Blueprint Medicines Corp (BPMC) 2021 Q1 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the Blueprint Medicines conference call. (Operator Instructions) I would now like to hand the conference over to your speaker today, Ms. Kristin Hodous with Blueprint Medicines. Thank you. Please go ahead, ma'am.

Thank you, operator. Good morning, everyone. This is Kristin Hodous of Blueprint Medicines, and welcome to Blueprint Medicines First Quarter 2021 Financial and Operating Results Conference Call. This morning, we issued a press release, which outlines the topics we plan to discuss today. You can access the press release as well as the slides that we'll be reviewing today by going to the Investors section of our website at www.blueprintmedicines.com.

Today, on our call, Jeff Albers, our Chief Executive Officer, will discuss Blueprint Medicines' first quarter 2021 business highlights; Christy Rossi, our Chief Commercial Officer, will provide a commercial update; Becker Hewes, our Chief Medical Officer, will review our clinical progress and highlight upcoming milestones across our growing pipeline; and Mike Landsittel, our Chief Financial Officer, will review our first quarter 2021 financial results.

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 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, Jeff Albers.

Thanks, Kristin, and good morning, everyone. 2021 is off to a productive start, and I'm pleased to provide an update on recent progress across our growing portfolio.

As we outlined on our year-end call, our 2021 efforts are centered around 3 strategic pillars: First, accelerating the global adoption of AYVAKIT and GAVRETO; second, advancing a next wave of therapeutic candidates to clinical proof of concept; and third, further expanding our precision therapy research pipeline.

Just a few months into the year, we've already made significant progress against each of these goals. As Christy will discuss in a moment, we continue to advance the commercial launches of AYVAKIT and GAVRETO.

In parallel, we're preparing for the anticipated approval of AYVAKIT in advanced systemic mastocytosis. As we near our PDUFA date in the U.S. and with a type 2 variation MAA under review with the EMA, we're moving forward with urgency to provide a therapeutic option for as many patients as possible fighting this disease.

At the AACR Annual Meeting earlier this month, we presented registrational data from our Phase II Pathfinder trial in advanced SM, which demonstrated a confirmed overall response rate of 75% with responses occurring rapidly and continuing to deepen over time. In addition, new patient-reported data showed that treatment with AYVAKIT significantly reduced disease symptoms and improved quality of life. We believe these results reinforce the potential of AYVAKIT to fundamentally change the outlook for patients with advanced systemic mastocytosis.

We also shared new data at AACR from several investigational medicines in our portfolio that comprise our next wave of therapeutic candidates, including BLU-263, and our next-generation KIT D816V inhibitor, BLU-701 and BLU-945 are 2 EGFR development candidates, and our newest programs, BLU-222, targeting CDK2 and BLU-852 targeting MAP4K1.

Collectively, these programs have the potential to dramatically expand our ability to reach patients on a global basis. In fact, each of these markets targeted by these new programs is forecast to more than double in size over the next 5 years, underscoring the opportunity for us to bring innovation to areas of significant medical need.

Since our founding 10 years ago, we've worked hard to integrate our discovery, development and commercialization efforts in order to maximize innovation and efficiency. We've already demonstrated the productivity of this approach, having successfully discovered and developed 2 approved medicines.

In the past 1.5 years alone, we've expanded our pipeline with 5 additional development candidates, all of which we intend to advance with the same sense of urgency. To that end, and as Becker will describe in a few minutes, we remain on track to initiate multiple clinical trials in the months ahead, positioning us to generate several significant proof-of-concept data sets in the near future.

Importantly, we continue to operate from a position of tremendous financial strength with the resources to invest in our commercial efforts, our pipeline programs and our research engine. As we aim to make real the promise of precision therapy for as many people with cancer and hematologic disorders as possible.

With that, I'll now turn the call over to Christy to discuss our commercial efforts. Christy?

Thanks, Jeff, and good morning, everyone. I'm pleased to share our first quarter results as we continue to progress the launches of AYVAKIT and GAVRETO.

In Q1, we generated net product revenue of $9 million, including $7.1 million in sales of AYVAKIT and $1.8 million in sales of GAVRETO.

