Agios Pharmaceuticals Inc (AGIO) 2016 Q4 法說會逐字稿

Good morning, and welcome to Agios' fourth-quarter 2016 conference call.

(Operator Instructions)

Please be advised that this call is being recorded at Agios' request.

I would now like to turn the call over to Renee Leck, Senior Manager, Investor and Public Relations of Agios.

Thanks, Ben. Good morning, everyone, and welcome to Agios' fourth-quarter +2016 conference call. You can listen to a live webcast with slides or a replay of today's call by going to the Investors section of our website, agios.com.

With me on the call today with prepared remarks are Dr. David Schenkein, our Chief Executive Officer, who will review our key milestones for 2017; Dr. Chris Bowden, our Chief Medical Officer, who will provide an update on our clinical development activities; and Andrew Hirsch, our Chief Financial Officer, who will summarize Agios' fourth-quarter and full-year 2016 financial results.

Before we begin, I would like to remind you that today's discussion will include statements about the Company's future expectations, plans, and prospects that constitute forward-looking statements for the purposes of the Safe Harbor provisions under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in the Risk Factor section of our annual report on Form 10-K which is on file with the SEC.

In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. While we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so even if our views change.

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

Thanks, Renee. Good morning, everybody. Thanks for joining us today. 2017 is set to be an extraordinary year for Agios, with two precision cancer medicines leading our transition to a commercial company; multiple pivotal trials in cancer and rare genetic diseases ongoing or in the planning phase; and a rich research pipeline, which is poised to deliver our next investigational medicine.

Before I dive into the 2017 milestones, I'd like to remind you of how far we've come since 2009 when we opened our labs with a blank piece of paper and a great team of scientists. We focused on culture and interrogating a new and disruptive area of cancer biology, that of cancer metabolism. In just eight years, our breakthrough discoveries in IDH have brought us on the verge of becoming a commercial organization, with a discovery engine capable of continued excellence in discovering novel first-in-class targets.

Now let me share with you some of our key priorities for 2017. I'll start with the IDH portfolio. In December, Celgene, together with our support, submitted the NDA for enasidenib for relapsed/refractory AML with an IDH2 mutation. Both companies are preparing for a commercial launch later this year.

We plan to follow a similar path and submit an NDA for a wholly-owned IDH1 inhibitor, AG-120 now known as ivosidenib in relapsed/refractory AML this year. This submission will be based on data from our ongoing Phase 1 clinical trial. To make sure that every patient with relapsed and refractory IDH mutant positive AML has access to our medicines, we've been building world-class capabilities to prepare for the expected launches of our IDH inhibitors.

In 2016, we hired our medical affairs and commercial leaders, who are now actively recruiting our field organization. In 2017 will be ready to fulfill our US co-commercialization responsibilities for enasidenib with Celgene and we plan to expand that organization to support the potential launch of ivosidenib, which makes it a truly exciting time for us as a Company. Chris will talk more about our plans to move into newly diagnosed AML patients with our Phase 3 AGILE trial, combining ivosidenib and VIDAZA, on track to begin in the first half of this year.

In pyruvate kinase deficiency, we continue to demonstrate our leadership by educating on disease burden and in our labs where we driving the science. Importantly, we're focused on moving AG-348 into a pivotal trial in the first half of 2018 for adults with pyruvate kinase deficiency. We expect to finalize and provide an update on the design of this trial in the third quarter of 2017.

At our core, Agios has always been and continues to be a research-driven organization. Upon completion of all the necessary preclinical studies, we're planning to submit an IND for our development candidate targeting MTAP-deleted tumors by the end of the year. MTAP deletions are present in approximately 15% of all cancers. As described in our 2016 Cell Reports publication, we have discovered a novel pathway in MTAP-deleted tumors, which, when inhibited, results in robust anti-tumor activity in animal models. Since sensitive patients can be selected by their MTAP status, this has the potential to be a next-generation precision medicine strategy. This pathway can be modulated by small molecule inhibitors and we will present data on our drug discovery efforts at next month's Keystone Tumor Metabolism Meeting in Whistler, British Columbia.

