Blueprint Medicines Corp

NASDAQ:BPMC

Earnings Call Transcript 2018-Q1

[Operator]

Good day, ladies and gentlemen, and welcome to the Blueprint Medicines First Quarter 2018 Conference Call. At this time, all participants are in a listen-only mode. Later, we will conduct a question-and-answer session and instructions will follow at that time. [Operator Instructions] As a reminder, this call maybe recorded.

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

[Kristin Hodous, Investor Relations]

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 that we plan to discuss today. You can access the press release as well as the slides that we will 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’ first quarter 2018 business highlights; Dr. Andy Boral, our Chief Medical Officer will provide an update on our clinical stage pipelines; 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 is our CEO, Jeff Albers.

[Jeff Albers, Chief Executive Officer]

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 in the foundation of our growing pipeline potentially transformative experimental medicines. Our early investments in building a proprietary kinase library and assembling a first class R&D team is powered our progress.

Today, we have three home grown and wholly owned clinical candidates with compelling proof of concept, rapidly expanding research portfolio and 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 by a pharmaceutical company over the long-term. This morning, we’ll focus on two key business updates demonstrated continued progress towards its vision and achievement of our 2018 goals.

First we’ll highlight the BLU-667 clinical data that we’re 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 a registration planned and 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 that this compelling clinical proof of concept data set we 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 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 impacted these even in early Phase 1 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 discoveries 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 at 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 of Blueprint Medicines.

Here we match to RET, well established the difficult to target disease driver with our ability to design highly selective kinase inhibitors. Using our proprietary library, we first identify compounds selective for RET,with these starting points, we optimize the therapeutic candidate to be equipotent against a range of RET fusion or mutation 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 achieve clinical proof of concept during a Phase 1 dose escalation study.

Second, we’re obviously very pleased to see high preliminary response rates and patients with non-small cell lung cancer and medullary thyroid cancer. Over 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 anti-tumor 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 that’s early clinical activity as 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 great one or mild and there was only one discontinuation out of 53 patients due to a treatment related adverse event.

Finally, I want to remind everyone that these are early data from a dose escalation portion of a Phase 1 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 that 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 in optimize 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 avapritinib program. Andy?

[Andy Boral, Chief Medical Officer]

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. 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 of 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 and tumor reductions, regardless of tumor type RET alteration or prior therapy. As Jeff noted, these showed remarkable consistency across multiple disease variables. Three dose escalation we evaluated once-daily dosing regimens ranging from 30 milligrams to 600 milligrams. Patients who started at lower doses will permitted to escalate one to higher dose level was deemed safe.

We’re very encouraged to see responses in patients starting at all dose levels ranging from 60 milligrams to 400 milligrams once a day. Often these responses were observed in the context of dose escalation and continued treatment overtime. However, 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 maybe 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 the favorable safety profile that we’ve seen to date with BLU-667.

At AACR, we reported at 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 the passage of time. Overall, we think these data are very exciting and have 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 1 trial, which we’re now calling the ARROW trial. As we discussed at AACR, we expect steady enrollment in the near-term, as patients of 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 systemic 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 two separate Phase 1 clinical trials showing strong clinical activity in patients with advanced GIST and advance systemic mastocytosis.

Based on these data, we’ve start 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 completed enrollment of the PDGFR-alpha and third line just plus expansion cohorts in the Phase 1 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, maybe possible based on data from the Phase 1 NAVIGATOR trial. Now that we’ve completed enrollment, we anticipate generating required data and being in a position to submit an initial new drug up application in the first half of 2018.

In addition, we recently activated the first clinical site for our Phase 3 VOYAGER trial which, 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 as population, based on additional Phase 1 data and ongoing dialogue with regulatory authorities.

Finally we’ve made significant progress in advancing our registration plan for in systemic mastocytosis following the presentation of a update to dada 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 on 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 development plan in indolent and smoldering systemic mastocytosis, which is also exciting given that there is no regulatory precedent in this particular issue.

Now here we show the plan design of the registration enabling Phase 2 trial of avapritinib in patients with advanced systemic mastocytosis, which we call the PATHFINDER trial. Based on FDA feedback to date, we believe the 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 for IWG criteria. In addition, we plan to enroll both previously treated and treatment naïve patients, so prior treatment might storm will not be required.