Let me start with GAVRETO. As I shared on our Q4 call, we are focused with our partners at Genentech on 2 key priorities for the launch. The first is growing our share of new patients who are starting on a selective RET inhibitor, and the second is increasing the percent of RET-positive patients who are identified and treated with a targeted therapy. We've seen good progress against our first priority.

Our share of new patient starts continue to increase over the course of Q1, exceeding 35% by the end of the quarter. An increasing number of new patients starting on GAVRETO is a key driver of future revenue growth based on the favorable duration of treatment we expect from our clinical data. And in March, we had our highest number of new patients starting on therapy since launch.

The number of GAVRETO prescribers is continuing to grow, and we've started to see stronger uptake among physicians in the community setting, many of whom are prescribing a selective RET inhibitor for the first time.

We continue to receive positive feedback on the deep and durable responses, predictable and manageable safety profile and once-daily dosing with GAVRETO, which makes it well suited to broad use in a community setting.

We see great potential to further grow the RET inhibitor market overall as fewer than half of RET patients are being tested for RET and then being given the opportunity to be treated with a targeted therapy.

We are working with our partners at Genentech to impact this through continued multidisciplinary education to increase comprehensive biomarker testing and ensure that it is appropriately acted upon. As we've seen with other targeted therapy launches, we expect ongoing growth in the number of identified patients, driven by these efforts by the availability of highly effective therapy, and by the waning impact of COVID in the U.S. as we approach the second half of the year.

Finally, we are excited about the progress we've made with our partners to bring GAVRETO to patients around the world. A few weeks ago, CStone Pharmaceuticals received NMPA approval in China for GAVRETO in RET fusion-positive non-small cell lung cancer, making it the first approved selective RET inhibitor in the market. We are also looking forward to the anticipated approval and launch of GAVRETO in Europe by our partner, Roche. We expect these global launches to be additional drivers of revenue growth in the future.

Now let's turn to AYVAKIT. In PDGFR-alpha GIST, we've seen consistent new patient starts quarter-over-quarter in the U.S. and are progressing our first EU launch in Germany. Our partner CStone, also recently secured an MPA approval of AYVAKIT, making it the first approved precision therapy for patients with PDGFR-alpha Exon 18 mutant GIST in China.

We anticipate seeing incremental growth in just revenue over time with additional country launches. Of course, our primary focus with AYVAKIT continues to be preparing for our anticipated approval and launch in advanced systemic mastocytosis in the U.S. this quarter.

As I've described before, advanced SM represents about 5% to 10% of the overall SM population or about 2,000 to 3,000 patients in the U.S., many of whom are treated at major centers. We plan to initially focus the majority of our educational efforts on about 70 hematology/oncology centers that treat about half of all advanced SM patients in the U.S.

Our existing commercial and medical affairs infrastructure allows us to prioritize these key centers while using our portfolio footprint to increase patient identification in the community over time.

As we begin to realize the tremendous impact that AYVAKIT can bring to patients with SM, we are focused in 3 key areas. First, on driving patient identification and appropriate diagnosis, which includes understanding current treatment and referral patterns to key centers. We believe that upon approval, initial utilization of AYVAKIT will be driven by already diagnosed prevalent patients who may be currently treated with midostaurin, other tyrosine kinase inhibitors, or cytoreductive agents.

Over time, we expect to see increasing utilization from newly diagnosed patients. We also believe that making blood-based testing for KIT D816V, the SM driver mutation, widely available will help remove barriers to diagnosis for both advanced and non-advanced SM patients.

In our fourth quarter call, we announced that highly sensitive blood-based test for KIT D816V are now commercially available in the U.S., and we expect that over the course of 2021 testing availability will grow to cover about 80% of SM patients in the U.S. We are confident that this, combined with the disease education and other efforts, will translate into an increased number of identified SM patients who are diagnosed and have access to treatment.

