Blueprint Medicines Corp (BPMC) 2018 Q1 法說會逐字稿

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

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

Thank you, operator. Good morning. This is Kristin Hodous of Blueprint Medicines, and welcome to Blueprint Medicines' First 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 investor section of our website at www.blueprintmedicines.com.

Today on our call, Jeff Albers, our Chief Executive Officer, will discuss Blueprint Medicines' first 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 first 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 Annual Report on Form 10-K 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. At Blueprint Medicines, our focus is clear. We craft potent and highly selective kinase medicines for patients with genomically defined diseases. This focus is the cornerstone of our strategy and the foundation of our growing pipeline of potentially transformative, experimental medicines.

Our early investment in building a proprietary kinase library and assembling a first-class R&D team has powered our progress. Today, we have 3 homegrown and wholly owned clinical candidates with compelling proof of concept, a rapidly expanding research portfolio, and the line of sight to delivering our first approved medicine to patients. We're proud of these accomplishments, and we're committed to building a sustainable and differentiated biopharmaceutical company over the long term.

This morning, we'll focus on 2 key business updates that demonstrate continued progress towards this vision and achievement of our 2018 goals. First, we'll highlight the BLU-667 clinical data that were recently presented at the American Association for Cancer Research, or AACR, annual meeting in Chicago. Second, we'll share an update on the avapritinib clinical program, including encouraging regulatory feedback on our registration plans in systemic mastocytosis.

Before we discuss the BLU-667 trial results, I want to take a step back and frame the broader context for these data. As you can see on this slide, the BLU-667 presentation at AACR represents the fifth compelling clinical proof-of-concept dataset we've presented at a major scientific meeting over the past 18 months. When viewed together, we believe the data for avapritinib, BLU-554 and BLU-667 demonstrate the power of our scientific platform.

We've design kinase medicines that are orders of magnitude more potent and selective than existing approaches, and these data show our experimental medicines have the potential to profoundly impact disease even in early Phase I clinical trials.

In addition, these results demonstrate our ability to quickly and reproducibly develop highly active candidates targeting both novel and difficult-to-drug biology. Our focus on early discovery is unyielding, and to that end, we recently nominated another wholly owned research program that we hope to advance in a similar manner. Overall, we believe the combination of great science and sound execution opens opportunity to scale a differentiated portfolio and build Blueprint Medicines into the leading selective kinase medicines company.

Now let's focus on BLU-667. Two weeks ago, we were thrilled to share initial results for BLU-667 in patients with RET-altered cancers in AACR. This morning, I want to highlight a few key points from these data before I ask Andy Boral, our Chief Medical Officer, to share his clinical perspective.

First, we think it's worth stressing how our progress to-date with BLU-667 is truly representative of our vision and scientifically driven approach at Blueprint Medicines. Here, we matched RET, a well-established but difficult-to-target disease driver with our ability to design highly selective kinase inhibitors. Using our proprietary library, we first identified compounds selective for RET. With these starting points, we optimized a therapeutic candidate to be equipotent against a range of RET fusions and mutations, including predicted resistant mutations.

We expanded that target profile to include these predicted resistant mutations with the hope of potentially extending durability of response. We then initiated clinical testing in a selected population and rapidly achieved clinical proof-of-concept during a Phase I dose-escalation study.

Second, we're, obviously very pleased to see high preliminary response rates in patients with non-small cell lung cancer and medullary thyroid cancer. Moreover, at this early stage in clinical development of BLU-667, we're thrilled with the consistency of clinical outcomes across multiple patient variables.

We're seeing response in antitumor activity regardless of tumor type, RET alteration or prior therapy. We're also seeing early evidence of activity against brain metastases. When combined with the pharmacokinetic and pharmacodynamic data showing dose-dependent exposure and RET pathway inhibition, we think this early clinical activity is highly encouraging as we advance BLU-667 into the expansion part of the trial.

Third, BLU-667 has demonstrated a very favorable safety profile. As a reminder, the primary goal of dose escalation is safety. So we report adverse events regardless of association to treatment. The majority of adverse events were Grade 1 or mild, and there was only 1 discontinuation out of 53 patients due to a treatment-related adverse event.

