Blueprint Medicines Corp (BPMC) 2018 Q2 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Second Quarter 2018 Blueprint Medicines Conference Call. (Operator Instructions) As a reminder, this conference call may be recorded.

I would now like to introduce your host for today's conference, Ms. Kristin Hodous of Blueprint Medicines. Ma'am, you may begin.

Thank you, operator. Good morning. This is Kristin Hodous of Blueprint Medicines, and welcome to Blueprint Medicines' Second Quarter 2018 Financial and Operating Results Conference Call.

This morning we issued a press release which outlines the topics we plan to discuss today. You can access the press release as well as the slides that we'll be reviewing today by going to the Investors section of our website at www.blueprintmedicines.com.

Today on our call Jeff Albers, our Chief Executive Officer, will discuss Blueprint Medicines' second quarter 2018 business highlights; Dr. Andy Boral, our Chief Medical Officer, will provide an update on our clinical stage pipeline; and Mike Landsittel, our Vice President of Finance, will review our second quarter 2018 financial results. We will then open the call for your questions. Dr. Marion Dorsch, our Chief Scientific Officer, is also on the call and will be available for Q&A.

Before we get started I would like to remind everyone that statements we make on this conference call will include forward-looking statements. Actual events or 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 Quarterly Report on Form 10-Q filed with the SEC and any other filings that we may make with the SEC.

In addition, any forward-looking statements made on this call represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update or revise any forward-looking statements.

Now here's our CEO, Jeff Albers.

Thanks, Kristin, and good morning, everyone. In the second quarter, we continued to build and strengthen our differentiated portfolio with important progress across multiple programs.

During our last call, we highlighted very encouraging initial data for BLU-667 in patients with RET-altered cancers, which were presented at AACR. This morning our objective is to update you on the recently disclosed avapritinib data in advanced systemic mastocytosis and on our new strategic partnership with CStone Pharmaceuticals in China.

First, however, I wanted to provide perspective on the growing strength of our business. At Blueprint Medicines, we focus on developing potent and highly selective kinase medicines for patients with genomically defined diseases. By leveraging our scientific platform we aim to build a sustainable and differentiated company capable of rapidly delivering multiple therapies to patients globally. Today our portfolio includes 3 clinical-stage therapeutic candidates with compelling proof of concept and an expanding research pipeline, including up to 9 additional programs focused on genomically defined cancers, rare diseases, and cancer immunotherapy.

We plan to submit our first NDA for avapritinib in the first half of next year. We're beginning to build our commercial organization and infrastructure while maintaining a view toward scalability and advancing our broader pipeline. Ultimately our portfolio-driven strategy separates us from our peers, and we believe the value we'll create for patients and physicians won't be measured by a single opportunity but by a constellation of transformative medicines and the leverage that that will afford us.

Over the last quarter, we continued to make tremendous progress towards making this vision a reality. In June we presented exciting new data for avapritinib at the European Hematology Association Congress showing deep and durable responses in patients with advanced systemic mastocytosis. These results, combined with compelling data in patients with advanced GIST, serve to strengthen our confidence in the avapritinib program as the centerpiece of our portfolio strategy.

In June we initiated the pivotal Phase 3 VOYAGER study in third-line GIST, which is now rapidly ramping up with more than 10 global sites activated already since initiation last month. With the potential to support approval in third-line GIST, this trial represents an important pillar of our avapritinib registration strategy.

As we announced last quarter, we plan to submit our first NDA for avapritinib in the first half of next year for PDGFR-alpha-driven GIST based on the remarkable data from the ongoing Phase I NAVIGATOR study. Importantly, given the data to date, we also plan to include fourth-line GIST within this NDA submission. By the end of the quarter, we expect to have four pivotal trials of avapritinib in GIST and SM underway with the potential to expedite approval in defined patient populations.

In addition, we're on track to report updated data from the NAVIGATOR study in multiple GIST patient populations later this year, including a first look at second-line GIST patients. These data will inform the design of a new second-line clinical trial to be initiated in 2019.

