Blueprint Medicines Corp (BPMC) 2022 Q1 法說會逐字稿

Morning. My name is Juan, and I will be your conference operator today. At this time, I would like to welcome everyone to the Blueprint Medicines First Quarter 2022 Financial Results Conference Call. (Operator Instructions) Thank you.

I would now like to turn the call over to your host, Jenna Cohen from Blueprint Medicines. Jenna, you may begin your conference.

Thank you, Juan. Good morning, everyone, and welcome to Blueprint Medicine's First Quarter 2022 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 set of our website at www.blueprintmedicines.com.

Today on our call Kate Haviland, our Chief Executive Officer, will discuss Blueprint Medicine's pillars for growth through 2023. Christy Rossi, our Chief Operating Officer, will provide an advanced SM launch update. Philina Lee, our Chief Commercial Officer, will provide a nonadvanced SM Market Opportunity update. Becker Hewes, Chief Medical Officer, will review our recent clinical progress and highlight upcoming milestones across our growing portfolio. And Mike Landsittel, our Chief Financial Officer, will review our First Quarter 2022 Financial Results. Percy Carter, our Chief Scientific Officer is also, joining our 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 factor section of SEC Filings. In addition, any forward looking statement made on this call represents 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, Kate Haviland.

Thank you, Jenna, and good morning, everyone. We appreciate you joining the call today. At Blueprint, we are clear in our goal to be the leading precision medicine company. Building on this quarter's success, the next 12 to 18 months will be unprecedented for us, as we execute on multiple milestones, driving value creation across all aspects of our business. Blueprint has an incredibly unique profile, with a diversity of significant growth drivers in a strong balance sheet, that will enable us to outperform the sector over time, as we expand global commercial execution, progress our clinical stage portfolio and drive innovation, through our leading precision medicine discovery platform.

The first quarter of this year was marked by a number of important milestones across our business; we continued to solidify Ayvakyt as the standard of care in advanced systemic mastocytosis or SM, in the U.S., and we closed the quarter with the European Commission approval of Ayvakyt in advanced SM. Our European launch is now underway. The global launch of Ayvakyt in advanced SM is building a strong real world value proposition in an important foundation of relationships, as we prepare for the top line data from our registration enabling Pioneer Trial, in non-advanced SM, late in the summer. Ayvakyt has the potential to be the first and only treatment approved for not advanced SM. With positive results from the Pioneer Study, we will have developed a comprehensive body of clinical evidence demonstrating the remarkable efficacy and profound benefits to SM patients across the spectrum of disease. While also, driving significant near term growth for Blueprint.

Another highlight from the first quarter were the data we presented at the AACR annual meeting across our EGFR and CDK2 franchises. It is early days for these programs, but there are many reasons for us to be encouraged about the differentiation of our investigational therapies, and their prospects to address major medical needs in difficult to treat and prevalent cancers. As our strength this past quarter demonstrates, we are well on our way of delivering on the goals we have set for ourselves this year, while also, building a foundation to drive value well beyond 2022. If you fast forward, for instance, to the end of 2023, we expect to be launching Ayvakyt in non-advanced SM, engaging regulatory authorities on registration plans for our EGFR and CDK2 development programs, and expanding our pipeline with new programs in areas of significant medical need.

With that, let me turn the call over to Christy, to discuss the progress we have made on the Ayvakyt launch, in advanced SM. Christy?

Thanks, Kate. Good morning, everyone. In the first quarter, we continued to build momentum in our ongoing launch of Ayvakyt in advanced SM, generating net product revenue of $23.8 million. The advanced SM indication contributed the majority of this revenue, and we anticipate that it will be the primary driver of Ayvakyt revenue growth over the course of the year. We are reaffirming our guidance of $115 million to $130 million in Ayvakyt revenue in 2022, based on the strength of the ongoing U.S. launch, which I will speak about in a minute, and our recent approval in Europe, where we received a marketing authorization in advanced SM on March 25.

Ayvakyt is now the first approved disease modifying precision therapy in the European Union, designed to selectively target KIT D816V, the primary driver of SM. Within one week of approval, the first patient was treated in Germany, where Ayvakyt is now reimbursed for its expanded indication, and we are looking forward to bringing Ayvakyt to patients in additional EU countries, as we work through country specific reimbursement processes.

Now let's turn to the U.S., which contributed $21.3 million in revenue this quarter. We expect revenue growth to continue through the year driven by 2 key factors; increasing new patient starts, as we reach more prescribers and support more patients, and extended durations of therapy, as we impact patients earlier in their disease. Our continued launch execution is driving positive momentum across both of these important dimensions. The launch of Ayvakyt has fundamentally changed the treatment paradigm in advanced SM. driving significant market growth and setting a new standard of care. Ayvakyt is now the treatment of choice for approximately 70% of all advanced SM patients, starting on, or switching to a new therapy. Since the launch of Ayvakyt, the percent of advanced SM patients who are being treated for their disease has grown by approximately 40%, as healthcare providers are now choosing to intervene, where historically they may have chosen to watch and wait. We know there is still significant room for growth, as many patients remain untreated.