Finally, I want to remind everyone that these are early data from the dose-escalation portion of a Phase I trial. But they also position us right where we want to be at this stage in development. From the outset, our primary goals from this initial dataset were to identify a maximum tolerated dose, demonstrate good safety and tolerability, and see a clear signal of clinical activity across a broad population of RET-altered cancers.

By these criteria, the data are very compelling and strongly support advancing BLU-667 into expansion, where we'll evaluate an optimized dose over an extended period of time, and ultimately, we hope to bring this investigational medicine directly to a larger population of patients in need.

Now I'd like to turn the call over to Andy to provide additional detail on the BLU-667 data and to highlight our recent progress with the avapritinib program. Andy?

Thanks, Jeff, and good morning to everyone on the call.

So as Jeff mentioned, all of us at Blueprint Medicines are very encouraged by the BLU-667 data. For me personally, as a thoracic oncologist, these initial results offer hope that patients with RET-driven cancers will soon benefit from the revolution in target therapies that's already transformed treatment for patients with EGFR, ALK and ROS-driven lung cancer. It's wonderful to have the opportunity to share such promising early data.

So this morning, I want to take a few moments to focus on some details from the dose-escalation results. First, 84% of patients with measurable disease had tumor reductions regardless of tumor type, RET alteration or prior therapy. As Jeff noted, these show remarkable consistency across multiple disease variables.

During dose escalation, we evaluated once-daily dosing regimens ranging from 30 to 600 milligrams. Patients who started at lower doses were permitted to escalate once a higher dose level was deemed safe. We were very encouraged to see responses in patients starting at all dose levels, ranging from 60 to 400 milligrams once a day. Often these responses were observed in the context of dose escalation and continued treatment over time.

However, it's worthwhile to note that only a few patients in the 400 milligram cohort and actually none of the patients in the 600 milligram cohort were evaluable for response at the time of the AACR presentation because the first tumor measurements hadn't been done yet. Importantly, all patients in the 400 and 600 milligram cohorts remain on treatment today.

In addition, most patients are now receiving 300 to 400 milligrams once daily, which we believe may be an optimal dose range based on the totality of data generated so far, and all patients are receiving a dose of 200 milligrams or higher. This is consistent with a favorable safety profile that we've seen to-date with BLU-667.

At AACR, we reported that 16 of 17 responders remained on treatment. All 16 of these patients remain on treatment today. In addition, we've seen more confirmed and initial responses with passage of time.

Overall, we think these data are very exciting and hold promise for the expansion part of the trial, where we'll evaluate the optimized dose in a larger population across multiple RET-driven cancers with focus on the rate and duration of response.

So based on the promising early clinical data, we're actively enrolling the global expansion part of our Phase I trial, which we're now calling the ARROW trial. As we discussed at AACR, we expect steady enrollment in the near term as patients have accumulated on a waiting list during dose escalation. To meet patient demand and support rapid enrollment, we're working hard to expand the trial footprint with additional sites globally.

In addition, we plan to increase target enrollment for the expansion cohorts later this year. And finally, if the safety and clinical activity data continue to evolve in a positive fashion, we'll look to initiate interactions with regulatory authorities to discuss potential expedited pathways to approval.

Now I'd like to shift gears and provide an update on the avapritinib clinical development program and our progress toward potential approvals in GIST and systematic mastocytosis. As you know, avapritinib is a selective KIT and PDGFR alpha inhibitor and our lead therapeutic candidate.

Over the course of 2017, we disclosed updated data from 2 separate Phase I clinical trials, showing strong clinical activity in patients with advanced GIST and advanced systemic mastocytosis. Based on these data, we've sought to establish clear pathways toward initial registration in both indications. I'm pleased to share several important updates on our recent progress.

In advanced GIST, we're excited to announce that we've completed enrollment of the PDGFR alpha and third line GIST plus expansion cohorts in the Phase I Navigator trial. In total, we've enrolled more than 50 patients with PDGFR alpha-driven GIST and more than 100 patients with third line plus KIT-driven GIST.

As a reminder, we received preliminary FDA feedback last year that an expedited approval of avapritinib for the treatment of patients with PDGFR alpha D842V-driven GIST may be possible based on data from the Phase I Navigator trial. Now that we've completed enrollment, we anticipate generating required data and being in a position to submit an initial new-drug application in the first half of 2019.