Our second priority is educating health care providers, patients and other stakeholders on the differentiated and compelling value proposition of AYVAKIT and SM. We believe AYVAKIT is a transformative precision therapy solution that will profoundly change the way patients are treated and meaningfully improve their lives. And we will work to ensure health care providers are fully educated on the clinical data supporting its use quickly upon approval.

Finally, and most importantly, we are committed to providing best-in-class access and support for patients. Consistent with our approach to our launch of AYVAKIT and GIST as well as GAVRETO, we will focus on meeting the unique needs of SM patients, facilitating access to therapy and providing best-in-class financial assistance and support through the YourBlueprint patient support program.

As we look ahead to the launch of AYVAKIT and advanced SM and continue to progress development in non advanced forms of the disease, we are excited to build on our leadership position with the goal of meeting the unique needs of all SM patients. AYVAKIT will play a key role as the cornerstone of our portfolio. And we look forward to further extending and expanding the impact we can have on SM with the development of BLU-263 as we initiate the HARBOR study this year.

With that, I would now like to turn the call over to Becker to review our clinical portfolio.

Thanks, Christy, and good morning, everyone. As we discussed a couple of weeks ago on our AACR call, we're in the midst of a period of robust research productivity, having nominated 5 new development candidates in the past 18 months. To those programs, BLU-263 and BLU-945 are anticipated to begin clinical development in the next few months.

Let me start with BLU-263 and continue Christy's discussion of our groundbreaking KIT franchise. BLU-263 is a non-brain penetrate KIT D816V inhibitor with similar potency to AYVAKIT. We presented Phase I data at AACR that showed BLU-263 was well tolerated at all doses tested in healthy volunteers. Pharmacokinetics were linear and dose-dependent with a half-life supporting once-daily dosing.

Based on these data, we plan to initiate the Phase II/III HARBOR trial later this year. Similar to the ongoing PIONEER trial for AYVAKIT in non-advanced SM, we will evaluate a range of doses, quantifying the impact on disease symptoms and safety. This will include a multiple dose part 1 to determine the optimal dose, followed by a randomized placebo-controlled of part 2, evaluating reduction in total symptom score as the primary endpoint.

One novel aspect of the HARBOR trial will be enrolling patients with a broader eligibility criteria, including patients with a lower baseline total symptom score. This provides the potential to extend our reach to a broader population of patients with non-advanced systemic mastocytosis, a central goal of the BLU-263 program.

In addition, we plan to include an exploratory cohort in Part 2 of the trial for patients with monoclonal mast cell activation syndrome, also driven by the KIT D816V mutation.

Turning now to our EGFR programs. During our AACR call, we outlined how our EGFR inhibitors are designed to address important unmet medical needs by providing comprehensive coverage of activating and on target resistant mutations. They have optimized selectivity profiles, enabling combination strategies and high CNS activity to treat or prevent brain metastases.

At AACR, we presented for the first time foundational preclinical data for BLU-701, our potent wild-type selective brain-penetrant double mutant EGFR inhibitor. We also presented additional preclinical data for BLU-945, our triple mutant EGFR inhibitor. As monotherapies and combination therapies, these rationally designed investigational candidates have the potential to address patient needs across all lines of therapy.

This quarter, we will initiate the clinical trial of BLU-945. And later this year, we plan to initiate a similar trial for BLU-701. The BLU-945 trial will include a dose escalation portion in patients with EGFR mutant non-small cell lung cancer who have previously received at least 1 prior EGFR targeted tyrosine kinase inhibitor, followed by expansions in cohorts of patients with tumors harboring specific mutation profiles. While our initial focus will be to rapidly demonstrate single-agent activity, we plan to quickly advance development of both of these agents into combinations with each other and other EGFR targeted therapies. A strategy that offers multiple shots on goal.

With the initiation of these trials across our clinical portfolio, we are well positioned for numerous milestones in the quarters ahead. At ASCO in June, we will present updated clinical data for GAVRETO from the ARROW trial in patients with non-small cell lung cancer as well as in patients with solid tumors driven by the RET oncogene. We also anticipate presenting preclinical combination data for BLU-701 and BLU-945 in the second half of the year.