At an upcoming medical meeting, we will be sharing new real world evidence, supporting Ayvakyt's impact on overall survival in advanced SM, which we believe will further catalyze urgency to treat. The momentum we are seeing in new patient starts is driven by our growing prescriber base; in Q1, we activated approximately 65 new accounts, particularly impressive, given the impact of Omicron early in the quarter. The strong base of Ayvakyt experience we are establishing is characterized by breadth in the community setting and depth in the academic setting; we have had strong penetration into academic centers of excellence, and as our prescriber base continues to broaden, the majority of new accounts are coming from the community, where half or more of advanced SM patients are cared for. This suggests that we are effectively reaching these patients where they are presenting for care, and also, that providers, who may historically have been less comfortable treating SM, are now motivated to treat patients with Ayvakyt.

We are also, seeing patients benefiting from extended treatment durations, as we continue to progress the launch. Our estimated duration of therapy for Ayvakyt in advanced SM is trending towards 18 months. In our clinical studies, patients stayed on therapy for an average of 2 or more years, some for far longer than that, and we expect duration of therapy to continue to extend, as we are able to reach and impact patient earlier in the course of their disease, when they can derive the most benefit from Ayvakyt. This extended treatment duration we are seeing across academic and community settings in the real world also, confirms that a broad range of prescribers are comfortable managing their patients with a Ayvakyt.

The insights that we are gaining throughout this launch cement my belief in the growing strength of our integrated organization, and the power of the leadership position we have built in SM.

With that, I'll turn the call over to Dr. Philina Lee, who was recently appointed as our Chief Commercial Officer, and now oversees our Global Commercial Strategy and U.S. Commercial Organization to discuss the medical need and market opportunity we see for non-advanced SM.

Thanks, Christy, and hello everyone. I've been a part of Ayvakyt's development from discovery through commercialization. As I step into the role of CCO, I am honored to lead our team and deliver on the promise of this important therapy for patients living with SM. Our strong advanced SM launch trajectory, which Christy spoke to, and our growing understanding of the non-advanced SM market, reinforce our belief that SM is a potential blockbuster opportunity for Ayvakyt. Symptoms of non-advanced SM are debilitating and arise unpredictably, disrupting patients' ability to go to work and spend time with their families. Patients can experience a range of symptoms such as uncontrolled anaphylaxis, extreme fatigue, diarrhea, skin lesions, and brain fog. Patients share that the symptom burden of non-advanced SM leaves them feeling depressed, isolated, and fearful that the disease will worsen.

There are no approved therapies for non-advanced SM today. Current treatment options are adequate and fail to address the underlying driver of disease. The polypharmacy burden for non-advanced SM patients is significant; 75% of patients have reported taking at least 4 or more classes of therapies to manage their disease. And these interventions are woefully inadequate. Greater than 80% of patients still report limitations in their work or daily activities, and 64% share that they avoid leaving their home due to their SM. Another study showed 83% of patients express frustration that current treatments do not address the root cause of disease.

Together with the SM community, our efforts to raise disease awareness and accelerate time to diagnosis are yielding a tangible impact. A 54% growth in the number of SM patients observed in U.S. claims, since the launch of Ayvakyt in January 2020; we now see more than 15,000 unique diagnosed SM patients in claims data, and most of these patients have non-advanced SM. We expect this population to continue to grow with our focus on disease education for healthcare providers, patients, and caregivers, and our emphasis on high sensitivity, blood-based testing for KIT D816V. In March, we launched a new disease awareness campaign for patients with FM, called It's Something; within the first week of launch the website had more than 6,000 unique visitors, including many undiagnosed patients seeking information and a path to diagnosis. An educated patient is a catalyst for diagnosis and treatment. As we await the Pioneer data later this summer, we're confident there are many highly engaged SM patients, both diagnosed and not yet diagnosed, who are searching for better options to manage their disease.

With that, I'll turn the call over to Becker, to review our R&D progress.

Thank you, Philina, and Good morning everyone. Today I'll provide updates in 2 areas; expectations for Pioneer, our registrational study in non-advanced SM and our anticipated clinical data milestones over the next year.

Let's start with Pioneer, which has 2 parts; part one was designed to select the optimal dose and demonstrate proof of concept to ensure a profound of symptoms and show tolerability for long term dosing. We saw that Ayvakyt demonstrated deep reductions of clinical symptoms at all doses, a rapid reduction in mass cell burden KIT D816V, allele burden, serum tryptase, and positively impacted patient quality of life. These data from part one were the basis for Ayvakyt's breakthrough therapy designation in non-advanced SM. Part 2 was designed to enable registration by demonstrating response rate superiority of Ayvakyt versus placebo, as assessed by total symptom score or TSS.

TSS is measured using the ISM Symptom Assessment Form or ISM ASF. This is a patient reported symptom assessment tool that we developed in collaboration with the SM community and regulatory authorities over the last 6 years. We believe that a roughly 30% difference in the proportion of responders with Ayvakyt versus placebo would be a clinically meaningful result that would be supportive of both regulatory filings and drive real world utilization in non-advanced SM. We've also, heard consistently from healthcare providers and patients, that any reduction in symptom burden, including the most burdensome symptom, will be viewed as clinically meaningful and potentially transformative for patients.