With all of this work happening in 2017, I'm excited to share our picture of what Agios could look like in the next 12 to 24 months. We expect to have two approved precision medicines in AML with multiple global pivotal studies underway for our IDH and PK deficiency programs. In addition, we expect our three active areas of research to continuous productivity.

Over the same period, we will continue to bring in new talent, all of them dedicated to helping to make an impact on patients' lives. This evolution of Agios is extraordinarily exciting because of the benefit that we believe it will provide to patients who are waiting for better treatment options.

I'll now turn it over to Chris to discuss our clinical activities.

Thanks David. This morning, we are pleased to announce a number of data presentations we expect to make this year across the IDH and PKR portfolios. In AML, our planned 2017 presentations will deliver data, supporting our speed and breadth clinical development strategy that is designed to demonstrate the clinical activity of our inhibitors across multiple lines of treatment. For AG-120, now ivosidenib, we plan to present the first Phase 1 expansion data in relapsed/refractory AML patients in the second half of 2017. This update will provide new efficacy and safety data in the group of patients that is the focus of our NDA activities for ivosidenib.

Also in the second half, we plan to present data from our Phase 1b front-line combination trial with standard of care intensive chemotherapy, commonly known as 7+3. This is one of two early stage trials underway in newly diagnosed AML patients; one combining enasidenib or ivosidenib with VIDAZA for patients ineligible for intensive chemotherapy and the other combining both targeted agents with 7+3 chemotherapy. Both have cleared a safety hurdle in the dose escalation component, demonstrating the ability to combine full-dose enasidenib or ivosidenib with full-dose standard of care therapy.

As we announced in January, we are on track to initiate the Phase 3 front-line AGILE study in the first half of 2017. Moving our drug to the front-line setting is an important component of our development strategy and will enable us to help more patients earlier in their diagnosis. AGILE will be a global randomized, double-blind, placebo-controlled trial and newly diagnosed IDH1 mutant positive AML patients who are not eligible for intensive chemotherapy. Participants will receive either the combination of ivosidenib at 500 milligrams once daily plus VIDAZA or placebo plus VIDAZA. The primary endpoint of the trial is overall survival with multiple secondary endpoints. The compelling single agent activity, unique mechanism of action, and safety profile of our IDH inhibitors gives us confidence that our medicines have the potential to change the treatment paradigm for patients with IDH mutant positive AML.

In addition to AML, we continue to explore the potential for our IDH inhibitors for people with IDH mutant positive solid tumors, where we have an opportunity to help a large number of patients with difficult-to-treat diseases and extremely limited treatment options. We presented promising data at the end of last year with ivosidenib in low-grade glioma, an indication where approximately 70% of patients have an IDH1 mutation. These data demonstrate that ivosidenib is safe and well-tolerated at a fixed daily dose of 500 milligrams with signs of prolonged stable disease.

We are also evaluating volumetric data to improve our understanding of response patterns beyond conventional methods. We believe more reliable endpoints and imaging techniques are needed to make clinical development in this disease more efficient. We plan to present additional data from the glioma expansion cohort in the second half of 2017.

We are also excited to initiate our first Phase 3 study for ivosidenib in cholangiocarcinoma in December of last year. ClarIDHy is a double-blind, placebo-controlled study with a two-to-one randomization of 186 cholangiocarcinoma patients who have had one or two prior therapies for advanced disease. Patients will receive either single-agent ivosidenib or placebo. The primary endpoint of the trial is progression-free survival with multiple secondary endpoints. Patients who progress on the placebo arm will have the option to cross over to ivosidenib. We plan to present at the data from the Phase 1 cholangiocarcinoma expansion cohort in the first half of this year. These data inform the design of ClarIDHy study and build on the clinical efficacy and safety from the dose escalation portion of the Phase 1 study.