In 2022, we plan to bring our 2 newest development candidates to the clinic. BLU-222, a potent and highly selective CDK2 inhibitor targeting Cyclin E aberrant cancers and BLU-852, a potential best-in-class MAP4K1 inhibitor developed under our immunotherapy collaboration with Roche. We look forward to providing further updates on these programs as they move into the clinic.

I'd now like to turn it over to Mike to discuss financial updates.

Thanks, Becker. Earlier this morning, we reported detailed first quarter financial results in our press release. For today's call, I'll touch on a few highlights from the quarter.

Total revenues for the first quarter were $21.6 million. This included $9 million in net product sales, as Christy mentioned, and $12.6 million in collaboration revenue, primarily from our agreements with Roche and CStone.

Our total operating expenses increased moderately compared to the fourth quarter of 2020, primarily driven by costs associated with advancing our early-stage pipeline towards the clinic, offset by cost-sharing from our agreement with Roche on GAVRETO. As we expand investment in our promising early-stage programs as they enter the clinic over the next few quarters, we expect to see continued increases in quarter-over-quarter operating expense growth. We ended the first quarter with $1.4 billion in cash, ensuring that we have sufficient resources to invest in our growing pipeline of wholly-owned drug candidates.

As we look forward to the second half of 2021, we are uniquely positioned to drive revenue growth through a variety of sources, including direct product sales of AYVAKIT in multiple geographies, royalties on both AYVAKIT and GAVRETO outside the U.S., profit sharing on GAVRETO sales in the U.S. and milestone payments from our various collaborations.

Based on our projected growth across these revenue sources and driven largely by the planned launch of AYVAKIT in advanced SM, global expansion of indications for both AYVAKIT and GAVRETO and anticipated milestone payments in the third and fourth quarters, we continue to be comfortable with the current total revenue expectations for 2021 of approximately $150 million. This revenue growth will build on the strong financial position that we are in today and help solidify our path to becoming a self-sustaining biopharmaceutical company.

I would now like to turn the call over to the operator for questions. Operator?

(Operator Instructions) We will now start the Q&A with Salveen Richter with Goldman Sachs.

Maybe with regard to RET patient identification and diagnostics. You've given us some sense of how that was tracking, I think, last quarter. Could you just talk about the trends in 1Q, and how you're thinking about the cadence moving forward?

Sure. So as I said, there's really 2 key levers that we are focused on. So one is our share of the RET market. But then the second, as you mentioned, is increasing the number of patients who are identified and treated, and I spoke about this in Q4 and said that something like maybe 20% of patients, if you look at testing as well as then the opportunity to be treated with a selective RET inhibitor are having that opportunity at this point. So there's still, I think, substantial room for growth.

I will say, we haven't seen as much growth quarter-over-quarter, as I'd like to see. I think that's partially driven by the impact of COVID, which we know has really had an impact on patient identification, testing, et cetera. But I'm optimistic that as we go into the second half of this year and then go forward from there, we will see that grow. And certainly, we've seen with other targeted therapies that the advent of effective treatment is in itself a primary catalyst.

We saw that with ALK, we saw that with ROS, and I think we'll see it here as well. So we'll look to see that number grow. And clearly, that's in the best interest of patient care. So we're working actively with our partners at Genentech to really make that happen.

Your next question comes from the line of Marc Frahm with Cowen and Company.

Sticking with Christy. Just the guidance on the patient numbers for ASM. Can you kind of detail the -- as we've seen in the clinical trials, right, the definition of a patient between ISM and ASM is very gray. And can you kind of detail how strict you're being in your definitions when you're kind of making the splits on your guidance and then kind of along those lines, would you expect some of those patients that are in your guidance in the ISM population to actually be able to gain access to the drug once you're approved in ASM?

Yes. So you're right on. We've seen that in our clinical studies. I think we see it in clinical practice, it can be challenging to accurately subtype patients, the world's leading KOLs may struggle to do it at times. And certainly, patient typing can evolve even in a given patient over the course of their disease, where I think we see most potential sort of gray or overlap is between patients with aggressive advanced SM or ASM and patients who may have ISM that's more severe.