In addition, we recently activated the first clinical site for our Phase III Voyager trial, which compares avapritinib to regorafenib in third line GIST. We anticipate initiating patient dosing in second quarter and rapidly activating additional sites across global geographies throughout 2018. Our base case requires this study for potential approval in refractory KIT-driven GIST. However, we do plan to continue to evaluate opportunities to expedite registration in this population based on additional Phase I data and ongoing dialogue with regulatory authorities.

Finally, we've made significant progress in advancing our registration plan for avapritinib in systemic mastocytosis following the presentation of updated data at the American Society of Hematology annual meeting in December and productive interactions with the FDA in the first quarter.

We recently received preliminary feedback from the FDA in our development plans in both advanced and indolent systemic mastocytosis. Most importantly, the FDA indicated support for our registration plan in advanced systemic mastocytosis, which is based on a single-arm study and may offer a potential expedited path to approval. In addition, the FDA indicated support for our development plan in indolent and smoldering systematic mastocytosis, which is also exciting, given that there's no regulatory precedent in this population.

And here, we show the plan design of the registration enabling Phase II trial of avapritinib in patients with advanced systemic mastocytosis, which we call the PATHFINDER trial. Based on FDA feedback to-date, we believe this single-arm trial could form the basis of an expedited approval in advanced systemic mastocytosis, should the data emerge in a manner consistent with our clinical data to-date.

The PATHFINDER trial will enroll approximately 60 patients with advanced systemic mastocytosis. Patients will be required to have an evaluable clinical finding or C finding per IWG criteria. In addition, we plan to enroll both previously treated and treatment-naive patients. So prior treatment with midostaurin will not be required. The primary endpoint is overall response per IWG. Key secondary endpoints include patient-reported outcomes, progression-free survival, overall survival and safety. We're on track to initiate the trial in mid-2018.

In addition, we received positive feedback from the FDA on our planned registration enabling Phase II trial in patients with indolent and smoldering systematic mastocytosis. We expect this trial to include multiple parts, including dose selection, a randomized placebo-controlled efficacy assessment and an open-label extension. Patient-reported outcomes will be the primary endpoint using a questionnaire developed specifically for patients with indolent systematic mastocytosis. We plan to continue to work with FDA and our advisers to refine our clinical plan with the goal of initiating Phase II trial by the end of the year.

So in summary, we're excited to expand the breadth and depth of the avapritinib clinical program -- clinical development program on a variety of fronts. Now I'll turn the call over to Mike Landsittel, our Vice President of Finance, to review our financial results for the first quarter. Mike?

Thanks, Andy. Blueprint Medicines continues to maintain a strong financial position. This will enable us to fund the clinical development of our pipeline assets across a range of tumor types while beginning to build infrastructure and operations for our next stage of growth as we seek to become a commercial company, while continuing to mind the potential of our platform to support the further expansion of our discovery efforts.

Turning to our first quarter P&L. Collaboration revenues were $900,000 for the first quarter of 2018 compared to $5.8 million for the first quarter of 2017. This decrease was primarily due to the termination of the Alexion agreement in the fourth quarter of 2017 as well as the impact on revenue recognized under our collaboration with Roche as a result of the adoption of accounting standards codification 606 on revenue recognition, which was effective January 1, 2018.

During the first quarter, we incurred $50 million in R&D expense compared to $28.5 million for the same period last year. This increase in R&D expense was primarily driven by increased clinical and manufacturing expenses associated with advancing avapritinib, BLU-554 and BLU-667 further through clinical trials as well as increased personnel-related expenses.

G&A expenses were $9.9 million for the quarter compared to $5.7 million for the first quarter of 2017. This increase in G&A expense was due largely to increased personnel-related costs and professional fees, including precommercial planning activities. Finally, we reported net loss of $56.5 million for the first quarter, or $1.29 per share, compared to a net loss of $28 million, or $0.84 per share, for the first quarter last year.

Turning to our balance sheet. We ended the quarter with cash, cash equivalents and investments of $621.1 million compared to $673.4 million as of December 31, 2017. This decrease in cash was primarily related to cash used in operating activities.