Overall, the opportunity for avapritinib to impact patient care is significant. Across the GIST and systemic mastocytosis populations we're focused on with avapritinib we estimate there are approximately 30,000 patients in the U.S., EU5 and Japan.

Beyond avapritinib, we continue to make exciting progress across multiple other programs. As I noted earlier, the initial dose escalation data from our Phase I ARROW study of BLU-667 showed favorable safety as well as high response rate and robust anti-tumor activity in patients with RET-altered lung and thyroid cancers.

Based on these compelling early data we rapidly expanded the ARROW study to evaluate BLU-667 at the maximum tolerated dose. Today we have more than 20 sites enrolling patients globally with plans to activate additional sites in the month ahead.

In the second half of this year, we'll focus on continued clinical execution and obtaining ongoing regulatory feedback for our registration strategy. Overall we've been very encouraged by the enthusiasm of patients and investigators, and we're working hard to move this program forward rapidly.

We're also advancing the BLU-782 ALK2 program towards the clinic for the rare bone disease fibrodysplasia ossificans progressiva. We're on track to submit an IND by the end of the year, which will enable us to initiate a Phase 1 clinical trial in healthy volunteers.

Recently we were excited to learn that a BLU-782 abstract was accepted for oral presentation at the American Society for Bone and Mineral Research Annual Meeting on September 30. At that meeting, we'll share the foundational preclinical data supporting the BLU-782 program as well as our initial clinical plan.

In addition, our research pipeline continues to flourish. Last month we achieved a significant research milestone under the ongoing cancer immunotherapy collaboration with Roche, resulting in a $10 million milestone payment. And earlier this year we initiated a new wholly owned program targeted an undisclosed oncogenetic disease driver.

Now I want to take a moment to highlight our strategic collaboration with CStone Pharmaceuticals which we announced in June. We believe this partnership is important for several reasons.

First, the partnership enables us to take advantage of recent regulatory reforms and an emerging focus on innovation in China to potentially reach a previously unaddressable patient population. Second, the collaboration will accelerate our global clinical development programs, particularly for BLU-554.

By the end of this year, we plan to submit an IND for BLU-554 to the China health authorities. This will enable us to activate clinical sites in China for our ongoing Phase 1 monotherapy trial focused on TKI in naive patients and initiate a new clinical trial in combination with CStone's anti-PD-L1 checkpoint inhibitor in 2019. Worldwide more than half of all liver cancer cases occur in China each year, so there's a clear opportunity to rapidly enroll these studies.

Then finally the collaboration's financial terms reflect our companies' shared view of the significant opportunity in China. Along with a $40 million upfront payment the agreement includes $346 million in potential future milestones to us and tiered percentage royalties ranging from the mid-teens to low 20s on annual net sales. Ultimately we believe the partnership has the potential to fuel further investment and growth at Blueprint Medicines over the long term.

Now I'll ask Andy Boral to provide his clinical perspective on the avapritinib data in advanced systemic mastocytosis. Andy?

Thanks, Jeff, and good morning, everyone. As Jeff described, we've made tremendous progress across our clinical-stage programs. We're working hard to advance our ongoing trials and expand clinical activities across our portfolio, with the goal of quickly delivering new medicines to patients.

Last month we were pleased to share an important update on the ongoing Phase 1 EXPLORER trial in patients with advanced systemic mastocytosis at the EHA Congress in Stockholm. As a reminder, the trial includes 2 parts.

Last year we completed the dose escalation part of the trial and reported results at the ASH Annual Meeting. Subsequently, we initiated the expansion part of the trial, and at EHA we shared long-term results for patients enrolled in the dose escalation part of the trial, with a focus on durability, as well as initial results for patients enrolled in the expansion so far.

We're very encouraged that the data show profound and durable clinical activity, with an overall response rate of 83% based on the rigorous IWG response criteria. This represents a deepening of response from the earlier data set we presented at ASH. Importantly, the preliminary results of avapritinib appear to be better than the data for Midostaurin, the only FDA-approved medicine for advanced SM, which had a comparable response rate of 28% based on the IWG response criteria.

