment of patients predominantly with solid tumors. And 2 areas if you think about the frequency of MTAP deletions with high unmet need, non-small-cell lung cancer and pancreatic cancer come to the fore as 2 important indications because taxanes can be cornerstone therapy depending on the setting, et cetera. So that's why we select them as our first 2 combination indications that we want to look at.

--------------------------------------------------------------------------------

Michael Werner Schmidt, Guggenheim Securities, LLC, Research Division - Senior Analyst & Senior MD [12]

--------------------------------------------------------------------------------

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

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [13]

--------------------------------------------------------------------------------

Overall, we're very satisfied with the progress of the trial in terms of -- information we've got in terms of 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 setting, so yes.

--------------------------------------------------------------------------------

Operator [14]

--------------------------------------------------------------------------------

Our next question comes from Chris Shibutani with Cowen.

--------------------------------------------------------------------------------

Chris Shibutani, Cowen and Company, LLC, Research Division - MD & Senior Research Analyst [15]

--------------------------------------------------------------------------------

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 realized it's still early to go 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.

--------------------------------------------------------------------------------

Jacqualyn A. Fouse, Agios Pharmaceuticals, Inc. - CEO & Director [16]

--------------------------------------------------------------------------------

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 quite a number of drugs coming to the AML market in the last 12 to 18 months. We had 3 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 mean I think it is 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've heard me use the analogy of how we saw the multiple myeloma play out over the past 4, 5 years and now there were a bunch of new therapies that came to market there as well. So I think for our drugs in particular, when you think about patients with an IDH mutation, there's no reason why patients shouldn't see one of our drugs over the course of their treatment paradigm. And I believe that, and as we have our ongoing label expansions, then we will 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. So 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 a lot of experience building in that geography. And hopefully, we'll be 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 it to. So you'll hear more to come from us on that in the future.

--------------------------------------------------------------------------------

Chris Shibutani, Cowen and Company, LLC, Research Division - MD & Senior Research Analyst [17]

--------------------------------------------------------------------------------

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

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [18]

--------------------------------------------------------------------------------

Well, we had -- we were thinking at JPMorgan, we would get everything, the 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, the 2 combination cohorts and the monotherapy expansion.

--------------------------------------------------------------------------------

Operator [19]

--------------------------------------------------------------------------------

Our next question comes from Mohit Bansal with Citigroup.

--------------------------------------------------------------------------------

Mohit Bansal, Citigroup Inc, Research Division - VP and Analyst [20]

--------------------------------------------------------------------------------

I mean just to follow up on the AG-270 program, when we see the data in the later half of the year, should we be expecting any responses as that? Or we should be more focused on the biomarker testing lines. And then I have a follow-up after that.

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [21]

--------------------------------------------------------------------------------

It's Chris here. When I look at Phase I 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 hitting the target, how well is that target validated is important than that. The exposures of 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 focus in 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 doses taken with Phase II for further development. I mean if you think about this trial, it's a solid tumor study where we see just a variety of patients with different diagnoses. They've had varying levels of varying prior therapy. And so to -- and from your question around efficacy, making conclusions on the basis of 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 objective of the study.

--------------------------------------------------------------------------------

Mohit Bansal, Citigroup Inc, Research Division - VP and Analyst [22]

--------------------------------------------------------------------------------

That's 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 which will make you move ahead in trials there?

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [23]

--------------------------------------------------------------------------------

Yes. So the bar for declaring an effective drug is not something I can answer right now. The way we design the study is a pilot study, designed to see what level of clinical activity we could see. Based on our hypothesis, what 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 a lots of things happening and 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 with a single agent or with some of these new drugs coming in combination. So there's just a lot of possibility here, but the thing that we're really wanting to do first was to see if we can demonstrate proof of concept in a relatively small number of patients.

--------------------------------------------------------------------------------

Operator [24]

--------------------------------------------------------------------------------

Our next question comes from Terence Flynn with Goldman Sachs.

--------------------------------------------------------------------------------

Terence C. Flynn, Goldman Sachs Group Inc., Research Division - MD [25]

--------------------------------------------------------------------------------

Maybe just 2 for me. First on vorasidenib in low-grade glioma. Just wondering what's [date you are] starting the Phase III 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 DLT. Was that on target or off target? And any potential venue in mind yet for the presentation of that data?

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [26]

--------------------------------------------------------------------------------

Yes. So vorasidenib and moving forward with a pivotal trial now, Terence, it's Chris here, we're interacting with regulators, getting feedback, defining the patient population, understanding from them what -- how they see this patient population and this watch-and-wait approach, what they think are 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 toxins, some not. That's pretty typical for Phase I 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.

--------------------------------------------------------------------------------

Operator [27]

--------------------------------------------------------------------------------

Your next question comes from Peter Lawson with SunTrust Robinson.

--------------------------------------------------------------------------------

Unidentified Analyst, [28]

--------------------------------------------------------------------------------

This is [Waleed] on for Peter. Just a quick question on the upcoming ASCO presentation. Can you help set some investor expectations on what we may be able to see in that data?

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [29]

--------------------------------------------------------------------------------

Mostly what you're looking at on the heme side is 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 a 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 2 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, but it's not the only data set. And you've heard us reference [there's no] data for both TIBSOVO and vorasidenib in these patients with low-grade glioma.

--------------------------------------------------------------------------------

Unidentified Analyst, [30]

--------------------------------------------------------------------------------

Great. That's really helpful. And just a follow-up. If we're thinking about mitapivat, can you talk about how you're thinking about the market opportunity for PKR deficiency given it's widely underdiagnosed? And do you expect that to be a hurdle for patient enrollment in your clinical studies?

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [31]

--------------------------------------------------------------------------------

The commercial opportunity?