We'll also, be looking at a range of additional outcome measures, including mass cell burden and other measures of quality of life. Across this constellation of outcomes, we expect to see a consistent impact with Ayvakyt treatment. We remain on track to report topline data in late summer of 2022 and pending results, we plan to submit an sNDA to the FDA by the end of 2022.

Now let's shift gears to talk about the additional clinical data milestones that will drive significant growth for Blueprint. Over the next year, Blueprint will be defining and executing registration enabling strategies across our pipeline of investigational medicines. In addition to the Pioneer top line data in late summer of this year, we plan to report multiple clinical proof of concept data sets across our EGFR and, and CDK2 programs into early next year, including combination data that will enable us to expand into earlier lines of treatment and increasing numbers of patients. By the end of this year, we expect to have early clinical data for blu-945, in combination with osimertinib, and initial data for blu-701 in EGFR mutant lung cancer. In addition, we expect to have initial clinical data for blu-451 in the first half of 2023, in EGFR Exon 20 mutant lung cancer. We will continue to initiate combination cohorts in progressively earlier lines of treatment and look forward to seeing early data from some of those cohorts in 2023.

I'm equally pleased about the speed with which we're advancing towards clinical proof of concept for Blu-222 in CDK2 vulnerable cancers, with our first clinical data expected in the first half of 2023. Importantly, we plan to explore both monotherapy and combination dose escalation in part one of VELA, and accelerate development across multiple populations; this includes previously treated estrogen receptor positive breast cancer patients as well as frontline patients in combination with other agents, including CDK4/6 inhibitors and hormonal therapy. Also, in patients with CCNE1 amplified tumors, including subsets of ovarian and endometrial cancer, where we plan to explore biomarker driven strategies with our CDK2 inhibitor alone, and in combination with standard of care. As a leading precision medicine biotechnology company, we continue to build on our successful and strong R&D engine, by bringing additional transformative opportunities to patients with severe diseases, including our targeted protein degradation work currently underway.

We look forward to sharing more on our vision at our planned R&D day, in the second half of the year.

With that, I'll turn the call over to Mike to review our financial updates.

Thanks, Becker. Earlier this morning, we reported detailed financial results in our press release. For today's call, I'll touch on a few highlights from the quarter. Total revenues were $62.7 million for the quarter, including $23.8 million in net product sales of Ayvakyt, and $38.9 million in collaboration revenue. This represents approximately 164% growth in Ayvakyt product sales from the same period last year. As Christy noted, we saw solid growth in advanced SM, which is, and will continue to be, our major driver of Ayvakyt product revenue, given our strong momentum with the U.S. launch, and recent approval in Europe. In addition, in the first quarter, we recognized a $30 million development milestone payment from Clementia, related to blu-782, our out licensed ALK2 inhibitor in development for the rare bone disease, fibrodysplasia ossificans progressive.

Turning to expenses. Our total costs in operating expenses for the first quarter were $168.5 million, including $23.4 million of non-cash, stock based compensation expense. This reflects moderate planned growth in R&D expenses, related to the initiation of 4 new clinical trials across our EGFR and CDK2 programs. These new clinical programs will drive the next wave of value inflection points for Blueprint, and highlight our ability to sustain meaningful innovation through our best in class discovery platform.

As Christy noted, we are reiterating our previous revenue guidance for 2022; this includes $180 to $200 million in total revenues, and $115 million to $130 million in Ayvakyt net product revenues. In addition to our diverse revenue drivers, we are in an exceptionally strong position with nearly $900 million in cash on our balance sheet, and we are now entering a period where we expect our revenue growth rate to exceed our expense growth, moderating our cash burn and setting the stage for us to become a self-sustaining company.

Earlier in the call, Kate and Becker outlined the significant potential we are unlocking, as we invest in a breadth of exciting pipeline and discovery plans over the next 12 to 18 months, which we anticipate will lead to continued modest growth in R&D expenses. Our strong cash position and disciplined approach to capital allocation will ensure that we are well positioned to execute on these opportunities, while driving towards sustainable profile.

With that, I'll now turn the call back over to the operator for any questions. Operator?

(Operator Instructions) And the first question comes from the line of Marc Frahm from Cowen.

Congratulations on a strong quarter. I think you discussed part one results that showed a 60% response rate in the 25 milligram arm, and I was wondering if you could remind us what the rate was in the higher dose, with the 50 and 100 milligram doses? And also, looking forward to the part 2 results, beyond response rate; are there any components of the TSF that you think are important commercially, and will drive patient use?

So with respect to the part one data, we saw consistent response rates across all 3 arms; you'll remember it was 10 patients per arm, and we saw both consistent rates and depth of response across all 3 doses. With respect to part 2, remember the TSF score is not a clinical tool; this is a clinical trials tool, so it's not something that providers will be using in the field. However, what it does is it breaks down the patients' experience into a number of different measures of potential improvement. So patients tend to have a number of different organ systems where the disease manifests, so really a myriad of symptoms, with often one that's most bothersome, but it's rarely just one symptom, particularly at this moderate to severe level.