The initial view on durability is also very positive. In our EHA poster, we reported durable, ongoing responses up to 22 months. In addition, almost 2.5 years after the study start 80% of patients remain on treatment, which is an impressive length of time in patients with an advanced hematological malignancy. These data are consistent with our view that avapritinib has the potential to be used chronically in these patients.

In addition, the data showed that avapritinib is generally well tolerated. Most adverse events were mild or moderate, and only 3 patients discontinued therapy due to treatment-related adverse events.

Looking forward, we are implementing a PRO, or patient-reported outcome survey, specifically designed for patients with systemic mastocytosis. We expect this tool to further characterize the benefit that avapritinib provides to a patient's quality of life.

Importantly, all patients showed objective reductions in mast cell burden. These very robust clinical data give us confidence that avapritinib has the potential to be approved in a broad population.

The data show profound improvements in bone marrow mast cells, serum tryptase, spleen volume, and KIT D816V mutant allele fraction. In addition, 58% of patients showed complete resolution of neoplastic mast cells in their bone marrow, an exciting outcome that's never been seen before with other therapies.

We also see encouraging clinical data in the two patients with smoldering systemic mastocytosis, which is an intermediate form of the disease, and those patients were enrolled in the EXPLORER trial. Similar to patients with more advanced disease, these patients show robust improvements on multiple measures of mast cell burden. Overall, these data demonstrate avapritinib's unique and exquisite selectivity for the KIT D816V mutant, the common disease driver in nearly all patients across the spectrum of systemic mastocytosis.

So with compelling clinical data and favorable FDA feedback, we have some clear next steps. We plan to initiate the PATHFINDER, an open-label, single-arm Phase 2 trial designed to support approval in patients with advanced systemic mastocytosis, in the third quarter. This trial will enroll up to 60 patients with advanced SM, including both previously treated and treatment-naive patients.

Patients will be required to have an evaluable clinical finding, or C finding, per the IWG criteria. The primary endpoint will be response per IWG, and the key secondary endpoints will include patient-reported outcomes, progression-free survival, overall survival, and safety. Importantly, avapritinib has demonstrated strong clinical activity across all dose levels tested, and we believe the wide therapeutic index will enable investigators to optimize dosing to maximize clinical benefit and tolerability.

The second study, PIONEER, will be a randomized Phase 2 trial intended to support approval in patients with indolent and smoldering SM. The trial will follow a seamless design, including dose escalation -- excuse me, dose selection -- we do not expect to escalate sequentially in the study, so dose selection, a placebo-controlled efficacy assessment, and open-label extension. Importantly, all patients who enroll in the trial will have the opportunity to receive avapritinib in the extension. The primary endpoint will be a patient-reported outcome survey developed specifically for patients with indolent and smoldering systemic mastocytosis.

Now I want to close by highlighting how personally excited I am by the updated avapritinib data in advanced SM. We've heard many encouraging stories from patients and investigators that bring home both the devastation of this disease and the possibility for improved treatment with avapritinib.

This program embodies our strategy at Blueprint Medicines, where we've matched a genomic driver of disease with a highly selective kinase inhibitor medicine; demonstrated strong clinical activity in an early Phase 1 trial; and identified a potentially rapid path to approval. Our goal now is to quickly advance this program as well as additional therapeutic candidates that can help patients with cancer and other serious diseases.

Now I'll turn the call over to Mike to review our financial results for the second quarter. Mike?

Thanks, Andy. So I'll start by reviewing our Q2 operating performance, and then I'll cover our cash position and run rate guidance.

We recognized $41.4 million of collaboration revenues in the second quarter of 2018. The increase in revenue from the prior year was due to the recognition of the $40 million upfront payment that we received upon the execution of the CStone agreement.

With respect to operating expenses, we incurred $58.6 million in R&D expenses in the quarter, which represents an increase of $25.3 million from the second quarter of 2017. The key drivers of the increase were the initiation of the Phase 3 study in third-line GIST, preparations for our Phase 2 trial in advanced SM with avapritinib, the expansion of our Phase 1 study with BLU-667, investments in manufacturing across our late-stage portfolio, as well as growth in personnel costs as we continued to build our development infrastructure.