As you recall, we have a third IDH mutant inhibitor, AG-881, that we are studying in hematologic malignancies and solid tumors. We designed AG-881 to be brain penetrant and we are focusing our development efforts in glioma. We have reached the maximum tolerated dose in the dose escalation phase of the Phase 1 solid tumor study. We are continuing to explore additional doses in glioma to confirm a recommended Phase 2 dose and expect to complete dose escalation in the first half of 2017. As we have previously communicated, our development strategy for glioma will be informed by the clinical data we are generating from our ivosidenib and AG-881 trials in consultation with investigators and our clinical advisors.

We've completed the accrual of the Phase 1 dose escalation trial in hematologic malignancies and demonstrate a proof of mechanism for AG-881, as measured by reductions in 2HG levels. Consistent with the findings from our other IDH inhibitors in hematologic malignancies, a maximum tolerated dose was not reached. Given the compelling clinical data generated with enasidenib and ivosidenib in AML, AG-881 will remain back-up molecule in hematologic malignancies.

Moving to rare diseases. We are committed to leading the science and driving disease awareness for pyruvate kinase deficiency, as we work to rapidly initiate a pivotal development program for AG-348. AG-348 has the potential to be the first treatment to address the underlying causes of pyruvate kinase efficiency, a rare hemolytic anemia.

The data from DRIVE PK, presented EHA and ASH last year, demonstrate compelling proof-of-concept for AG-348 in patients with pyruvate kinase deficiency. Approximately 50% of patients saw rapid, profound and sustained hemoglobin increases. For those who responded, AG-348 resulted in a mean hemoglobin increase of 3.6 grams per deciliter. This is a remarkable finding that splenectomy is generally associated with a 1 to 2 gram per deciliter hemoglobin increase.

The durability of responses and tolerability of the drug seem to date give us an increasing confidence in the potential for AG-348 as a long-term disease modifying treatment for pyruvate kinase deficiency. We plan to present updated data from the ongoing DRIVE PK trial in the first half of 2017. In the second half of the year, we will be in a position to share longer follow-up data from DRIVE PK in addition to secondary analyses and updated data from the natural history study.

We are actively working to move AG-348 into pivotal development and expect to initiate our first pivotal trial in the first half of 2018. As we outlined in January, the key aspects of the clinical development plan under consideration are patient population, trial size, dose and endpoints. We look forward to providing an update on our pivotal development strategy, including trial design, in the third quarter of this year once we have the appropriate regulatory interactions on the considerations I just described.

I'm now going to turn the call over to Andrew to review our financials.

Thanks, Chris. Today, we are in a strong financial position to support the activities that David and Chris just outlined, as we continue to build commercial capabilities and infrastructure to support the anticipated product launches for IDH inhibitors in AML, advance our clinical programs into multiple Phase 3 trials, and maintain our investments in our discovery research engine which has delivered six development candidates in the past eight years.

As we disclosed in early January, we ended 2016 with cash, cash equivalents, and marketable securities of approximately $574 million. This compares to approximately $376 million at the end of 2015. This increase in cash was driven by cash received from Celgene, totaling $258 million; net proceeds of $162 million from our September follow-on offering; and $8 million from other sources, including exercises of stock options.

These cash inflows were offset by expenditures to fund our operating activities and capital purchases, approximately $231 million for the full year. Based on our current operating plans, we expect that the year-end 2016 cash balance, together with anticipated payments from Celgene under our collaboration agreements, will enable us to fund our operating expenses and capital purchases through at least the end of 2018.

Turning to the full-year P&L, we recognized $70 million of collaboration revenue in 2016, compared to $59 million for 2015. This increase in collaboration revenue was primarily driven by the early completion of our discovery efforts for the MTAP program and new research efforts under the 2016 Celgene agreement. During 2016, we incurred $220 million in research and development expenses compared to $142 million for 2015. The year-over-year growth in R&D expense was primarily driven by increased clinical trial enrollment as well as increased manufacturing activities for all of our ongoing clinical stage programs. In addition, as of August 2016, we are responsible for 100% of the R&D cost for ivosidenib.

General and administrative expenses were $51 million for the full-year 2016 compared to $36 million for the prior year. The year-over-year increase was largely due to increased headcount and other professional expenses to support our growing operations.