And so I think that people will pay attention both to the overall score, but they'll be particularly interested, depending on the types of patients that they're treating, on specific domains. You can imagine a patient who's got 20 to 30 episodes of diarrhea a day, being particularly interested in those patients that have diarrhea, and the improvement there. And then patients who have a more global manifestation where they're just not able to get out of bed to go to work, or they're really worried about recurrent anaphylaxis, looking at the skin score and the fatigue and the ability to alter a number of different symptoms, and decrease frequency of a number of different types of manifestations, would speak to those providers and patients as well.

That's very helpful. If I can have one more question for Christy, I think you mentioned the 70% of market share for the new prescriptions; I was wondering what market share has Ayvakyt captured for the overall advances in market or potential market?

Sure. So as I said, we're really pleased to see Ayvakyt very quickly through this launch, becoming the standard of care for treatment. And there's really 2 aspects to kind of overall treatment rates that we look at. So one is market growth, so this is a market where historically a lot of patients, unfortunately, have not received SM directed therapy. So the launch of Ayvakyt has grown the market by about 40%. And then we're looking at, of course, how many patients are actually being treated with Ayvakyt, as opposed to other therapies, and that's where we're seeing now 70% of all new initiations going on Ayvakyt. Our overall share is trailing that, given where we are in the launch, and actually that's a good thing when your new start share is above your total share; it's a signal that you're growing, and so we're continuing to see Ayvakyt very rapidly -- I think we're kind of close to 50% of all patients now being on Ayvakyt, and we expect that number to continue to grow as we progress the launch.

Congratulations again.

Our next question comes from the line of Dane Leone from Raymond James.

Congratulations on all the progress over the course of the quarter. Two from me, if I may. Firstly, could you maybe provide a little bit more commentary? We've had some questions around what you said around 18 months expected, of treatment duration; could you maybe contextualize that, given that the drug hasn't been commercially launched for 18 months now, just kind of how you're doing that math, and what you're seeing play out in the clinic. And then could you maybe comment on what you're seeing in the second quarter?

I think everyone expected the launch in ASM to experience the normal issues that most drug companies have in the first quarter of the year. But any commentary on maybe how things are now progressing, April into May, on some of the key metrics that you talked about, would be super helpful. And then finally, could you just maybe level set expectations for the clinical updates in the back half of the year for 945, 701 and 451? I think investors are always trying to figure out for these early datasets, is this really an ORR data set, where we're going to establish something like an RP2D, or are we going to be looking more for the safety signals and emerging signs of clinical effect doses reported? Thank you.

Okay. Thanks, Dane. So Christy, do you want to take the 18 months and talk a little bit about the quarter on quarter growth? And Becker, will you take the clinical updates and what to expect?

Sure. So thanks for the question, Dane. So duration is obviously one of the 2 key drivers that we're watching very closely, in terms of the trajectory of the overall launch. And the context here is that we know that Ayvakyt patients can have quite long treatment durations and advanced SM in our clinical studies, we saw treatment durations of 2 plus years, and so our expectation is that over time, as we continue to find patients closer to a point of diagnosis, we'll continue to extend those treatment durations in a real world setting. You're absolutely right, we have not been on the market for 18 months, and so at this point, we are essentially looking at curves, and comparing, sort of, the curves that we see around duration of therapy in the real world, to what we saw in our clinical studies.

And so we're estimating how we're trending, in terms of a median duration of therapy. We'll continue to take a look at that over time. One positive note there is that we're even seeing that patients who have started more recently in the launch, seem to be trending even more favorably. And I think, again, that reinforces this expectation that we have, around being able to impact patients who are not as sick, as we move through the launch and see those durations extend. Regarding the quarter over quarter dynamics, you know, we certainly -- this is our first SM full Q1 that we've gone through, and had an expectation that we would see many of the dynamics that, you know, certainly other oncology products and, and more broadly we see in pharma, around Q1, in the U.S., where revenue can be impacted by factors around gross to net, compliance as well as some other factors.

We were pleased to see really not a lot of impact through the quarter there. Certainly, we had some minimal impact on gross net because of co-pays, et cetera, but some of the other factors that often impact the first quarter, did not impact Ayvakyt as much as we thought they may. And I attribute some of our excellent patient support services and distribution programs to meeting that impact. So as we go into Q2, we continue to be really happy with the trends around new patient starts and treatment duration, and we expect really more steady growth as we go through the year, in line with the overall revenue guidance that we gave.

Becker, can you take the question?