G&A expenses were $12.3 million for the second quarter, an increase of $5.5 million from the prior year. This increase was primarily due to increased personnel-related expenses and increased professional fees, including pre-commercial planning activities.

Turning now to our balance sheet, we continue to operate from a strong financial position, which allows us to focus on execution across our entire portfolio.

We ended the second quarter with cash, cash equivalents, and investments of $616.7 million, as compared to $673.4 million as of December 31, 2017. The decrease was related to cash used in operations partially offset by the $40 million upfront payment from CStone and a $10 million milestone payment from Roche, both of which were received in the second quarter.

We believe that our current cash position provides us the necessary capital to fund our operations into the second half of 2020.

We are very pleased by the progress we've made year-to-date, and we look forward to further expanding our clinical development efforts and precommercial activities in the months ahead. As such, we expect that our operating expenses will continue to increase as we accelerate our efforts to bring meaningful new therapies into the hands of patients with genomically defined cancers and other rare diseases.

With that, I will now turn the call over the operator for questions. Operator?

(Operator Instructions)

Our first question comes from Terence Flynn with Goldman Sachs.

Maybe first, Jeff, on avapritinib, you mentioned this during your remarks, that you're going to be filing for fourth-line KIT-driven just as well. Can you tell us if that decision was just based solely on the data or did you also have some dialog with FDA on that front? And then for the avapritinib NAVIGATOR data in second-line GIST, what do you guys want to see there to advance into the next trial that you mentioned in 2019, and would that be a pivotal study?

All right. Thanks, Terence. I'll take the first question and I'll pass the second one on to Andy. So as with any filing it's an accumulation of both data and regulatory feedback. And so with the data we have in hand to date, based on general feedback and the clear medical need in fourth-line GIST where there are no available treatments, we currently are in the position or of the view that it makes sense to blend the PDGFR-alpha and fourth-line GIST, which obviously, as you know, is at one study into our filing. And we'll continue to evaluate that. We still have patients on and will gather more data and will provide a more concrete update when we share that clinical data later this year. And then the second question was around second-line and what that path forward would look like.

Yes. So thanks, Terence. So the second-line arm in the NAVIGATOR study does continue to enroll well, and as we've said before, we will disclose results from that, on that arm when we update on the study in general later this year. The plan there is to -- we really see a two-pronged potential approach. We plan to initiate the trial in second-line in 2019 that could either focus on all comers, and that would be a randomized study against something like Sutent, or it could focus on a subset of patients based on a genetic selection where we have a very high degree of activity with avapritinib. And that will be a data-driven decision as we look at the data later this year.

Yes. And in either case, that would be a registration study.

Our next question comes from Laura Chico with Raymond James.

I guess I have 2 on SM. Andy, thanks for the comments around the EHA data. I'm just wondering if you could help me put that into context against RYDAPT, and I think you did a little bit there. If I look at the RYDAPT label and focus just on CRs and PRs versus avapritinib, response rate looks like it's still about 3 times higher. So am I estimating that correctly on that CR/PR basis? And I just wanted to understand the CRH responses, as well, and kind of how that fits in. And then one follow-up on PATHFINDER, I might've missed it, but I don't think we got much clarity yet on the planned doses that you're going to be using there. And I know you mentioned in PIONEER you're exploring a lower range, but just curious, how should we be thinking about potential dosing in the PATHFINDER study?