Based on our current plans, we continue to expect that our cash, cash equivalents and investments, excluding any potential option fees and milestone payments under our collaboration with Roche, will be sufficient to enable us to fund our operating expenses and capital expenditure requirements into the middle of 2020.

We are excited about the progress we've made so far this year, and we plan to keep broadening our clinical development efforts and expanding our precommercial planning activities. To that end, we expect that our operating expenses will continue to increase as we continue to accelerate our efforts to bring new medicines into the hands of patients.

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

(Operator Instructions) Our first question comes from Terence Flynn with Goldman Sachs.

Maybe just on the avapritinib SM development front. On the PATHFINDER trial, can you help us frame kind of the minimum bar for success there with respect to the endpoint and duration? And then on PIONEER, in the indolent setting, do you need to validate the PRO first? Or is that going to be embedded in the trial?

Andy, why don't you take that on PATHFINDER first?

Yes. I'm sorry, (inaudible) can you repeat your question about the -- the specific question about the PATHFINDER trial? The...

Minimum bar for success.

Minimum bar for success. Yes. So yes, at the PATHFINDER trial, which is our Phase II study that we're kicking off in the middle of this year for patients with advanced systemic mastocytosis. So again, just to remind everyone, that's a single-arm Phase II study, specifically in patients with advanced systemic mastocytosis. And what distinguishes it -- I think I'll just give a little background -- what distinguishes it from our current ongoing study, our Phase I study, is that it includes patients who have -- must have an IWG C finding, so they must be eligible for evaluation of response. And thus the primary endpoint is response. And we are in the middle of discussing the potential path -- accelerated path with the FDA. We know that the accelerated approval would require a substantial and acceptable response rate with reasonable durability. But we don't have specific numbers on that at that point in time -- at this point in time. And I think that'll be outcome of ongoing discussions. Based on our current study with the Phase I -- the ongoing Phase I study, we do expect to see high response rate. As we -- as Dan DeAngelo showed at ASH looking at [CRPR] and clinical improvement findings, we've reported a 72% response rate with avapritinib in advanced systemic mastocytosis. So we do expect a pretty high bar for response. And the -- in terms of the PIONEER study, so this is the study that we're planning to start for the end of the year in the smoldering and indolent systemic mastocytosis. So as I said earlier, the primary endpoint is based on the patient-reported outcome tool. That tool is in development specifically for patients for systematic mastocytosis. It's -- many of the steps of validation have already been performed. We've had initial meetings with actually both regulatory agencies and are having some back-and-forth discussions. There's multiple steps for the validation and much of which has been complete. The final validation would actually happen during part 1 of the study, where we actually tested for the first time in patients with indolent systemic mastocytosis. But we are ready to apply it in that study.

Okay. And then, maybe just on the dose. It sounds like there's going to be some dose-finding work that's part of PIONEER? Do you guys still expect that you're likely to end up in a different spot for dose for the advanced setting versus indolent smoldering? Or is there a possibility the dose could be the same?

Yes. We'll definitely end up at a lower dose in the indolent and smoldering population. We -- first part of the study -- actually, I want to just clarify, it's a dose-finding study, but it's not a classic Phase I sequential dose-finding study. We'll -- since we know the MTD, we can look at multiple doses simultaneously, which makes that piece of the study go quite a bit faster. And we'll look at a range of doses. We haven't quite pinned it down yet, but even the highest dose would likely be below the 300 milligram dose level that we're starting at in advanced patients.

Our next question comes from Eric Schmidt with Cowen and Company.

Maybe just a follow-up on Terence's question on PATHFINDER and the regulatory hurdle in advanced systemic mastocytosis. I guess, question might be what do you hope to get from this next study that you can't get or maybe you don't already have from the current Phase I, given the very high responses we've already seen?