And so the patient estimates that I gave of 2,000 to 3,000 approximately, those reflect that uncertainty, right? I think that as we get into the market, we'll have a better sense of how health care providers are subtyping patients.

Fundamentally, I think the diagnosis codes, et cetera, are overlapping in this disease, and we've seen that it's not a space that payers tend to manage closely. So our assumption is that our initial utilization will be driven by patients for whom the health care provider believes that they have adapt to them. And we are optimistic that we will have good access for those patients given the really compelling value proposition that AYVAKIT will have in that patient population.

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

Congrats on the start to the year, and thanks for the guidance. Maybe 2 questions for me. One, in terms of guidance on the SM launch. Could you maybe provide more color in terms of how many patients are currently treated with mido and what the patient population and opportunity would be for other switch therapies beyond mido that do you think docs would be willing to cross over to avapritinib once approved?

And then second question would be in terms of thinking about the development of 945, do you think it would be interesting to perhaps partner with AstraZeneca and add an adaptive arm into the ORCHARD study?

All right. So Christy, why don't you take the advance ASM question, and then Becker can take that 945 question around combinations.

Yes. Sure. So as I mentioned in the prepared remarks, we would assume that upon approval, where we would expect to see initial utilization would be on patients who are diagnosed and currently being treated. And we know that those patients can be treated with midostaurin, they may be treated off-label with other TKIs, cladribine, et cetera.

The utilization of midostaurin, we don't have perfect insight into. Health care providers will report that maybe 30% of advanced SM patients are treated with midostaurin. The data would suggest it's probably less than that. And I think a driver of the difference there is that patients have a hard time staying on. And so what we hear is that duration of therapy in advanced SM with midostaurin is unfortunately suboptimal and can be well less than a year in many patients.

And so we are feeling confident, certainly amongst the SM KOLs and people who are very comfortable managing this disease that they understand sort of the value proposition that AYVAKIT will have and would expect to see uptake there quickly. However, we'll go broader than KOLs and get into the community, and we'd expect to see that patient identification grow over time and have that be sort of the driver of longer-term growth along with treatment of newly diagnosed patients, which again would happen over time.

And with respect to the 945 program, our strategy is within our studies to really look at the combinations closely. BLU-945, as you may remember, is a compound with an extremely high window over wild type, so very little inhibition of wild-type EGFR, which makes it a great combination partner for a number of different agents we'll be looking at combinations of drugs like osimertinib and BLU-701. And in the future, even drugs that address mechanisms of resistance like mat inhibitors.

So we're going to take it on within our trials initially to understand the tolerability of the combinations and look for preliminary activity at this point.

Your next question comes from the line of Michael Schmidt with Guggenheim.

I had 1 on labeling considerations in indolent SM. And my first question is would you potentially pursue a different brand or label for avapritinib in SM versus GIST. And then thinking further upon potential approval in advanced or indolent SM with different dosing, I guess how would that potentially affect labeling, given that side effects and other factors might potentially differ given the different doses used in those 2 subtypes of exam.

Christy, do you want to take that?

Yes, sure. So we are eagerly and urgently working to make AYVAKIT available for us in advanced SM. And then in non-advanced forms of the disease and are obviously working actively to finish enrollment of PIONEER. We are excited about the profile of ava in non-advanced forms of the disease. So we don't anticipate making a different brands available. We know that the benefit risk of AYVAKIT, just like in many other -- with many other therapies that are approved at different doses for different indications, is going to look different.

And so for non-advanced SM, the preliminary data we've seen at the 25-milligram dose at a Part 1 of PIONEER makes really confident that we're going to have a very favorable benefit risk profile and allow us to impact patients with non advanced forms of the disease.

Of course, we're also excited about BLU-263 as our sort of next-generation KIT inhibitor, and as Becker said, we anticipate that, that could potentially broaden even further the number of non-advanced patients that we can impact.

So in terms of the dosing, again, there's plenty of precedent in labeling to be able to differentiate what a benefit risk profile and safety and efficacy look like, both across different indications as well as a different dose profile.