Thanks, Laura. So in terms of the SM data, the mastocytosis data from EXPLORER that's emerging, so again, when we look at CR/PR and CI, as I said, we see a response rate of about 83%, and that's comparable to a look at 28% in Midostaurin. The U.S. label in Midostaurin was based on CR/PR. I imagine that's where the question is coming from. And there the response rate there was 17%, and ours is about 50%. Sounds funny. I should remember the exact number. It's in the 50s. It's well in excess in either cut. So now CRH is an important question. So we are incorporating CRH into the CR/PR. And I guess I want to make a couple of points. One, CRH, it doesn't - CR/PR together will always include CRH, because whether you call them out of CRH or not they are either PRs or they're CRs. So it doesn't affect the total CR/PR rate. The CRH is really taken from the leukemia field at the strong recommendation of our investigators, where patients have complete resolution of their mast cell burden but their platelet count or their hemoglobin or their neutrophil count has not completely recovered. And in that case, if they have resolution of mast cells with lack of complete recovery of other blood counts that's a CRH, and that's used commonly now in acute leukemia. So I do think that's an important and relevant endpoint in advanced systemic mastocytosis, as well. So as far as the PATHFINDER study, we have recently decided to proceed with an avapritinib dose of 200 mg once a day in PATHFINDER. We've seen very potent activity with avapritinib across a wide range of doses as we reported both at ASH and at EHA in advanced SM, and this gives us the luxury to optimize dosing in order to support chronic use that we anticipate to be used in these patients. So it will be 200 mg a day.

Our next question comes from Marc Frahm with Cowen and Company.

First, a follow-up on the last question, okay, the dosing. I understand certainly lower doses should have better tolerability, particularly in the chronic setting. But for the indolent and smoldering sections of the disease, when you've been going through kind of making your PROs, is there something kind of surprising to you about what patients are identifying as their most burdensome parts of the disease, and maybe does that match up with where you've started to see some of these efficacy signals at lower doses, to give us more confidence that you're truly going to retain robust efficacy at that lower dose for these -- for those patients.

So maybe I'll take the first part of the question around the decision on 200 mg, and then Andy talk a little bit about the PRO tool, and obviously they do blend together. And just as a reminder, when we were doing the dose escalation, the data that we first shared at ASH in 2016, we saw evidence of clinical benefit at all doses starting as low as 30 mg per day and then moving up, up to the 300 mg range. And so when we look at PATHFINDER in the advanced setting, what's striking is that -- Andy used the word luxury, but when you get into a situation where virtually all patients are conferring a clinical benefit and you have a response rate of 83% with a very rigid criteria, that does afford you some flexibility to think about what that optimal dose is. And you can't push efficacy higher than where we sit, so our view, and this is really driven by work with our investigators, was that we were seeing that maximal benefit starting to get closer to 200 mg, so it just feels like the right step. But clinicians will always want flexibility to continue to evaluate do they want to go higher or do they want to deescalate. And when you're talking about a chronic therapy treatment that's going to be important. So I think that blends a little bit of both, that we clearly have a very potent inhibitor of D816V, which is the driver across the span of systemic mastocytosis. And then the second piece was more specific to the PRO about what we're focused on.

And Marc, maybe just correct me, I think it was also about the ISM piece in particular in the lower dose. So yes, so in the -- so I think I want to just remind everyone we're looking at the ISM dosing actually quite a bit different than the advanced SM dosing. So there we will be exploring substantially lower doses in the first part of the PIONEER study. Really we understand that in those patients if the drug is active these patients have a normal life expectancy and could be on an active therapy for decades, so they're, of course, finding the lowest active dose is pretty critical, just to allow very prolonged dosing, potentially. The PRO tool is going to include a -- look at a range of it's actually 8 to 10 criteria, patient-reported outcome criteria, and we will actually describe that in more detail when we present data, updated data, on the ongoing EXPLORER study later this year. So actually maybe I'm mixing two things. We'll give a fair bit of detail on the advanced SM PRO. The ISM PRO is closely related and looks at similar criteria. Maybe I'll just say that we, just from our data so far from EXPLORER we're pretty confident that the kinds of symptoms that we see improving are relevant to the PR that we're developing.

I guess my question is more the data we have, right, is in the advanced setting, and you do see signs of efficacy at 30 mg, much lower. But are those aspects of the disease that you see improving at 30 mg and things lower than 20, than the 200, is that matching up with what you've found as you design your PRO for the indolent disease, or is it more (inaudible) for patients, there's no real pattern as to which symptoms they see improvement with when?