Yes. Eric, yes, that's a question that we've thought a lot about. And it's complicated. I think there are -- so we've now had several discussions with FDA and the EU agencies, and they're onboard with our concept of a 2-study approach. There are a couple of key things that we'll get from the PATHFINDER study that are not, at least from the start, weren't embedded in the ongoing Phase I mastocytosis study. It's really -- I think the 2 key things are: one, is that all patients in PATHFINDER will have an IWG evaluable C finding. And so if you remember from the -- from Dr. DeAngelo's presentation at ASH and we had only a subset of patients were actually evaluable for response. From a regulatory perspective, it's really expected that these large majority of patients are evaluable for response in a pivotal study. So in this case that will be the case. Actually, evaluability for response will be required for entry. And the other key differences, we will have central review of the bone marrow pathology from the start of the study. We're actually implementing that now retrospectively in the ongoing study, but we won't be able to apply it to everybody because it's actually pretty hard to get all the samples, retrospectively. In this case, we'll have a central pathology review by a -- actually one of the world's experts in systemic mastocytosis. So I think the dataset will just be much more robust. Maybe I want to point out just one other quick thing that the -- together the -- the total number of patients is probably actually pretty similar, whether we do a new study or just expanded the ongoing Phase I study, we would have to add patients to the current study in either case. And so we think this actually gives us a higher probability of regulatory success without really adding many more patients and probably not really affecting the time line much.

Okay. We didn't hear much about 554 today. Just -- are we still on track for another data update in second half, including TKI-naive patients? Or how's that program going?

So this is Jeff. We're very much still on track. So as we've highlighted before, with BLU-554, we're focused on 2 primary paths forward. The first one, as you allude to, is that TKI-naive arm of our ongoing Phase I trial. And the second one is initiation of a trial in combination with a checkpoint inhibitor. And so those -- we didn't add much on the update because it's very much in line with what we've discussed before. That we'll look to share data later this year on -- from that Phase I study and the various cohorts and look to initiate that combination trial later this year.

Our next question comes from Arlinda Lee with Canaccord.

I had a few question on 667 and the RET landscape. One, you alluded to more responses over time that you've seen. Can you provide any additional color on those responses? Secondly, there's been a couple of case reports on treatment with another selective RET treatment. And I'm kind of curious. Have you had patients with prior selective RET inhibitors therapy, either Ignyta or LOXO in your trials? And if so, can you provide any color on their baseline and how they did on 667? And then, if you haven't seen any of these patients, maybe would you expect to provide information on this at a later point given the overlap in KOLs? And then, thirdly, on the [KIF5G] RET fusion among patients in this other report, one of the -- this patient had a response but discontinued due to a recurrent depressive episode, and I'm wondering, Andy, given your background as a thoracic oncologist, how often do you see this? Would you expect any -- I guess, I'm just curious. Can you talk about discontinuations of 667, whether you've seen any neuro effects? Or is this something you've seen before?

Right. So this is Jeff. So there's 3 questions I have. Maybe I'll take the first one on responses and hand it over to Andy to comment on the second 2. So obviously, as you know, this is an ongoing Phase I study, and as Andy mentioned upfront, those patients for the longest period of time are at the lowest doses, but we're continuing to enroll patients over time. And so not surprisingly with the passage of time -- it's been about a month since our data cut -- we've continued to see responses emerge. I think that Andy pointed out both. We've had new -- a blend of new responses or earlier responses become confirmed with that month passage of time, which I don't think is a surprise. The important piece from our perspective is those patients are staying on and continuing to see a benefit. So obviously, that will evolve over time, and we'll find an opportunity, again, to provide a more fulsome update at a -- in the context of a medical conference. But yes, as of today, we continue to be very encouraged by the data as they emerge. And then your second and third questions, Andy, I'll have you take these. The first one is, any patients that have had RET -- a selective RET inhibitor prior treatment. I know we highlighted the multikinase inhibitors. And the second one is, any indications of depression.