I will now turn it back to David to wrap up

Thanks, Andrew. As we finish the call, I'd like to leave you with the vision we have for Agios that we articulated in early January. We are excited to become a commercial Company in 2017 with the ability to impact patients' lives.

I'd like to thank all of the tremendous employees at Agios for their dedication and their passion to make a difference for patients. I also want to thank all of the patients, the caregivers, and physicians who participate in our clinical trials and to thank our partner, Celgene.

With that, operator, we will now open the line for questions.

(Operator Instructions)

Eric Schmidt, Cowen and Company.

Thanks for the opportunity to ask a question and for all the updates. Maybe for David or Chris on 881, I think Chris commented that you're seeking a Phase 2 dose. Does that mean you've made a go-decision on Phase 2 for glioma or is that still in the works and when will we see the Phase 1 data?

Thanks Eric. Good morning. Let me turn it over to Chris to give you that.

So what we want to do, Eric, is identify a recommended Phase 2 dose. As you know, we have also data with 120 so we've got two viable candidates to think about developing in glioma. 120 is farther ahead in terms of the glioma experience and it's also going to be helpful in terms of the thinking about what the next steps would be with 881 as well based on some of the data we got from that expansion cohort we published at SNO.

So whether -- I wouldn't say that identifying a recommended Phase 2 dose is a go, a clear go for 881. I mean, we will have to look at both molecules and we will certainly need to work with Celgene on 881 as well in terms of thinking what the next steps would be. Right now, we're really focused on understanding the safety and pharmacokinetics in honing in on what dose or doses we might want to think about as a recommended Phase 2 dose to go forward with 881.

As far as publishing the data, once we've got the requisite information around that dose escalation and recommended dose piece, then we will be bringing that data forward. But we don't have guidance on that yet.

Okay. And then second question is just on 348 in the DRIVE PK study. Have you made a decision to expand or re-open enrollment with the potential second cohort?

Eric, do you mean the third optional arm that we have in there?

Sorry, the third cohort; yes

At this time, Eric we don't have anything plans to open that third arm. We feel like the data that we have from DRIVE PK at 50 and 300 milligrams as well as the duration of data that we have now with that we last published at ASH in December is providing us with ample information in terms of our forward plan.

Okay. Thank you.

Anupam Rama, JPMorgan.

On AG-348 in the 3Q update on trial design. I'm wondering what additional steps need to be taken between that point and say, trial initiation in the first half of 2018 and then just a quick one. Can you remind us for AG-221, or enasidenib, if that was filed for breakthrough designation? Thanks so much.

Anupam, thanks for your questions. Let me take your second one first and then I'll turn it over to Chris to talk about 348. So we don't -- we have never shared any information around our regulatory interactions with that level of detail, whether we applied or didn't apply for breakthrough. As you know or may remember, that both enasidenib and ivosidenib so 221 and 120 both have fast track and both have orphan designation.

Turning back to 348, as you know, as we design the pivotal trial, its goal is to seek global regulatory approval, and maybe I'll have Chris walk you through what we expect to guide you in terms of -- in the third quarter and what it will take to open the trial.

Anupam, Chris here. Chris Bowden. The way I think about your question is that there's the kind of qualitative phases of development and you're in the conceptualization phase and then you have to present your plans to regulators, and in this case, EMA, FDA and potentially others. That feedback that you get on your design is rarely 100% consistent.

And so then you get into some judgments in terms of which directions you're going to take. You also are interacting with investigators and so putting all the information is what drives you to what your final plans are around your clinical development plan, which translates into protocols. And that's -- those are the things that we need to pull together and that gets us into the third quarter of this year.

And at that point, we'd be talking about issues around patient population, sample sizes, and some of the other factors that I alluded to in my prepared remarks when I was showing the slide. And then your -- the other part of your question was then what happens? And that's when you get into the operation phase and that's getting your sites on board, getting through IRBs, and then ultimately, starting accrual.