Yes, I see what you're saying. Yes, no, it's very in line with what we would want to see for indolent disease. So I think the important thing is that we see dramatic reductions in mast cell burden in all of the body compartments, in the spleen, in the bone marrow, in the D816V allele burden, which really shows you the total body burden. And that is what drives the whole variety of symptoms, really. Patients who have splenomegaly and GI symptoms it's often due to enlarged spleen. Patients where the issues are around fatigue, that might be related to blood count. So the reduction in the systemic disease burden and the (inaudible) filtration is the driver of the broad range of symptoms, and that's what we see improving.

Okay, great. And then just I think we had also thought that there would be data updates from the RET program and then possibly also the treatment-naive cohort of FGFR4 HCC in the next 6 months or so. Are those still planned, or is that something that's going to have to wait till 2019?

So there's a range of updates. So as Andy highlighted, we will be providing update on the ongoing GIST data later this year. We -- or maybe I'll do them one at a time. Avapritinib for systemic mastocytosis we've indicated we'll provide a further update later this year on clinical data. For BLU-667, a RET inhibitor, we've indicated we'll provide an update later this year or early next year. And BLU-554 we'll look to find opportunity to provide an update on the ongoing trial. But really more importantly there and what we highlighted today is the CStone collaboration. We view that as an accelerator of the FDFR4 and BLU-554 strategy broadly, both within the TKI-naive patient population as well as the combination strategy, given the evolving landscape in HCC. We'll provide a preclinical update on BLU-782 later this year. As I indicated, September 30 we have an oral presentation. And then there's a variety of additional updates that we've discussed in the past that we have ongoing regulatory discussions in both avapritinib and GIST and SM as well as with BLU-667 in lung and medullary thyroid cancer. So as we have definitive, or not -- never definitive, as we get feedback that we view as important we'll look to provide updates there. And then in terms of new trials, Andy walked through those, the two pivotal trials in systemic mastocytosis, and then we'll also provide an update as we amend or evolve our ongoing BLU-667 trial.

Our next question comes from Konstantinos Aprilakis with JMP Securities.

So for BLU-667, your RET program, I think this is the first mention of these 4 cohorts in the expansion phase. Could you -- I'm sorry if it's been covered, but could you walk me through sort of the rationale there and what do we need to see from either cohort to move on to Phase 2?

Andy, do you want to take that?

Yes. So thanks, Konstantinos. So for BLU-667, as our other initial studies were designed, it's a seamless Phase 1 to MDD with expansion, and then further expansion of the current study will effectively be a Phase 2, and as I'll get to in a minute, we think potentially a registration path. So as we reported at AACR this year, we've escalated to the MDD and we're now expanding at the recommended dose. We are looking at 4 cohorts there. There are 2 lung cancer cohorts, both in RET-altered non-small cell lung cancer. We divide those according to whether the patient's had a prior TKI or not. And then we have a medullary thyroid cancer cohort and then another basket for all RET-altered solid tumors. Those are actively enrolling now, and we're increasing the footprint of the study substantially in anticipation of increasing the number of patients, going to more sites in the U.S., Europe, and Asia, as well, so expanding the number of sites. We already have more than 20 sites open on the study, and that'll continue to go up. And I think the very robust data that we've seen already offer, we think, several potential registration paths. So we're really pleased with consistent clinical activity that we've seen across RET fusions and across point mutations, so we think that actually offers the opportunity for both a tumor-agnostic and alteration-agnostic approach. But there are also opportunities for tumor-specific approaches to approval that could be based on -- could be lung cancer focused with fusions, could be medullary thyroid cancer focused with point mutations, or potentially both. And those can all emerge from the ongoing expansion of the current study. We will update our plans as the data emerge and based on discussions with FDA.

What's the target enrollment per cohort? Have you guided that yet?

The new -- the current study has 20 per cohort, where we'll be increasing that, and that'll be coming out on ClinicalTrials.gov soon.

Okay. Thanks very much.

Our next question comes from Arlinda Lee with Canaccord.