Yes. So Arlinda, thanks. So in terms of patients with other RET inhibitors. So of course, this is a Phase I study in patients with advanced disease, and patients have had a very broad range of prior therapies. About half the patients, as Dr. Subbiah showed, have had multikinase inhibitors. We've seen patients with prior chemo, prior immunotherapy. And I'm aware of at least one patient on the study who had a -- who was previously treated with a selective RET inhibitor, actually with the loss of compound. They enrolled on our study after either progressing or not tolerating treatment with the prior RET inhibitor. And they came on relatively recently. At this point, we know that they're doing well and continuing on treatment. And of course, we're -- we look forward to seeing how the disease evolves. Of course, I hope that both of the -- that there's -- well, I think there's room for multiple RET inhibitors out there, and I would very much hope that patients who don't do well with one RET inhibitor can do well with another, either from a prior -- a therapy other than 667 to 667. And conversely, I'm sure patients who progress or for some reason don't tolerate 667 will have the opportunity to have other RET inhibitors, and I hope they do well in that situation. So I think it's an area where we need multiple treatments. In terms of the case that you brought up, the case report in the publication, with the KIF5B patient with lung cancer that received LOXO-292. So in terms of just our own study, we have not seen depression or other CNS effects that we -- that are thought be related to BLU-667 at this point in our study. Taking off my Blueprint hat for a moment and putting on my oncologist hat, the description of the published case does surprise me a bit. I -- in my experience treating patients, when a patient with advanced metastatic lung cancer is responding to treatment and having improvement in brain mets with reductions in CNS effects of those brain mets, the patients usually feel better, and both the doctor and the patient really do whatever they can to maintain treatment. So I think it's -- of course, if it's a case report, I don't have the details, but that aspect of it did surprise me.

And -- this is Jeff. I mean, obviously, there are multiple early studies ongoing, and so I think -- I've said this many times that this is a marathon, not a sprint. And so I guess, I would caution on digging too much into any case study at this time. But I think we're going to learn a lot. I think the more important piece is one that Andy made early on is that, this is a patient population. You don't have to meet many of these patients to understand there is a need for effective therapies in this population. And what is really encouraging is that there now appears that there could be multiple effective therapies, at least, showing preliminary evidence of activity that can help these patients in need.

Okay. Can you maybe -- just a last question, maybe. Can you talk about the discontinuations you've seen on 667?

Yes. So we have had one patient discontinue due to an adverse event on 667 as Dr. Subbiah presented. It's actually -- it's -- as often is the case on these studies, it's a patient with very complex disease, a patient with -- who had a dose-limiting toxicity at the 100 milligram dose level, who had widely metastatic lung cancer with liver metastases, who had elevation of ALT, a liver enzyme. I think in those -- in that kind of case, it's always complex to determine if the liver enzyme effects are due to the disease, due to the therapy being used. In this case, the physician thought it was possible that BLU-667 contributed, and thus it's considered potentially related to drug, and the patient discontinued for that reason.

Our next question comes from Laura Chico with Raymond James.

I guess, just following up on 667. I think you guys have provided some good landmarks in terms of the estimated opportunity for NSCLC patients, roughly 10,000. I'm wondering if you could opine a little bit on the tumor agnostic category and kind of what your thoughts are in terms of the size or breadth of that opportunity.

Laura, this is Jeff. As you mentioned, we look at the patient landscape -- or potential patient landscape. That 10,000 number from us goes to what we describe as major markets, which is U.S., EU 5 and Japan. In medullary thyroid cancer, we estimate that, that number to be around 1,300 patients in those same major markets. And then we've not provided a number for the tumor agnostic arm of the study. And we've done that intentionally because, really, the range is variable enough that we wanted first provide them -- have some data in hand and further characterize that opportunity. And so we haven't guided that. We do know that RET fusions do occur at low frequency across a fairly broad range of solid tumors. And to that end, actually, as we continue on this round moving to expansion, already seen an acceleration of the identification of some of those patients. So the next time we provide a clinical update, we'll have a more fulsome dataset to take a look at. And then, maybe we'll start to provide some level of guidance on what that opportunity can look like over time. But I can tell you that, where we sit today, we're very encouraged. We know those patients are there, and we know that there's a need for an effective therapy in that population. Andy, anything to add?

Our next question comes from Konstantinos Aprilakis with JMP Securities.

As per prior guidance, avapritinib was slated for a dose escalation and [POC] trial in indolent and smoldering SM. And now it appears that post FDA feedback, you've got the green light for a registration enabling Phase II trial in those settings. I was wondering if you could provide some color on what caused the agency to adopt such a favorable stance. And also, can you share the components of the patient-reported outcome tool of the use of the primary endpoint in PIONEER?