The primary endpoint is overall response for IWG, key secondary endpoints include patient reported outcomes, progression free survival, overall survival and safety. We’re on track to initiate a trial in mid-2018.

In addition, we received positive feedback from the FDA on our planned registration enabling, Phase 2 trial in patients with indolent and smoldering systemic 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 is a questionnaire developed specifically for patients with indolent systemic mastocytosis. We plan to continue to work with FDA and our advisors to refine our clinical plan with the goal of initiating Phase 2 trial by the end of the year.

So in summary, we’re excited to expand the breadth and depth of the avapritinib program clinical program – clinical development program on a variety of fronts.

Now, I’ll turn the call over to Mike Landsittel, our Vice President or Finance to review our financial results for the first quarter. Mike?

[Mike Landsittel, Vice President of Finance]

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. By beginning to build infrastructure and operations for our next stage of growth as we seek to become a commercial company, while continuing to mind a 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 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 pre-commercial planning activities.

Finally, we reported net loss of $56.5 million for the first quarter or $0.29 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 pre-commercial planning activities. To that and, 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]

[Operator Instructions] Our first question comes from Terence Flynn with Goldman Sachs. Your line is now open.

[Terence Flynn, Goldman Sachs]

Hi, thanks for taking the questions. Maybe just on the avapritinib as some development front, on the PATHFINDER trial, can you help us frame kind of the minimum bar for success there with respect to the end point in duration? And then on PIONEER in indolent setting, do you need to validate the PRP first? Or is that going to be embedded in the trial? Thanks.

[Jeff Albers, Chief Executive Officer]

Andy, want to take that on PATHFINDER first.

[Andy Boral, Chief Medical Officer]

Yes. I’m sorry. So to your question about – the specific question about the PATHFINDER trial, the…

[Marion Dorsch, Chief Scientific Officer]

Minimum bar for success.

[Andy Boral, Chief Medical Officer]

Minimum bar for success, yes. So yes, the PATHFINDER trial which is our Phase 2 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 2 study, specifically in patients with advanced systemic mastocytosis, and what distinguishes – background, what distinguishes it from our current ongoing study – our Phase 1 study is that includes patients who have – must have IWG finding.

So it must be eligible for evaluation of response. And that’s the primary endpoint is response. And yes, we’re 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. We don’t have specific numbers on that at that point in time – at this point in time. I think that will be the outcome of ongoing discussions.

Based on our current study with the Phase 1, the ongoing Phase 1 study, we do expect to see high response rate as Andy, Angelo showed at ASH looking at CR, PR and clinical improvement findings we reported a 72% response rate with avapritinib in advanced systemic mastocytosis, so we do expect a pretty high bar for response.

And in terms of the PIONEER study, this is the study that we’re planning to start for the end of the year in the system – smoldering and indolent systemic mastocytosis. So as I said earlier the primary endpoint is based on patient reported outcome tool. That tool is in development specifically for patients for systemic mastocytosis. Its 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 is a multiple steps for the validation and much of which has been complete the final validation actually happened during part one 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.

[Terence Flynn, Goldman Sachs]

Okay. And then maybe just on that dose, it sounds like there is 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 a dose for the advanced setting versus indolent smoldering or is there a possibility of dose could be the same?

[Jeff Albers, Chief Executive Officer]

Yes. We’ll definitely end up at a lower dose in the indolent and smoldering population. The first part of the study actually I want to just clarify it is a dose finding study, but it’s not a classic Phase 1 sequential dose finding study. Well – 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 that we’re starting at in advanced patients.

[Terence Flynn, Goldman Sachs]

Thanks a lot.

[Operator]

The next question comes from Eric Schmidt with Cowen and Company. Your line is now open.

[Eric Schmidt, Cowen and Company]

Well, thanks, and congrats on all the progress over the last quarter. 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 don’t already have from the current Phase 1 given a very high response as we’ve already seen.

[Andy Boral, Chief Medical Officer]

Eric, yes, that’s a question that we’ve talked a lot about and it’s complicated. I think, there – so we’ve now had several discussions with FDA and the EU agencies and they are on board with our concept of a two study approach. There are couple of key things that will get from the PATHFINDER study, that are not a – at least, from the start weren’t embedded in the ongoing Phase 1 mastocytosis study. It’s a really – I think, the two key things are; one is that all patients in PATHFINDER will have an IWG evaluable C findings.