Yes, so Dane, with respect to our EGFR mutant lung cancer program, just a reminder, that what we are trying to do is make sure that we bring everyone along with us on this journey to understand our compounds better, and the disease better. EGFR mutant lung cancer has become a disease of combinations; as is often the case as we get better and better at treating these tumors, these tumors find more mechanisms of resistance, and finding the right combination partners is really important. 945 is an inhibitor that has a very high window to wild-type, so, we see it as a backbone for future treatment; it has activity, not only in preclinical models, where there's T790M, but also, in the LR mutant population of cells. So we have presented at ACR, initial data showing that this compound behaves exactly as we expected it would, with very little toxicity, really not even much of a hint of EGFR wild-type toxicity, and a rapid reduction in the circulating tumor DNA alleles that it's designed to inhibit.

As we move into the next phase of this study, we start combining with osimertinib; this is a strategy to cover a more heterogeneous tumor population and drive deeper remissions. We will be in a dose-finding phase of this osimertinib combination over the next portion of the study, and similar to what we do it at AACR, we expect to continue to update the community on both the combination and the single agent activity.

With respect to 701, which is our brain penetrant inhibitor; this one has really high potency on the driver mutation and then activity in central nervous system; it really is class defining with respect to penetration of the central nervous system. We are in escalation right now, and we, similar to the way that we presented data for 945, plan to bring people along and help you understand circulating tumor DNA, and the early evidence of activity. And then our strategy and early data, as we combine in 2023, both with 945 and with osimertinib in that program.

And then Blu-451 is a more straightforward biology, where the tumors are driven by single driver mutation, the Exon 20 mutation; we are in escalation now, and we expect to be in escalation for most of the rest of the year. But in that case, we might expect a more straightforward evidence of response, as we've seen with some of the other EGFR20 inhibitors in the clinic. And so as we have a good body of data, that's what we'll be updating in that program.

Our next question comes from the line of Salveen Richter from Goldman Sachs.

This is [Elizabeth] on for Salveen. Just maybe if you could provide some color on the sustainability of the growth drivers underpinning the Ayvakyt sales, you know, this year, and then looking forward.

Christy, are you going to take that?

Yes. Thanks for the question. So as we shared, we're really looking at, at a very simple level, kind of a few key drivers around the Ayvakyt launch; new patient starts and duration of therapy, and, you know, I think that both of those are trending in a way that really sets us up nicely for steady growth, as we go through the year. On the new patient start front, as we mentioned, we continue to have a lot of head room; many advanced SM patients are not receiving a therapy for their disease, and Ayvakyt has very quickly grown to become the standard of care, as new patients are initiating therapy.

And so we're continuing to focus on broadening our base of prescribers, going out and identifying patients closer to diagnosis, and continue to see a lot of room to grow. And then as I mentioned, you know, we're pleased to see the trends and duration that we're seeing already. I think we have some room to continue to improve there, as we go through the year, but in general, very happy to see the patients look to be staying on for extended periods of time. And as we move through the year, that will help us also, drive ongoing revenue growth. So we're reiterating the overall guidance, and are looking to see more steady quarter on quarter growth, as we go through the year.

And just to add one thought to that is, that, you know, as Christy mentioned in her prepared remarks, SM has been a condition where physicians have been really in a wait and watch for quite a bit of time, right; they just haven't had directed therapies that have been very impactful to patients. And so I think the enthusiasm we're also, getting from the physicians that were talking to about the clinical aspects, you know, their early experiences with Ayvakyt has been really promising. And as Christy mentioned as well, at a near upcoming medical conference, we plan to also, present data based on some real world evidence, showing improved survival in patients who are receiving Ayvakyt, relative to standard of care and other therapies, which I think is going to be incredibly compelling. And so you add kind of the early experience, plus this kind of additional data, as we see the benefits of Ayvakyt, turning to really a life extending type of therapy, I think will very much continue to catalyze physicians out of this wait and watch attitude they've been in previously.

The next question comes from the line of Reni Benjamin from JMP Securities.

Congrats on the quarter. Can we get a little bit more color on the European launch? I guess in particular, you know, how that's going to build out over time, and should we be thinking about, you know, maybe a year from now, the revenues or the uptake kind of mirroring what's happening here in the U.S.? And then just kind of related to that the, I'm pretty intrigued by the U.S. claims data that you guys are showing; how much granularity do you have with that data? And do you know which sites per se might be having a lot of the non-advanced SM patients, so that once the launch takes place, you can actively target those sites?

Thanks, Reni, for the question. Christy, if you could take the question on the EU launch dynamics, and then Philina can answer the question about the claims data.

Great. So we were really pleased to see the European approval come through several weeks ago, and as I mentioned on the call, have already launched in Germany and seen, you know, a lot of interest, coming from German healthcare providers and patients already out of the gate, which is really encouraging. The overall dynamics in Europe, I think will be very similar to the U.S. Certainly, the epidemiology is similar, and in fact, I would argue that some European markets, and Germany is one of them, may be a bit more organized in their treatment of SM patients, through the efforts of the European cooperative network around treatment of SM or EC&M.

So we're excited to see this roll out. We expect in terms of the cadence of the launch, Germany is obviously often the first market out of the gate in Europe, given the reimbursement dynamics. And because we already have a reimbursed price there, we expect Europe -- Germany to really be kind of the primary driver in the immediate term. We will have additional European markets coming online as we move through the year, and then certainly into next year, as we look through those reimbursement processes. But generally speaking, would expect kind of the overall cadence of the launch to not look very different and, you know, expect Ayvakyt to become the standard of care for treatment of advanced SM in Europe, over time, as well.