And that really accounts for the time it takes to do what David emphasized, which is a global trial, which will capture those patient populations that we talked about.

Great. Thanks so much for taking the questions.

Kennen MacKay, Credit Suisse.

Maybe, David, one for you first. I was wondering if you could give some sort of sense of when we could see data from the submission package of AG-221, especially given that the endpoints of a confirmatory Phase 3 is for both 221 and 120 are survival, and hoping maybe we can get a sense of how long these patients are living here?

Yes, thanks. Good morning, Kennen. Thanks for your question. So as you know, together with Celgene, the enasidenib submission went in, in December, and obviously, this quarter, we'll hear from the FDA around their acceptance or not of the package and the PDUFA date and obviously, Celgene and Agios will give you an update on that.

We haven't articulated today what the disclosure presentation plans are for enasidenib 221. Obviously, Celgene will take the lead on that with Agios' support. I think it's too soon that you will see data during the year, but I can't give you that right at the moment. Celgene will articulate that and then we will follow up with that and so during the year, both 221 enasidenib, and as Chris articulated in his prepared remarks, you will see data from ivosidenib.

Got you. Thanks David and as far as I understand, FDA had 60 days to let you know about acceptance so that should be coming up based on the December NDA filing. Am I thinking about that right?

You are. The FDA does have 60 days to accept the NDA and therefore, we expect to see that this quarter. We haven't articulated exactly when that submission went in December though it did go in near the end of year, so we're obviously waiting to hear that together with Celgene.

Okay, thanks David. And then Chris, maybe just one for you. You had mentioned AG-881 is now going to be a back-up molecule in hematologic malignancies. So just wanted to get a sense of where that evolved from, whether it's based on conversations with Celgene or whatnot. This obviously seems like a best case scenario for Agios and the outlook for 120 given your full ownership there and split economics of 881. Thank you.

Kennen, this is David. Let me start there and then if I need be, Chris can follow up. Remember that 881 was never expected to be a lead molecule in the hem side. It was developed, as you remember, as a back-up molecule for AG-120, or ivosidenib because with better brain penetration.

Our expectation was that given how far ahead both enasidenib and ivosidenib were in the hem malignancy space, that the only utility on the hem side for 881 would be if one of those molecules had something that caused it to be delayed or stumble, et cetera, which we had not seen. And so really, the Phase 1 study in the hem space was really a safety study to give it the information we need, if we needed to move that molecule forward. So it's always been viewed as a back-up on the hem side and it's still in that same pole position.

Got you. Okay, thanks for the clarification, David. And then maybe just one more on 348, if I can work it in. Just wanted to get a sense of whether the timeline for your outline for registrational design in Q3 was based on guidance from meetings you already had with the FDA, or whether this was based on expectations following future meetings. Thank you.

Yes, Kennen, I can't share any of the details about whether we've -- when we've scheduled meetings and things like that. We do believe that it's fair to say that we expect to have conducted all the regulatory interactions and other internal work and work with investigators we need to be able to articulate for you and the rest of the outside world what the pivotal plans look like in the third quarter.

Okay. Thank you so much and looking forward to the update on 221 filing. Thank you.

John Newman, Canaccord.

Question is, in terms of AG-120, can you talk about maybe the endpoint that you think the FDA is going to focus on when you submit that data set? Do you think they are simply going to be looking at the response rate. Do you think they are going to looking at PFS? Do you think they are going to want to follow patients for survival? Obviously, this is a narrow indication given that you have to have mutation but curious of how you're thinking about that?

Thanks John. This is David. I'm going to turn it over to Chris

John, they are going to be interested in all of the endpoints that you talked about and then some. We're in a patient population relapsed/refractory AML that has limited-to-no treatment options. The -- and we've talked about a number of assets, our IDH inhibitors that offer clinical benefit to patients and that's the overall response rate, the CR rate, the duration of response.

And they will also, as they always are, even in single-agent studies, interested in overall survival. So those are a number of the aspects that we need to bring forward from an efficacy standpoint. And then, of course, the other perspective is what does the safety profile of a molecule look like? And there, they are going to be looking at a number of the same aspects, that is, what does a safety profile look like in the early phase of dosing?