--------------------------------------------------------------------------------

Jacqualyn A. Fouse, Agios Pharmaceuticals, Inc. - CEO & Director [32]

--------------------------------------------------------------------------------

I can talk about that. I think there is excellent enrollment in the studies based on the...

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [33]

--------------------------------------------------------------------------------

No, our accrual has been going well, and we expect to complete by the end of the year for both studies. In ACTIVATE-T, we -- actually were able to find more patients than we initially anticipated, which is why we increased the sample size.

--------------------------------------------------------------------------------

Jacqualyn A. Fouse, Agios Pharmaceuticals, Inc. - CEO & Director [34]

--------------------------------------------------------------------------------

So -- and it's Jackie. I think we maybe 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 are pretty broad. So over time, we'll be refining what we think about 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 physicians in that regard, and we'll, again, give you more information around those opportunities as we take them forward.

--------------------------------------------------------------------------------

Andrew Hirsch, Agios Pharmaceuticals, Inc. - CFO & Head of Corporate Development [35]

--------------------------------------------------------------------------------

This is Andrew. I think what we've said previously is we think there's about 3,000 to 8,000 patients in U.S. and EU that are addressable. We know that, 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. As you know, since it's an underdiagnosed disease, you'll never be perfect until you're actually on the market.

--------------------------------------------------------------------------------

Operator [36]

--------------------------------------------------------------------------------

Your next question comes from Mark Breidenbach with Oppenheimer.

--------------------------------------------------------------------------------

Mark Alan Breidenbach, Oppenheimer & Co. Inc., Research Division - Executive Director & Senior Analyst [37]

--------------------------------------------------------------------------------

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 plans -- or label expansion plans in this population, or if the plan right now is to kind of let the AGILE trial run its course and file after that completes?

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [38]

--------------------------------------------------------------------------------

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 discussed to discuss TIBSOVO 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 beta AML where we're treating patients with TIBSOVO and azacitidine as well as our 005 study. So we've got a number of different data sets that we'll want to discuss with them -- with -- in the setting [up] 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 says -- shows might allow us to think about another way of building on to 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.

--------------------------------------------------------------------------------

Operator [39]

--------------------------------------------------------------------------------

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

--------------------------------------------------------------------------------

Alexander Daniel Duncan, Piper Jaffray Companies, Research Division - Research Analyst [40]

--------------------------------------------------------------------------------

This is Alex Duncan on for Tyler. 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 of the maintenance phase?

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [41]

--------------------------------------------------------------------------------

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 time lines.

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 prespecified, then you can unblind the study. So it's -- and that really is a very interesting question you raised. I just can't answer now, but it's really going to be dependent on when patients progress, meet that primary endpoint of event-free survival is when it would be unblinded. 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.

--------------------------------------------------------------------------------

Operator [42]

--------------------------------------------------------------------------------

Our next question comes from Michael Schmidt with Guggenheim.

--------------------------------------------------------------------------------

Michael Werner Schmidt, Guggenheim Securities, LLC, Research Division - Senior Analyst & Senior MD [43]

--------------------------------------------------------------------------------

I just had a couple more. Regarding ACTIVATE-T, so the addition of these 20 additional patients, I guess, can you help us understand the time lines to potential data -- data release? I guess does that impact potential data disclosure or the endpoint itself? And then, I had a second question after that.

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [44]

--------------------------------------------------------------------------------

So we're guiding to getting the first 20 patients in by the end of the third quarter, and we hope to get additional up to 40 patients in. Now -- then you have to follow them to -- because this is in 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't guide to when we have a data readout. We're thinking about ACTIVATE-T in the setting of ACTIVATE as well, but we're very encouraged by this development and it sort of ties into all these questions about how many patients are there, how many patients are regularly transfused versus not.

--------------------------------------------------------------------------------

Unidentified Company Representative, [45]

--------------------------------------------------------------------------------

But it doesn't change the time line that we've given you before. Same time line.

--------------------------------------------------------------------------------

Michael Werner Schmidt, Guggenheim Securities, LLC, Research Division - Senior Analyst & Senior MD [46]

--------------------------------------------------------------------------------

Will the endpoint now be based on the 40 patients? Or it will be assessed based on the initial 20 as before?

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [47]

--------------------------------------------------------------------------------

Can't say yet. I think that the way we wrote the study is that it's -- was really dependent on a number of patients we would have -- we could accrue. And so then we'll take a look at how we would do that and how many patients we need. It's an open-label study and that will really depend on how things go.

--------------------------------------------------------------------------------

Michael Werner Schmidt, Guggenheim Securities, LLC, Research Division - Senior Analyst & Senior MD [48]

--------------------------------------------------------------------------------

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?

--------------------------------------------------------------------------------

Christopher J. Bowden, Agios Pharmaceuticals, Inc. - Chief Medical Officer [49]

--------------------------------------------------------------------------------

We were validated in January. So we expect to see the day [120] questions before the -- it was in the first half of the year and it's May, so some time within the next 8 weeks or so, but, yes we're right in the period we're expecting to receive them. And the next steps whether there is 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 questions, how long of a clock stop we take, whether there's an oral explanation and other factors.

--------------------------------------------------------------------------------

Operator [50]

--------------------------------------------------------------------------------

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

--------------------------------------------------------------------------------

Jacqualyn A. Fouse, Agios Pharmaceuticals, Inc. - CEO & Director [51]

--------------------------------------------------------------------------------

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 complete our first full year of U.S. launch of our first wholly owned commercial product, TIBSOVO, and we will commence our plans for commercialization outside the U.S. I would like to take this opportunity to thank 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 clinical trials. Without them, we cannot do what we do. Thank you all for joining us on the call today.

--------------------------------------------------------------------------------

Operator [52]

--------------------------------------------------------------------------------

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