And speaking to the U.S. -- absolutely Christy, so Reni, regarding the us claims data, we have visibility into a number of factors in our patients and provider claims. We can see that the majority, in fact, of these patients have non-advanced SM, and in fact, these patients we think are on the more modern to severe spectrum of disease, in terms of how they're engaging with the healthcare system. We have visibility into the fact that it's mostly medical oncologists and allergist immunologists, who are the most involved in the diagnosis and overall management of these patients with other specialties, such as dermatology and GI, more focused on the symptom management of these patients.

And to your question, we do have some visibility into who is treating and managing these patients, and are very focused on efforts to raise disease awareness among these providers.

Our next question comes from the line of Brad Canino from Stifel.

Morning, and congrats on the quarter. Now that we're closer to the ISM readout, can you outline the degree of data disclosure you expect to put in the top line press release, versus what data points you might save for a medical conference? And then I want to ask them the 945 plus OC combination specifically, where you're focused on LR subgroup; what doses are you going to start at? And based on your 945 TKPD analysis, will those doses already provide predicted therapeutic coverage of all the potential compound and single EGFR mutation combination clones, for those LR patients in the trial?

Thanks Brad, this is Kate. I'll take the first, and hand on over to Becker for the second part of your question. In terms of expectations on top line data; this is going to be very similar to what we've done in the past with (inaudible) with Ayvakyt in the advanced setting, and PGFR, alpha driven gist. So we will plan to put out, particularly the results on the primary endpoint, a safety overview as the primary kind of anchors to that communication; we will save the majority of that data for presentation at a medical meeting. So we'll certainly talk about the overall results of the study, and what are the critical pieces for pursuing FNDA. So that's what you can expect there. And then Becker, do you want to talk about...

Yes. So Brad, with respect to the combination of osimertinib and blu-945, we'll be starting blue-945 at 200 milligrams; this is a dose that begins to approach the OR coverage in the blood, but it's important to remember that we're really trying to get deeply into tumors, in patients with very bulky disease, in some cases. We have a number of different -- and we'll start with full dose osimertinib; we have a number of different combination doses to test during this escalation period, to get the right balance between the 2. We don't expect there to be additional toxicity by adding blu-945, because it doesn't hit the wild-type EGFR until very high doses. But nonetheless, we'll still need to look at a number of different combinations, to get the optimal one for these patients.

Our next question comes from the line of Michael Schmidt from Guggenheim Securities.

This is Yige on for Michael. One on the long term strategy for your CDK2 program; you've spoken about potential combinations with CDK4/6 inhibitors; how should we think about that combination from a safety perspective, and in terms of sequencing therapy? And how would it be positioned relative to Pfizer's CDK2/4/6 inhibitor in any way through, from their initial data in San Antonio?

Yes. So with respect to CDK2 inhibitors, well particularly our CDK2 inhibitors; we don't expect overlapping toxicity. Certainly, we need to look at single agent data, before we know that for sure, but based on our preclinical data, we expect these to be complementary to CDK4/6 inhibitors. We've looked at a number of different combinations with chemotherapy pre-clinically and 46 inhibitors. And so we look at Pfizer's data and we're pleased by the fact that they're seeing activity. However, I think that it's been mentioned, both by us and them, multiple times, that being able to control CDK2 versus 46 is going to be important, to both manage potential toxicity, and make sure we are, in different lines of therapy, addressing either the initial driver or the resistance mechanism, or both at the same time.

With respect to the Pfizer compounds; both their selective CDK2 inhibitor, and the 246 inhibitor, we see this compound is highly competitive; it's a very selective CDK2 inhibitor, and we see it as having potential to combine with a number of different CDK4/6 inhibitors in multiple lines of therapy in hormone resistant breast cancer.

Our next question comes from the line of from Andrew Berens from SVB Securities.

Can you give some additional details on the development plan for the combo of 945 plus Tagrisso? It sounds like initially you're going to go after the LA58R subgroup, developed the 797 S point mutation Tagrisso; do you expect that to be an accelerated pathway? And then, what are the plans to penetrate the first line? Are you going to test the 2 drugs, small molecule cocktail, or the met inhibitor, either a small molecule or a large molecule?

So let me address those individually. So with respect to the combination, again, as I mentioned, the reason for the combination is twofold; one is to hit the driver mutation as hard as possible. So the combination of either osimertinib or blu-701, plus blu-945 would be expected to do that. But also, in the resistant setting, to address heterogeneous tumors, and in the frontline setting to present the emergence of resistance. Our goal in the frontline setting is to really shutdown the EGFR signaling pathway, and it's been shown multiple times in hematologic tumors that when you can do this, you get longer durations of response, and eventually longer overall survival.