And so if you remember from the – from Dr. DeAngelo’s presentation at ASH when we had only a subset of patients were actually evaluable for response. From a regulatory perspective, it’s early expected the large majority of patients are evaluable for response in the pivotal study, so in this case that will be the case actually, evaluability for responsibly 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 are actually implementing that with retrospectively, in the ongoing study, but we won’t be able to apply it to everybody because it’s actually pretty hard to get off the samples retrospectively.

In this case, we’ll have essential pathology review by actually one of the world’s experts in systemic mastocytosis. So I think, the data set will just be much more robust. Maybe, I want to point out, just one other quick thing, that the – yes, together the total number of patients is probably actually pretty similar, whether we do a new study or just expanded the ongoing Phase 1 study, we would had to add patients to current study in either case. So we think this is actually gives a higher probability of regulatory success without really adding many more patients and probably not really affecting the timeline much.

[Eric Schmidt, Cowen and Company]

Okay, thanks for that Andy. We didn’t hear much about on BLU-554 today, just are we still on track for another data update in second half including TKI-naïve patients or how is that program going? Thank you.

[Jeff Albers, Chief Executive Officer]

So this is Jeff. We’re very much still on track. So as we highlighted before with BLU-554, we’re focused on two primary paths forward; the first one as you allude to is that TKI-naive, arm of our ongoing Phase 1 trial and the second one is initiation of a trial in combination with a checkpoint inhibitor. And so those, we didn’t had much on the update because it’s very much in line with what we’ve discussed before. And then we look to share data, later this year on – from that Phase 1 study in the various cohorts and a look to initiate that combination trial later this year.

[Eric Schmidt, Cowen and Company]

Thank you, Jeff.

[Operator]

The next question comes from Arlinda Lee with Canaccord. Your line is now open.

[Arlinda Lee, Canaccord]

Hi guys, thanks for taking my questions. I had a few question on BLU-667 and the RET landscape. One, you alluded to more responses over a time that you seen can you provide any additional color on those responses. Secondly, there’s been a couple of case report on treatment with another [indiscernible] treatment. And I’m kind of curious have you had patients with prior selective RET inhibitors therapy, either or neither or Loxo in your trials and also can you provide any color on their baseline and how they did on BLU-667?

And then, if you haven’t seen any of these patients, may be would you expect to provide an information on the suddenly the point given the overlap in KOLs. And then, thirdly, on the KIT 5G RET fusion among patients in the other reports and one of those – that this patients had a response but discontinued due to recurrent depressive that episode and I’m wondering Andy, given your background, as a theoracic oncologist, how often do you see this would you expect any – I guess, I’m just curious, can you talk about discontinuations on BLU-667, whether you’ve seen any neuro effects or is this something you’re seeing before. Thanks very much.

[Jeff Albers, Chief Executive Officer]

So this is Jeff. There is three questions I have, maybe I’ll take the first one, on responses and had it over to Andy, to comment on the second to. So obviously, I do know this is an ongoing Phase 1 study and as Andy mentioned up front, those patients on for the longest period of time are at the lowest doses but we are continuing to enroll patients over time. And so, not surprisingly with the passage of time, it’s been about a month since our data cuts, we’ve continued to see responses emerge, I think that Andy pointed out both, we’ve had newest – blend of new responses or earlier responses become confirmed, with that month passage the 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?

[Andy Boral, Chief Medical Officer]

Yes. Yes, so Arlinda, thanks. So in terms of patients with other RET inhibitors, so of course, this is a Phase 1 study in patients with advanced disease and patients have had a very broad range of prior therapies, about half a patients says [indiscernible] have showed have 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 relevantly recently.

At this point, we know that they’re doing well and continuing on treatment and, of course, we look forward to seeing, how the disease evolve some, of course, I hope that both of the – I think, there is 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 BLU-667 to BLU-667 conversely, I’m sure patients who progressed or for some reason don’t tolerate BLU-667, will have the opportunity to have other RET inhibitors and I hope they do well in that situation.

So they get near area where we need multiple treatments. In terms of the case that you brought up in the KIF department of publication with the KIF5b patient with lung cancer that received LOXO-292. So in terms of just our own study, and 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 after a moment and putting on my oncologist hat, the description of a 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 maths of reductions in CNS effect of those brain maths, the patients usually feel better and both the doctor and the patient really do whatever they can to maintain treatment. So – I think, of course, it’s a case report, I don’t have the details but that aspect but it did surprise me.