I wanted to follow up on the avapritinib second-line data set that we're expecting to see later this year. Can you -- you've talked about starting a 2019 trial. Will what we see in the update later this year in terms of duration and efficacy and subsets be sufficient for us to see why you're doing what you're doing in 2019, or will there need to be another update? And then on the indolent and SSM patients, are the patients going -- and I know you're going to update later this year as you start the trial, but are the patients going to receive a fixed dose, or is the treating doc going to be allowed some kind of a leeway on dose titrating, since -- based on burden or whatever, and is there going to be some kind of (inaudible) based on the mastocytosis components of the disease? Will these patients be allowed to get other drugs for other compartments of the disease?

Sure. Thanks, Arlinda. I'll take the first question around the data update later this year and then Andy, maybe you can talk about the different components of systemic mastocytosis. So the data update will be from the overall ongoing Phase 1 trial, and obviously that trial, much in the way that Andy just talked about the RET trial can evolve over time, that trial has evolved over time. And so we think it'll be a pretty important update, because it will include the updated PDGFR-alpha data that we have in hand at that time, the updated fourth-line plus that, as you know, was the basis of an amendment to the earlier protocol that will guide to our decision to move forward with filing that data set. It will include third line patients, so that'll be a good indicator of what we, or an early indicator, or what we'd expect to see as we move forward in our VOYAGER trial in a head-to-head study that's ongoing with avapritinib versus regorafenib. And then it will include patients from the latest amendment, which was to add a second-line arm to that trial to help guide our decision on what the optimal registration path is in that second-line patient population. So I think that's -- if you take that in totality that's a blend of all of that. To your question on will it be enough for you to understand our registration path going forward, that's hard for me to answer at this moment. We'll share all the data we have. We think with the total data package we have and the understanding of the circulating tumor DNA and biopsy data that we have we're getting an increasingly clear handle on avapritinib's clear benefit for GIST patients and the understanding of how different therapies, stage of disease, prior progression, all impact that disease. And so core to our strategy is that with a molecule like avapritinib that is clearly showing benefit in the later line that there's a real clear rationale to move earlier. What we've been intrigued by and have talked about on the last several calls is that understanding exactly what the range of mutation we're seeing by line, that matters, and seeing what the consistency or breadth of activity we're seeing with avapritinib matters. And so our second-line decision will be based or is based both on the pure second-line patients but it's also the totality of activity we're seeing in GIST patients across various lines. So I will speculate that at that update you will have a clear understanding of what our overall strategy is within GIST and why we've decided to go across such a broad array of patient populations, because we think there's a clear need, and based on the data to date a clear benefit that avapritinib can offer to these patients. And then the second piece around --

Yes, Arlinda, so regarding the studying in ISM/SSM, the PIONEER study, So again, the first part of the study is the dose selection part, and we will use that implementing the PRO tool to determine the optimal dose to take forward in that population. Then the plan is that all patients will start at the same dose in the randomized efficacy assessment part of the study, which, again, is a placebo-controlled randomized portion to robustly assess efficacy using the patient-reported outcome tool. Certainly patients will be able to dose reduce if necessary for side effects. But we do expect to be at a dose that's very well tolerated for a prolonged period of time. In terms of other drugs it will certainly be on the backbone of standard of care symptomatic therapy. And of course the placebo group will get standard of care symptomatic therapy, as well. There are no approved drugs that affect the underlying disease, so there would be nothing else to give patients that would be targeting -- specifically targeting the disease itself. The patients would certainly be able to take antihistamines and (inaudible) and that kind of thing.

Okay. Thank you. And then maybe a last question, the $10 million milestone on Roche, I guess just curious, are we going to hear anything about these programs or really not until something hits the clinic?

That's a decision that we'll make along with the team at Roche. But obviously the milestone's indicative of the nice progress we continue to make. And as we advance some of the programs that were started earlier on we will look to find opportunities to provide updates I would certainly hope before we enter the clinic.

Okay, great. Thank you.

Our next question comes from Kyung Yang with Jefferies.

A couple of questions on second-line GIST. So competitor KIT inhibitor showed about 24% of a response rate in second-line GIST. So is that the kind of a bar that we should be thinking about in the overall patients? And also, I don't know if you can comment on this, given the small number of patients, but as you genotype patients can you estimate what percent of second-line GIST patients hover at (inaudible) and 17 mutation?