With respect to pathways to approval; in the relapse refractory setting, even in the second line following first line osimertinib, there's really not much besides chemotherapy that's showing activity at this point. And so we do think that there are potential rapid pathways to approval, either for the single agents or a combination with standard of care, that would then be followed up with randomized trials to confirm that clinical benefit of that combination. So we will look early in our study of 945 plus OIB for evidence of activity in the relapse refractory setting, but then shortly thereafter, looking in the frontline to show that we can achieve rapid deep responses with that combination.

With respect to met inhibitors, met is an important, but certainly not overly dominant mechanism of resistance. I think that it is important to remember that some of these other non-EGFR mediated mechanisms of resistance are really the drivers of early resistance, where patients that have been on osimertinib for a longer period of time will have higher rates of on target or EGFR mutations driving the resistance. So we will, using 945, start to explore combinations with a number of different compounds, and that will likely include a met inhibitor, and the utility of that in different lines of therapy, or maybe in early relapse patients, will be something that we'll be determining over the next year to 15 months.

Our next question comes from Mike Ulz from Morgan Stanley.

Maybe just a follow up on an earlier question related to the claims data and the diagnosis rate; it looks like you're still getting some nice traction there. Just curious, at peak, you ultimately expect the majority of SM patients to be diagnosed, or for some reason, could that number be lower, and maybe it's because you're not capturing mild patients, for example? And then secondly, can you remind us what the current diagnosis rate is in Europe? Thanks.

Christy, can you take that?

Sure. So we are really excited to see kind of the ongoing growth in diagnosed patients. I know many of you remember a couple years ago, when we started talking about non-advanced SM in sort of more detail, and at that point in time, maybe 10,000 patients were diagnosed in the U.S., and now we're close to half. So our expectation is that the majority of SM patients will be diagnosed, as we approach the launch and then move through the launch, through our ongoing efforts and our focus. And, we're kind of close to that point now. We also, think that moderate to severe patients, because of their symptomatology are on the margin, more likely to find their way to a diagnosis, versus patients who may be milder. So we will continue to really be putting effort against that.

In Europe, we are building that picture, market by market. I can say that, you know, we were able to get a look at sort of analogous claims like data in Germany, and it painted a very similar picture to what we see in the U.S., which was really encouraging, because I think it validates the idea that these patients are definitely out there, they're being diagnosed, and we're continuing to see that growth, both through our efforts as well as, I think just the efforts of the overall SM community, and these patients who are just so, motivated to really seek diagnosis and treatment.

And just to add one other element to that for Christy, is that I think one of the things we've seen in other kind of similar launches, whether that be at Jakafi or others, is that we expect a very compelling risk benefit profile coming out of the Pioneer study in the non-advanced setting. And as physicians start treating and get comfort, we certainly see that less symptomatic patients start to be more included in those treatment paradigms. So I think, you know, upon the Pioneer study and our launch in the non-advanced setting, we would expect that patients with less symptomatology would start to be included, again as physicians gain that experience and comfort.

Our next question down from the line of David Lebowitz from Citi.

First on non-advanced SM; you had indicated that 70% of new patient starts we're going to Ayvakyt. I guess, how can we look at the growth trajectory going forward, as it seems that it's going to be shifting more from, I guess, new patients, to duration over the long haul? How does that affect the run rate?

So Christy -- I think David, you're saying that in the advanced setting that 70% of new patients start, but Christy, do you want to answer the run rate?

Yes. Right. So as I said, there's really 2 kind of factors to think about, when we're thinking about kind of new patients starting in advanced SM. So one is just the overall rates of treatment in this indication, and despite the fact that it is such a severe disease with a very limited life expectancy, we know that many patients have not been treated; providers have taken more of a watch and weight approach, I think largely because the available therapies simply haven't been very effective at treating the disease.

And so the fact that we've seen 40% growth in the number of patients being treated, such as sort of the overall market, since Ayvakyt has launched, I think really speaks to that. But, the majority of patients are still not being treated, and so there is a lot of room to continue to grow the overall size of the market. And with Ayvakyt getting about 70% of those new starts, I think we're very well positioned, as the market continues to grow, to continue to drive new patient starts on Ayvakyt. So I continue to see both new starts as well as treatment duration to be very important drivers for ongoing growth, and in fact, in the near term, I think new starts will be probably the more important of the 2 of them, and we continue to see a lot of health there, expanding prescriber base, continuing through even the last 2 months in Q1. And so I think we're well set up as we go through this year, for the steady growth that we expect.

Sure. Thank you for that. And, we're looking at the claims data regarding, systemic mastocytosis as a whole; how are those numbers actually determined? What factors goes into determining differentiating one patient versus another, given that polypharmacy is a substantial issue, which could hamper such analysis? Many of the drugs often used are antihistamines, things that actually don't require prescriptions. How do we break those numbers down?

Philina, can you take that? If you can take a stab, and Christy, please add color.

I'm happy to start, yes. So thanks for that question. So first off, I would say we're fairly confident that these are indeed unique patients that we're looking at, as we're able to follow their journey through initial diagnosis and their health care utilization, which includes things like the treatments that they may use as well as the different physician specialties that they're interacting with, both for chronic care as well as sort of acute or episodic care. And so some of the features that we're able to see, are both the initial diagnosis of SM as well as the SM diagnosis code associated with all of these care interactions along that journey.