[Jeff Albers, Chief Executive Officer]

This is Jeff. I mean, obviously, there are multiple early studies on going and so I think, that I said this many times, this is a marathon not a stringent. So, I guess, I would caution on taking too much into any case studies 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, in order 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.

[Arlinda Lee, Canaccord]

Okay, thank you. Can you maybe – just a last question, maybe, can you talk about the discontinuation you’ve seen on BLU-667? Thanks.

[Jeff Albers, Chief Executive Officer]

So we have had one patient discontinue due to an adverse events on BLU-667 as [indiscernible] presented. It’s actually a – as often as the case on these studies, it’s a patient with very complex disease, a patient with, who had a dose metastatese that the 100 milligram dose level who had widely metastatic lung cancer with liver metastatese, you had elevation of ALTA, a liver enzymes. 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 innovation discontinued for that reason.

[Operator]

Our next question comes from Laura Chico with Raymond James. Your line is now open.

[Laura Chico, Raymond James]

Hey, thanks guys for taking the question. I guess, just following up on BLU-667, I think, you guys have provided some good landmarks in terms of the estimated opportunity for NSCLC patient, 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 and breadth of that opportunity?

[Jeff Albers, Chief Executive Officer]

Well this is Jeff. As you mentioned, we look at the patient land – potential patient landscape, that 10,000 number from us, it goes to what we describe as major markets, which is U.S., EU5 and Japan. In medullary thyroid cancer, we estimate 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 intentionally because with a range is variable enough that when it first provides them, have some data in hand, and further characterize that opportunity until we haven’t guided that. We do know, 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 of 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 data set to take a look at. And then, maybe we’ll start to provide some level of guidance on what that opportunity could 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 is a need for an effective therapy in that population.

[Laura Chico, Raymond James]

Okay that’s helpful.

[Jeff Albers, Chief Executive Officer]

Okay.

[Operator]

Our next question comes from Konstantinos Aprilakis with JMP Securities. Your line is now open.

[Konstantinos Aprilakis, JMP Securities]

Good morning and thanks for taking my question. As per prior guidance and it was slated for a dose escalation in PoC trial, and indolent and smoldering SM. And it now appears that post FDA feedback you’ve got the green light for registration enabling Phase 2 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 a patient report outcome tool that were used with primary endpoint and PIONEER. Thanks.

[Andy Boral, Chief Medical Officer]

So this is about that Phase 2 study that we’re planning in the indolent and systemic mastocytosis. So there’s a few components to it. One, I think that the preliminary data that we’ve seen in advance systemic mastocytosis has been impressive and demonstrates that avapritinib is highly active in this population. And I think another very important point connecting those together it is that the D815V mutation, which is driver in advance 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 advances.

And so we do you and I mean I don’t want to put words in their mouth, but my impression is that they also agreed that there has been some potential read through from the data we’re seeing in advance 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 I’ll answer a variety of questions. Of course the dose question is critical, but I think we can answer that in a part of a multipart study and then seamlessly move on to an efficacy question. I think there was 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 we provided so far in terms of the development of that PRO tool that are following the guidance as they’re expecting.

And so I think they were comfortable with the way we’re approaching that. And not to say that they are not going to have input there are some discussions we 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. Righteously safety will be an important question. And so I think it’s a matter of the agencies understanding that this is a group of patients with a very severe unmet needs despite having normal life expectancy that the really encompasses a single disease from indolent through advanced systemic mastocytosis at the preliminary data that with avapritinib look quite promising and that the endpoints will address their questions. In terms of the peer outcome specifically – we have not gotten – we haven’t disclosed details of the questions and as the study proceeds, and we have definitive agreement on exactly the structure of the DRO, well, I think we would decided when to talk more about it.

[Konstantinos Aprilakis, JMP Securities]

Great, thanks, Andy.

[Operator]

Our next question comes from Eun Yang with Jefferies. Eun, your line is now open. If you phone is on mute, please unmute it. Hello?

[Jeff Albers, Chief Executive Officer]

Hi, Eun.

[Eun Yang, Jefferies]

Hi, thank you very much. I have two questions. One previously you mentioned that for avapritinib, you are pushing for accelerated approval in PDGFRa as well as fourth and later line GIST. So was the initial NDA submission in the first half? When are you expect to submit fourth and later line GIST data?