So this is about the Phase II study we're planning in the indolent and systematic mastocytosis. Yes, so the -- there's a few components to it. One, I think that the preliminary data that we've seen in advanced systemic mastocytosis has been impressive and demonstrates that the -- that avapritinib is highly active in this population. And then, I think another very important point connecting those together is that the D816V mutation, which is a driver in advanced disease, is also a driver in indolent and smoldering disease. And I think together -- the FDA essentially agreed with our perspective that this really represents a single disease across a broad spectrum of severities, from indolent through advanced. And so you can -- so we do and I -- I mean, I don't want to put words in my mouth, but my impression is that they also agree that there's some potential read-through from the data we're seeing in advanced to the data we're seeing in indolent. The other, I think, piece is that the study we're proposing has several discrete parts, and so it will answer a variety of questions. Of course, the dose question's critical, but I think we can answer that in a part of a multipart study and then seamlessly move on to an efficacy question. The -- I think there is general agreement with -- across multiple regulatory agencies, actually, that in the smoldering and indolent population, there really is no response measurement that you can use that's analogous to the IWG. The patients are very severely affected by symptoms, and so a patient-reported outcome tool is the most appropriate measure. The data we've provided so far in terms of the development of that PRO tool are following the guidances they're expecting. And so I think they were comfortable with the way we're approaching that. Not to say that they're not going to have input on -- there's still discussion to be had in terms of the exact structure of that -- of the PRO and exactly how -- what's expected in terms of outcome. And then with having the third part, we can allow crossover from placebo to avapritinib in the follow-on part of the study, which gives us an opportunity to provide more safety data in a very different population, where obviously safety will be an important question. And so I think it's just -- I think it's a matter of the agencies understanding that this is a group of patients with a very severe unmet need despite having a normal life expectancy that really encompasses a single disease from indolent through advanced systemic mastocytosis that the preliminary data with avapritinib looked quite promising and that the endpoints will address their questions. In terms of the peer outcome, specifically, we have not -- we haven't disclosed details of the questions. And as the study proceeds and we have definitive agreement on exactly the structure of the PRO, well, I think, we would decide when to talk more about it.

Our next question comes from Eun Yang with Jefferies.

I have 2 questions. One, previously, you mentioned that, for avapritinib, you are pushing for accelerated approval in PDGFR alpha as well as the fourth or later-line GIST. So (inaudible) initial NDA submission in the first half, when are you expect to submit fourth and later line GIST data?

So this is Jeff. The question's about the avapritinib data in GIST. So as Andy laid out that we've had discussions around PDGFR alpha and plan to submit on that dataset. With respect to refractory third line plus driven GIST, [part of this] case continues to be that we require a head-to-head study versus regorafenib focused on the third line, and that's to say that, that we're in the process of ramping up that -- as Andy already highlighted. I think the piece you're alluding to is that, in the 100-plus patients, we're continuing to evaluate that data. And if they mature in such a manner that we believe an accelerated approval is possible, we will -- we would file that in conjunction with the PDGFR alpha filing. So it would either happen simultaneously with PDGFR alpha or we'll seek an approval off of the third line head-to-head study that is just now starting.

Okay. And the second question is on FOP product. So we are expecting preclinical data sometime this year. When you present the preclinical data, are we going to see some differentiation [compared] to other products in development? Or do you think it's too early to show any difference?

So I'll have Marion take that question.

Yes. I mean, we continue to be very excited about our full program that is targeting the genetic driver of the disease going after the actual -- within actual kinase. And as you alluded to, we're planning to present preclinical data at a scientific conference later this year. I think there the package most likely will be focused on BLU-782 and the characteristics of that molecule because it's very early in the program. But however, as Jeff alluded to earlier, we have initiated the IND-enabling studies for BLU-782 of a highly potent and selective inhibitor for ALK2 earlier this year. And we're very -- we're really looking forward to advance BLU-782 to patients as soon as possible.

(Operator Instructions) Our next question comes from Dane Leone with BTIG.

I wanted to press a little bit more for details on the indolent smoldering effort. Specifically, a couple questions in terms of, I guess, the PRO and some of your thoughts around eligibility criteria and/or background therapy. So I guess, specifically, what are your thoughts on baseline corticosteroids, antihistamines for these poorly controlled patients? Will the PRO be separate from a biomarker around serum tryptase levels? And then generally kind of combining those together, how do you think about PRO sensitivity and the main drivers of the PRO sensitivity for these patients?