Got it. And the last question is, the denominator of those questions on the left of Slide 6; patients on polypharmacy; is that denominator essentially equivalent to this, the population that's in the claims data or are there differences in the sample?

Yes, that's a great question. There are actually a number of different publications on this topic, and so, some of these facts that we're showing on slide 6 come from a touchstone survey that has been done with both patients living with non-advanced SM as well as the allers, immunologists and hematology oncologists that are managing these patients. We also, see though that these numbers correlate very well across a number of other published literature that surveys patient and provider healthcare populations.

Our next question comes from the line of Eun Yang from Jefferies.

I have questions on non-advanced SM. Previously, you mentioned about 70,000 patients in major global markets, and based on Phase II entry criteria, what percent of patients do you think would be realistically candidates for Avapritinib? And if you are targeting majority of 70,000 patients, what do you think would be reasonable pricing for rapid adoption?

And the second question is what percent of a target patient population in ISN, would be treated with hematologists versus allergy specialists?

So Philina will take some of the first part of that question, just around the addressable patient population, and then Christy, if you could wait on the pricing, that would be great.

Yes. Thanks for that question, Eun. So just to kick it off, as we look across multiple data points, suggests that 60% or more of patients may ultimately be candidates for disease modifying therapy. So we've talked about the vast majority of these patients receiving polypharmacy, and despite this, still reporting significant impacts on their quality of life. For example, we hear that up to 50% of patients are reporting potentially life-threatening anaphylaxis, and we've heard an example of a patient who keeps an EpiPen in every room of her house. As we speak to allergists and hematologist oncologists, they also, share with us that they see 60% approximately of their patients, being moderate to severe, and really not well controlled on symptom directed therapies.

Okay. And Christy, do you want to weigh in on the pricing question from you?

Absolutely. So the context that Philina just shared about this disease, I think is important when we think about pricing. So non-advanced SM is clearly a much bigger indication versus advanced, however, it is still very much a rare disease, and it's a rare disease where patients are suffering from very severe morbidity, impact on ability to work, quality of life, along the lines of cancer patients, et cetera. You know, as we've engaged with payers, they very much understand that context, and in fact through our experience with the launch of Ayvakyt so far, we've had really no barriers to access from a payer perspective, a very rapid time to fill, and we've seen some reimbursement, in fact, in the non-advanced setting, as well. And so our expectation as we go forward, the Ayvakyt we're on the market and price certainly in the U.S. at all doses, would expect to be able to continue to ensure patient access, as we go forward into the non-advanced launch.

And so I don't really see price as being kind of a major driver of that launch; I think it's going to be much more about our continued engagement with healthcare providers and patients' education around patient identification and testing. And of course, the very positive benefit risk profile that we're expecting to see from Ayvakyt in this indication, particularly at the doses for non-advanced SM, based on the data that we've seen so far, from Pioneer, in part one.

Hematologist versus allergist; so what we see is that non-advanced patients generally are managed by allergy, primarily; hematology is often involved in co-managing these patients. And so we expect that our efforts will be primarily focused in allergy as well as in the hematology call points that we're already focused on, for the advanced patients.

Well, can I ask you one more question to that then? Would you need to add the sales reps to target allergy specialist?

Our expectation is that we may modify our commercial footprint as we go forward towards that non-advanced approval, to make sure that we are really adequately directing resources into the allergy space. But, we don't expect those changes to be significant. This is a very tractable call point, for a specialty commercial organization, and kind of the context of a biotech company, and we are already quite adept and skillful at utilizing some of the claims data that we've already been talking about, to make sure that we're directing our efforts in a really efficient way.

Eun, this is Becker. I just wanted to make a point about the first part of your question. I think we need to think of these patients as having a chronic disease that does progress over time. The story that we've heard from patients has been that they start out -- may start out with mild symptoms, but that they tend to get worse and worse over time, and become more and more debilitating. To date, we haven't had an option for these patients, so I think that what we're going to see is providers looking to understand the depth of the disease, sometimes by trying the treatment that we know wipes out the clone that causes the disease. And also, starting to work with the community to understand the value of preventing the progression of this disease, even in the non-advanced setting. So I wouldn't think of patients as showing up at a certain level of severity and simply staying there for good.

At this time, we have run out of time for further questions. So I will turn the call back to Kate Haviland for any final remarks.

Thank you, operator. Our strong performance in Q1 sets the foundation for us to achieve the priorities we've laid out, as a company this year. Ayvakyt, as we just talked about, is off to a very strong start in its first full year of launch, with the opportunity to expand to the non-advanced SM right around the corner. We are also, maintaining our growth momentum with the execution of our pipeline through key data milestones this year and next. We look forward to talking with all of you on this continued progress very soon. So thank you for taking the time to join us today, and thank you for your continued support of Blueprint Medicines.

This concludes today's conference call. Thank you so much for joining. You may disconnect your lines.