What does it look like over time? There's a lot of questions around disposition. How many patients came on? How many discontinued from progressive disease, drug-related side effects, side effects overall. So all kinds of pieces of information come into play in terms of their overall assessment. We tend to get a lot of questions and there's an appropriate focus on what the primary endpoint is and that's important. I certainly acknowledge that, but it's really the totality of data that really sways them in terms of making a decision, yes or no.

Great and then I have just one additional question on 348. It's actually a follow-up to the first question from Eric, which is, I think in the past at ASH last year, when you gave the update, I think I remember correctly you alluded to potentially being able to modify the dose for 348 going forward. I'm just wondering if we should assume that this is a program where there's still active discussions with the agency and it's still a possibility that if you chose to, you could potentially think about a different dose for 348 or should we just assume that at this point in time, you're going forward with just one dose? Thanks.

If you look at the data that we -- that was presented at ASH, that's where in December of 2016, that was where we were talking about the fact that we were seeing durable responses and responses that were maintained at doses below 50 milligrams, and over the course of -- since we published the data first at EHA and then ASH, we've also talked about patients who had very robust increases in their hemoglobin and then [preferred] their dose titrated down.

So we don't have a guidance right now on what a dose would be and there's certainly some discussion as we look at the data and talk to investigators who are using the drug that there might be a range of doses where there could be an upper limit that where -- they won't go any higher but at this point, one of the things we are gratified by is the fact that we are able to explore range of doses and that we're seeing robust and sustained increases in hemoglobin in those who do respond at a range of doses.

So I could see us -- I'm not going to commit us to 50 milligrams at this point for sure since we are seeing durable responses at 25 milligrams and even lower. So it will be an active area of continued investigation and certainly in our interactions with regulators and IRBs is going to be an important part of the program.

Great. Thank you.

Yatin Suneja, SunTrust.

Just following up on John's question. I think earlier this year, in January, you said you might use a dose titration up to optimize hemoglobin responses for 348, but you -- have you done that in the DRIVE PK? Do you think that trial is enough or do you have to do another, like, a small trial to figure out an ideal dose titration strategy for 348? And then I had one more.

Yatin, it's Chris here. We have not done a, I would say a, formal dose titration up. We are -- investigators are exploring some opportunities to dose between 50 and 300 milligrams. They are allowed to do that. At the same time, what the data is telling us from the patient experience as we showed at ASH is that we tend to see pretty robust hemoglobin responses.

And then most of the moves, when investigators have titrate been going down is because the hemoglobin response is so robust they are into the normal range and so they start to titrate them down to keep them there.

The second part of your question is, do we think we need to do additional work that is a separate trial to study this further? At this point, I do not think so, and one of the reasons why that is it's because the safety profile between that 50 and 300 milligram range and below gives us a sense at this point that we can probably start to -- that we can ask this question and answer this type of question when we get into our pivotal trial design but more details to come there.

Got it, thanks. And then just one more. So you are planning to include transfusion dependent patients in the pivotal program. Could you maybe tell us what gives you confidence in that patient population given that you have not evaluated that subset yet and what sort of data you have? And then what needs to be done to evaluate this drug in kids in the future? Thank you

Yes, so Yatin, David here. We have not yet articulated the patient population that you should expect to see in the global pivotal study. That's part of the information that you will see in the third quarter. Obviously, we're having that discussion with regulators and investigators, as Chris articulated earlier. So I shouldn't make any assumption yet about what the patient population is; that's some of the work we are doing now.

As you may remember from our national history study, the incidence of adults who are transfusion dependent is very small. We are exploring that; we are trying to understand that. And so you'll need to stay tuned on that piece.

And the second part of your question was about pediatrics. As we've talked about before, our commitment is to develop a disease-altering therapy for all patient population, including pediatrics. Obviously, we need to capture more adult safety data before we can move down to children.