Sure. Maybe I'll start and then Andy or Marion can add color to that. So in second-line in GIST I think we want to provide an update in terms of what a bar is, or a regulatory bar, as we share actual data or get regulatory feedback. So I think it's too early. The only approved therapy is Sutent, which has shown a 7% response rate. I guess importantly whether you're at 7% or 24% that would still mean 90%-plus, or 75% are not seeing a benefit. So we think that that intersection of understanding the underlying genetic drivers and range of mutations matters as well as the activity of avapritinib in determining what that right bar is. But it is consistent. We would expect to see greater activity as we move up in line to therapy. I mean, that's classic across most forms of cancer, and there's no reason to believe GIST is different there. In terms of what mutations occur, I think maybe I'll answer it in two ways. One is that's an important question of better understanding of what the specific mutations, not just by exon but the actual specific point mutations are within a patient, for a patient who's only treated with Gleevec. But the second piece is based on the data we've shared to date, whether or not that's exon 17 matters less for avapritinib. So understanding what they are matters, but specific for avapritinib we've seen activity across a much broader range of KIT-driven GIST, and so we'll look at providing updates both on what the mutations we're seeing, what they are across lines, as well as where we're seeing activity when we provide a clinical update later this year.

That's helpful. And with avapritinib, as you move into registrational trials and doing -- start doing preclinical, pre-commercial activities, how are you thinking about pricing, because you are going after multiple indications in different dosing, and particularly (inaudible) there is a precedent of drug or the high-priced drug out there. So can you comment on what you're thinking about, how you think about pricing strategy?

So I think it's probably early to give specifics, and we'll want to have all the data in hand and regulatory feedback in hand before we finalize a specific price. But I think where we start is with a molecule that in several different patient populations where there is a clear need we have seen very robust activity, whether you're talking about advanced SM or PDGFR-alpha or in this highly refractory KIT-driven GIST patient population. As we think about expanding into new areas such as indolent systemic mastocytosis I think that piece where we believe we'll move forward at a much lower dose will be important and actually likely consistent with our -- consistent with how we would think about pricing, in that there is the greatest need in those patients that have a shortened life expectancy, no doubt, but there's also a clear need in these patients with indolent systemic mastocytosis. So we think we'll have some pricing flexibility, potentially pricing lower in that population. But I do want to make clear there is a high symptom burden in those patients. I think if we've learned anything about indolent systemic mastocytosis over time is that a meaningful percentage of those patients have a very high symptom burden, sometimes more so than what we've seen in some of the advanced systemic mastocytosis patients. And so when you blend a very active molecule with a series of diseases with high need, we think that a clear, relatively clear pricing strategy will come into play over the next year or so.

Thank you. One really quick question, it's a yes and no question, so Roche's $10 million milestone, is it going to be booked at once in third quarter?

This is Mike. So we'll actually have -- when we file our 10-Q later today we'll have more details on the accounting. But effectively the Roche milestone is folded into the overall transaction price of the deal, and as you know, similar to how we've accounted for the upfront payment that will be essentially spread based on a proportional method of accounting over the research term of that agreement. But we'll have more details in the 10-Q filing later today.

David Nierengarten, Wedbush Securities.

I am not showing any further questions at this time. I would now like to turn the call back over to Jeff Albers for closing remarks.

Feel bad about David. So again, thank you, operator, and thanks, everyone, for joining and for taking the time. I know it is a busy day for all of you. As we talked about earlier, these are exciting days for us at Blueprint Medicines as we move closer to realizing our vision of building a fully integrated business. By the end of this year we'll have up to 5 registration-enabling clinical trials underway and we'll be on track to submit our first new drug application in the first half of next year. So we think this is really an exciting moment.

We plan to work on it every day and achieve our goal of delivering medicines to patients, and we look forward to sharing further updates on our progress with all of you. Thanks a lot, and have a great day.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude today's program, and you may all disconnect. Everyone have a great day.