Your next question comes from the line of David Lebowitz with Morgan Stanley.

This 2 questions from us. The first on GAVRETO. So in the early launch stage, what is the initial feedback from physicians on how the RET inhibitor may be used versus, say, Retevmo? Are there specific types of patients that lend to 1 therapy versus the other?

And our second question is on AYVAKIT. So in the review of the registration by the FDA, where have questions been focused? How should we expect the labeling to look in regards to the safety given the patient in the clinical trials?

Maybe I'll start with the second question first, and then I'll have Christy talk about the differentiation components from physician perspective with GAVRETO. So obviously, we're in the middle of our review and as we highlighted last quarter that given that timing and then given the active progress that we're making. We're not going to comment on the back and forth. I mean, questions change day-to-day. And I can tell you we're making nice progress. The agencies very engaged and going through the data and understanding of the disease.

But in terms of the specifics, we're not -- wouldn't dig into that level of detail.

And then regarding GAVRETO and Retevmo and how the feedback we're hearing. We certainly hear that there are points of differentiation. Certainly, the breadth of efficacy and the consistently deep and durable responses across patient types. I think it's something that's been compelling to physicians about GAVRETO. And then, of course, as I mentioned before, there are differences in safety as well as administration that can become important. And I think more important even as you get into a community setting. And certainly, QT prolongation and not having that with GAVRETO has been an important point as well as once-daily dosing.

The bigger picture, though, with this is that there are some physicians who have used both what we are seeing is that we are still at the beginning stages of really developing this overall market. And so we are continuing to really add new prescribers. And the majority of the prescribers we're seeing for GAVRETO are new-to-market prescribers. So they're prescribing a RET inhibitor for the first time.

And what that tells me is that the opportunity here really is to go out and educate new prescribers and help them identify new RET patients, and there's still a ton of potential to do that because we know that majority of our patients are not getting the opportunity to go on either one of these drugs.

Your next question comes from the line of Chris Raymond with Piper Sandler.

Just got a question on the EGFR molecules. So just going through the preclinical data you guys have published on these looks like you're able to reach a therapeutically active dose with 701 at much lower doses than 945?

So obviously, there's differences in underlying mutations. But just kind of curious around how do you think about that translating to the clinic in sort of the efforts here to find a therapeutic index.

Becker, do you want to take that?

Sure. So taking preclinical data as a guide to where we're going to start the study is really how I look at preclinical data on dosing. There obviously are differences between animals and humans with respect to exposure and metabolism. So we've got a starting dose for 945, and we're working towards that for 701, we have some predictions about where we will see activity and get full coverage of the EGFR molecule for the full day. Both of them we expect to be amenable to once-daily dosing. And then as we combine them, we expect them to combine very easily because they both have a huge window of wild type.

So we'll have to get into the client to really get more specifics that. The programs are not separated in time substantially we do expect 701 to potentially catch up with 945, which is great because then we can look at the combination of the 2 in real-time as we dose escalate and really get MTDs for single-agent and combinations in about the same time frame. And as I mentioned earlier, also combination dosing with other molecules such as osimertinib.

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

Maybe just on BLU-263. Can you -- I think you mentioned here that there's an exploratory arm in monoclonal mast cell activation. Can you just remind us what are the various types of non advanced SM patients that you'll be enrolling in the study in the registrational part? And will it be evenly split? And has this already been discussed with the FDA that you could ultimately lead to registrational purposes? Or is it kind of solely based on the data?

So the foundation of our program is in patients in the AYVAKIT program is in patients with a higher TSS score or symptom score. And so we have that cohort in Part 1 of our study, we're also going to be looking in Part 1 at the effect patients with a lower symptom score. The -- part of the reason that we have this 2-part program is to allow us to optimally set up a registrational study. The plan right now is to look at both groups of patients in that registrational study, the obvious one being those with a higher symptom score.

So there will be an opportunity to refine the registrational portion of the study as we move forward. We have had discussions about the general design of our program with the agency. But we're really going to let the data drive how we ultimately design the registrational part of the study.

Your next question comes from the line of David Nierengarten with Wedbush Securities.