And as we've articulated before, with known mild-to-moderate aromatase activity we're seeing with 348, the real question is going to be, as Chris articulated, as we go down in the dose, can we get to a dose where it makes sense for us to move into pediatrics? It's just too early to commit to that at this point other than our overall plan is to, at some point, get to children once we've established safety and efficacy in adults.

Got it. Maybe one for Andrew. Andrew, could you help us figure out how should we model the revenues this year? Any milestones that we should be modeling this year or that you anticipate to receive this year?

Sure. Thanks. So the revenue model, I think as we've disclosed in 10-K, probably several pages on that is quite complex. So what we've done is we have assigned a value to each of the elements of deliverables under that collaboration agreement, and then we recognized revenue as we progress along those deliverables. And so it's hard just to give you guidance on how to do that because, for example, this quarter, one of the deliverables was the development candidate around the MTAP program.

We had to pick up the revenue because we completed that earlier than the planned timeline we assumed in the initial revenue model so we had to pick-up. It may be worth us spending some time off-line to go through that in some detail.

As to the second part of your question, around milestones, so we don't anticipate any milestones in a sense that we would recognize as a one-time pick-up in revenue. I think as we've disclosed once Celgene accepts the MTAP development candidate, as a collaboration development candidate, there is an $8 million milestone but that gets folded into this revenue recognition model so you won't see a pick-up, a one-time pick-up.

All right. Thank you very much, guys.

Debjit Chattopadhyay, Janney.

So as you think about 881, as you move forward 120 and 221 in the front-line settings, how do you see 881 play out in patients who have disease progression on either 120 or 221? What I'm trying to get at is in the completed Phase 1 safety study, do you have a feel for activity patients who have had disease progression with the other IDH inhibitors?

Thanks Debjit. I'll have Chris take that.

When we think about the use of the IDH inhibitors in AML, our main focus is, really, with ivosidenib and enasidenib. David and I talked to some of the aspects around 881 and how we thought about it in hematologic malignancies and how we presented it as a back-up molecule, just to be -- have it there in case either one of the lead molecules stumble.

I think the aspect of resistance and progression, when you're on IDH inhibitor is a very interesting one. We think it's going to be important to suppress the IDH clone over the course of treatment and one of the areas that we are very interested in studying and that we are starting to get some data on is what other malignant clones might emerge that would need an additional therapy put on, whether it's [fleck] three or some of the other potentially druggable clones that come up.

So at this point, we don't see a role for 881 coming in for those patients but rather, we were thinking more from a combination perspective and really understanding what count in the molecular signature changes over time, with the intent that there's going to be -- there's a strong scientific hypothesis at least to consider continuing to suppress your IDH clone.

There is some precedent for that and probably the one we think about the most is in the treatment of breast cancer, metastatic breast cancer with Herceptin, where you see that drug continued on over multiple different other therapies in an attempt to maintain disease control. So we have a lot of work to do there, but we're focused more on thinking about adding other therapies that dictate emerging patterns of resistance since we've demonstrated that we continue to suppress 2HG in the presence of progressive disease in AML in our patient so far who are on at least AG-120.

Great and just one follow-up on 348. Given the preferential response that you're seeing in certain genotypes, do you think the pivotal study is likely to be enriched for the very specific patient groups where you see activity and hence see or narrow label to go out with based on the data at hand or the interactions you may have had with the agency so far. Thank you so much.

Yes, thanks Debjit. It's too early to speculate on that. For DRIVE PK, we have not restricted enrollment by genotype. As you know, even though we put the genotypes into broad classes, each individual mutation is different, and that's why we've not restricted enrollment and it's just too early for us to comment on what the pivotal design will look like with respect to that factor. So we'll just need to stay tuned.

Thank you so much and good luck.

Thank you. At this time, there's no questions in queue. I will turn it back to Mr. Schenkein for any closing remarks.

I'd like to thank everybody who listened in and participated today. Thanks for your questions and look forward to speaking to you again in the future. Enjoy the rest of your day.

Ladies and gentlemen, thank you participation in today's conference. This concludes the program. You may now disconnect. Everyone, have a great day.