[Jeff Albers, Chief Executive Officer]

Okay, this is Jeff. The question is about avapritinib data in GIST. So as any lead out that we have had discussions around PDGFRa and plan to submit on that that dataset. With respect to refractory third-line plus driven care, our syndicate continues to be that require a head to head study versus regorafenib focused on the third line and that that to say that we’re in process of ramping up that as Andy already highlighted. I think the piece you are alluding to is that in the 100 plus patients, we are continuing to evaluate that data and if they mature in such a manner that we believe an accelerated approval as possible. We will – we would file that in conjunction with that PDGFRa filing. So it either happens simultaneously with PDGFRa or will seek an approval off of the third line head to head study that is Jeff now starting.

[Eun Yang, Jefferies]

Okay, thanks. 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 agreed to see some differentiations compared to other products in developments or do you think it’s a product to show any difference?

[Jeff Albers, Chief Executive Officer]

So, Marion, take that question.

[Marion Dorsch, Chief Scientific Officer]

Yeah, I mean we continue to be very excited about our four programs that is targeting the genetic driver of the disease going after the actual – actual kinase. And as you alluded to we are planning to present preclinical data at a scientific conference later this year. I think they are the package most likely will be focused on BLU-782 in – 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 de-enabling studies for BLU-782, our highly potent and selective inhibitor for ALK2 earlier this year and we are really looking forward to [indiscernible] to patients as soon as possible.

[Eun Yang, Jefferies]

Thank you.

[Operator]

[Operator Instructions] Our next question comes from Dane Leone with BTIG. Your line is now open.

[Dane Leone, BTIG]

Hi, thank you for taking the questions and update on the programs. I wanted to press a little bit more for details on indolent and smoldering effort, specifically a couple of question sin 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 and histamines for these poorly controlled patients, will the PRO be separate from a biomarker around serum tryptase levels and then generally you know kind of in combining those together. How do you think about PRO sensitivity and the main drivers of the PRO sensitivity for these patients?

[Andy Boral, Chief Medical Officer]

Dane, it’s Andy. I will take that. So a couple of things. So of course these patients have very difficult disease have many symptoms and we certainly can’t stop their background therapy. So that 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 systemic mastocytosis should go on a study with 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 the mastocytosis society in – just patients with mastocytosis to understand how it behave 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, where we are essentially inventing severe Indolent Systemic Mastocytosis, but it 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 or looking at things like steroids gives us a real opportunity and actually antihistamine as well, because – and a secondary endpoint will actually be the ability of patients to vein 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 it 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 improvements, like tryptase, like bone marrow mast cell numbers in patients of more than patients don’t have – or excuse me – all indolent patients don’t 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 of real burden is another potential objective correlates.

So what we are proposing is a primary endpoint based on the CRO – excuse me, based on PRO – a minimum score required for entry that we’ve already established correlates with a reasonably high level of needs based on correlating our PRO with other quality of life measures. And then, over the course of the study, we do think it will be important to show that improvements in the PRO also correlate with other more objective findings like D816V burden, mast cell burden, tryptase. So this is kind of how we are thinking about it.

[Dane Leone, BTIG]

Great. If I could just to be clear the way you’re laying it out is, that there would be a demonstratively significant or square to something like the lab findings like serum tryptase.

[Jeff Albers, Chief Executive Officer]

So as I – 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 yes, it’s – one of the reasons we need a PRO is the available objecting, “objective measures of traditionally not been predictive of improvement in symptoms in patients with indolent disease”.

[Dane Leone, BTIG]

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

[Jeff Albers, Chief Executive Officer]

So maybe I wasn’t clear earlier. We don’t have any preference for prior mytosterone patients treatment. Patients may or may not have received prior mytosterone. So we actually think, it makes the study actually very easy to enroll. There are some countries and sites that are being mytosterone believers and the patients coming from there will have mytosterone and there are many places, where it’s either not – reimbursed yet, maybe not approved, and or we just not used very much. So we expect a mix actually and on the ongoing studies, 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 are seeing a few more patients with prior mytosterone but even though it’s approved now in both the U.S. and Europe, it is not a bulk of patients by any means.

[Dane Leone, BTIG]

Great. Thank you very much.

[Operator]

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.

[Jeff Albers, Chief Executive Officer]

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 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.

[Operator]

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.