I just had a quick one on diagnosing mastocytosis patients, you mentioned the blood test. Can you just remind us currently -- you require, as I recall, a bone marrow aspirate to confirm diagnosis. Would this replace that? Or would patients still be going in for a confirmatory or other testing? Maybe just walk us through how you see testing becoming a little bit more patient-friendly in the future.

Sure. So yes, you're right. The diagnosis of SM per criteria does require a bone marrow biopsy that's recommended for every SM patient. However, we know that for some patients, that is a hurdle. And certainly for some non-advanced patients that are being treated by allergists, that can be a hurdle. And at times, patients are treated based on suspicion versus actually going through the process of getting a bone marrow biopsy.

For advanced SM patients, we would certainly expect that a bone marrow biopsy -- continues to be a very important part of diagnosis and management over time. For non-advanced patients, I think that blood-based testing can become a really important way of identifying potential patients in a much easier and simpler way that can be managed by allergists more broadly. And so the key to that is really making highly sensitive blood-based testing available. So there is KIT D816V testing that's available now. But you -- we know from our own data that you can miss patients if you're not using the right approach in terms of sensitivity and specificity.

So that's really our -- one of our very key pillars over the next few years is to increase the number of patients who are tested. Certainly once the patient tests positive, they may still require a bone marrow work-up to further understand their disease and pathology. But I think that blood-based testing will be a very critical lever to enabling more patients to get access to the right diagnosis more quickly.

Your next question comes from the line of Eun Yang with Jefferies.

This is Sarah on for Eun. I just have a couple of questions. First, on the EGFR program, where do you think that the combination of 945 and 701 would differentiate in first line therapy versus osimertinib? And then when do you think you would expect to start the first-line trial? Is there a potential to run that trial in a partnership?

And then just a quick one on this mast cell activation syndrome exploratory cohort. How many patients do you think there are with that diagnosis in the U.S. currently?

Becker?

So I'll start with the question about 701 and 945. Just remembering how patients present and why they're treated with osimertinib in the first line. They don't have T790M at the beginning. They have the driver mutation in the anti T790M activity of osimertinib is important to prevent emergence of that driver. Osimertinib also has a very high potency over that driver -- dose driver mutations. So the combination of BLU-701 and BLU-945, do those things plus additional activity.

So 701 has better penetration of the central nervous system than any compound available or in development that we're aware of. And so treating patients initially with the driver mutation, both in the periphery and in the central nervous system will serve to treat small -- well, existing central nervous system disease and any non-measurable central nervous system disease, but also prevent the disease from going to the central nervous system, which is often less well penetrated than the blood is. So we get amazing coverage throughout the body with BLU-701.

In that context, BLU-945 would be present to prevent the emergence of T790M. So here, we've got an all-oral regimen that would treat the entire body and treat all of the resistant mutations that we know of that can emerge. And so what we'd expect there is an enhanced treatment of patients with CNS disease as well as longer progression-free survival.

With respect to a frontline study, clearly, we will look at a number of different patient populations during our first 2 studies and determine the activity there. And then look to develop it in the front line in parallel with the other studies that we're doing to develop in resistant mutations.

The next question comes from the line of Peter Lawson with Barclays.

Just I guess a follow-up around the EGFR data. Just when could we see the initial clinical data in EGFR mutant patients? And then as we kind of think about ways to kind of break into that osimertinib market, are there areas that you think are kind of low-lying fruit essentially? Or is it -- you need to be in combination with additional agents, whether it's METs or ALKs, et cetera?

Sure. Maybe I'll take the first part of that, and then Becker can talk about the development plan. So in terms of when we see data, as Becker just laid out, our design with these trials is similar to what we've done with both AYVAKIT and GAVRETO of starting up getting -- finding the optimal dose and then expanding through various exploratory arms to best understand the potential activity of a molecule, both as a single agent and/or in combination. And so we want to get those trials up and running before we guide to when we'd be sharing data. But I think a safe assumption would be similar to the time frame of how and when we share data from AYVAKIT or GAVRETO.