Dane, it's Andy, I'll take that. So the -- so couple of things. So of course, these patients have a very difficult disease, have many symptoms, and we certainly can't stop their background therapy. So the study would be an evaluation of avapritinib in addition to standard ongoing background therapies. We -- one big question is, you alluded to it is, how do you decide, which patients should go on a study with indolent, in particular, systematic mastocytosis, should go on a study with a TKI such as avapritinib and what we're actually doing now is part of the early development of the PRO is evaluating it actually in collaboration with a mastocytosis society in just patients with mastocytosis to understand how it behaves in terms of correlating PRO scores with other quality of life measures. So we can, at this point, define a score that indicates severe -- this is a word we're essentially inventing, but severe indolent systemic mastocytosis that is not well controlled with available therapies. That will be an important piece of the eligibility criteria on the study. So we'll pick a score cutoff that identifies patients who are, based on correlating our PRO with other measures, are not well controlled. Those patients will be allowed to continue their ongoing therapies. And things like steroids, actually -- looking at things like steroids gives us a real opportunity actually and antihistamines as well because a secondary endpoint will actually be the ability of patients to wean off of steroids to reduce the number and frequency of other supportive and kind of reactive therapies. Another piece that we think is very important and I think will be very important to the regulatory agencies as well is to link or to show that the PRO improvements correlate with other maybe more objective laboratory-based evidence of disease improvement, like tryptase, like bone marrow mast cell numbers in patients often all smoldering patients don't have -- excuse me, all indolent patients do not have measurable bone marrow mast cells, but a reasonable number do. So in those patients changes in bone marrow mast cells, and actually, we think changes in D816V allele burden is another potential objective correlate. So what we're proposing is a primary endpoint based on the CRO -- excuse me, based on this PRO, a minimum score required for entry that we've already established correlates with a reasonably high level of need based on correlating our PRO with other quality of life measures. And then, over the course of the study, we do think it'll be important to show that improvements in the PRO also correlate with other more objective findings like D816V burden, mast cell burden, tryptase. So it's kind of how we're thinking about it.

Great. If I could just -- so just to be clear, the way you're laying it out is that there would be a demonstrably significant R-square to something like the lab findings like serum tryptase.

No. So I don't think that we will be -- that it will be held to that level because in smoldering disease and in indolent disease, there's actually not a lot of data -- that's an overstatement. There's really no data correlating things like tryptase, bone marrow mast -- and bone marrow mast cells with symptomatic improvement. So I don't think the bar would be an expectation of a linear relationship with some clear correlation. But I think we'd want to see some directional synchronization, maybe, I would say. We'd want to see some directional consistency between our PRO and one or more of the other measures. But it's the -- one of the reasons we need a PRO is the available "objective measures" that have traditionally not been predictive of improvement in symptoms in patients with indolent disease.

Great. And if I could just ask one more on the advanced side. Relative to the guidance of not having prior therapy with midostaurin, how -- what's the feedback from your PIs and clinicians in terms of how that could affect enrollment, maybe specifically, given that there is a pretty healthy discontinuation rate with midostaurin also. Those patients, a lot of them -- or the majority of them do have to be dose titrated. Is that something -- being able to avoid that step, does that -- do you think that accelerates enrollment for the study?

So yes, maybe I wasn't clear earlier. We don't have any preference for prior midostaurin patient -- treatment. Patients may or may not have received prior midostaurin. So we actually think that it makes the study actually very easy to enroll. There are some countries and sites that are big midostaurin believers, and the patients coming from there will have had midostaurin, and there are many places where it's either not reimbursed yet, maybe not approved and/or just not used very much. So we expect a mix, actually. And on the ongoing study, it's been an interesting evolution. Of course, when we started, there was very little except for patients coming off the ongoing studies. Now we're seeing a few more patients with prior midostaurin. But even though it's approved now in both the U.S. and Europe, it is not the bulk of patients by any means.

At this time, I'm showing no further questions. I'd like to turn the call back over to Mr. Jeff Albers for closing remarks.

Great. Thanks, operator, and thanks, everyone, for taking the time to join us today and for your continued interest in Blueprint Medicines. As we discussed this morning, we continue to be proud of the progress that we've achieved, particularly in the first quarter of this year. And we feel that we have momentum towards achieving key goals across the portfolio for 2018. So we look forward to sharing further updates on our progress. Thanks a lot. Bye-bye.

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