And then with respect to showing activity and breaking into, as you described the osimertinib market, the way I like to think about this is in 3 different buckets. The first is patients who have been through a first-generation inhibitor like Iressa or Tarceva and then moved on to osimertinib, and we'll develop either an on-target mutation, which often will be the C797S mutation in combination with the driver in T790M or those triple mutant patients. And then patients who have the driver mutation and we'll develop another mechanism of resistance like MET amplification.

So in both cases, you still need to inhibit EGFR. And so BLU-945 is -- will look for activity as a single agent in those patients that are -- have their disease driven by a subsequent mutation of EGFR and then eventually, in our program, we may need to, as you mentioned, look at other types of combinations with other tyrosine kinase inhibitors or other modalities to address the additional mechanisms of resistance in that really third line patient population.

The other bucket, I think, that is patients failing or patients whose disease is progressing following osimertinib. A in that case, BLU-701 is the molecule that we expect to show activity very early in that resistant population.

Again, there may be a rationale to combine with other agents, including osimertinib, to continue to keep the pressure on all of the mutation and then to prevent subsequent emergence of point mutations.

And then with respect to breaking into the larger part of the osimertinib treatment landscape, really looking at either our own proprietary combinations or adding on our drugs to an existing treatment with an EGFR inhibitor to allow longer progression-free survival. And really kind of mirror the way that osimertinib marched from (inaudible) lines into the frontline of EGFR mutant lung cancer.

Your next question comes from the line of Brad Canino with Crédit Suisse.

Just some clarity on the comments you made about BLU-945 in Phase I. You mentioned that the dose expansion will be in patients with specific mutations. And I assume that will include T790M and C797S. But are you planning to enroll any other mutations? And if so, could you outline the reason why you're doing that?

So with respect to other mutations, if you're asking about other EGFR mutations. We are currently preclinically profiling the -- both of the compounds further to identify the full spectrum of mutations against which they are active. And during escalation, we have the ability to expand while we're escalating. And so we expect to get early information about where the compound is active, so that we can tailor our expansion cohorts to fit these mutation profiles.

With respect to other mutations like MET amplification, that would be a later part of the Phase I where we would need to determine the optimal compounds to combine with. And then we could look at a combination of EGFR inhibition plus another modality of inhibiting the resistant pathway.

And there are no further questions at this time. I will now turn the call back over to Jeff Albers for closing marks.

Thank you, operator. So I'll wrap up with where we started. Given the strong position we find ourselves in at this quarterly call. Around our strategic imperatives. We spent less time talking about our early research pipeline today, but under leadership of Fouad Namouni, our President of R&D, we continue to identify new opportunities and new targets to focus on -- to further expand our portfolio. Becker walked us through the next wave of therapeutic candidates really anchored around these 5 recent development candidates that show exceptional promise. And then as Christy walked through the acceleration of our commercial efforts with AYVAKIT and GAVRETO and really our focus on ensuring that we're prepared to bring AYVAKIT to patients in advanced systemic mastocytosis potentially this quarter with the targeted PDUFA date in mid-June.

And all of that's really underscored by the strong financial position that we're in. And Mike walked us through financial is really focusing on the GAAP financials.

The way I look at it is probably a bit more broadly is I tend to anchor in on end-user sales and thinking about how we bring these medicines to patients, both directly in sales that we book as well as through our various collaborations, in the case of Genentech with a profit share, but then with Genentech, Ipsen and CStone, you also see royalty potential as well as milestones. And when we take all of that together, the growth potential, as Mike highlighted, going into the second half of the year, it's becoming increasingly clear to us and should position us to further expand our portfolio over time.

And so with that, we know we have a lot of work to do. It's nice. We're actually doing this call from a room together in our office for the first time in over a year.

And so we continue to be optimistic about, certainly in the U.S., the ability for business to accelerate as we come out to the backside of this pandemic. And so we look forward to continuing to update all of you and calls again in the near future. With that, thank you for taking the time today. Bye-bye.

Ladies and gentlemen, this concludes today's conference call. We thank you for your participation, and you may now disconnect.