Good morning. My name is Maxine, and I will be your conference operator today. At this time, I would like to welcome everyone to the Blueprint Medicines’ 3Q 2021 Financial Results Conference Call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer session. . Thank you.

Kristin Hodous of Blueprint Medicines, you may begin your conference..

Thank you, operator. Good morning everyone, and welcome to Blueprint Medicines’ Third 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' Third Quarter 2021 business highlights.

Christy Rossi, our Chief Commercial Officer, will provide a commercial update. Fouad Namouni, President of Research and Development, will review our recent clinical progress, and highlight upcoming milestones across our growing pipeline. And Mike Landsittel, our Chief Financial Officer, will review our third quarter 2021 financial results.

Becker Hewes, our Chief Medical Officer, is also on the call and will be available for Q&A. Before we get started, I would like to remind everyone that statements we make on this conference call, will include forward-looking statements.

Actual events or results could differ materially from those expressed or implied by any forward-looking statements, as a result of various risks, uncertainties, and other factors, including those set forth in the Risk Factors section of our 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, and thanks for joining us today. In the third quarter, we made tremendous progress toward bringing our life-changing precision therapies to patients around the world. Today on our call, you'll hear about three areas of fundamental growth.

The first is solid commercial performance anchored by AYVAKIT’s advanced systemic mastocytosis launch in the US. We're seeing broad demand from prescribers at both academic and community centers, and across patients with different advanced SM subtypes.

This momentum provides a foundation for continued leadership and growth for our SM franchise, as we look to deliver topline data from our pivotal Pioneer study of AYVAKIT in non-advanced systemic mastocytosis in mid-2022, and accelerate development of BLU-263, our next generation KIT inhibitor.

The second area of growth is based around the continued execution and expansion of our R&D vision, with a robust pipeline of innovative precision therapies advancing at all stages of development. As Fouad will describe, our next wave of clinical programs is progressing rapidly towards multiple proof of concept readouts.

We've been encouraged by widespread interest in our SYMPHONY trial of BLU-945, and we're on track to initiate a Phase 1 trial for BLU-701 in the fourth quarter. Beyond our EGFR franchise, we continue to expect BLU-222, our CDK2 inhibitor, and BLU-852, our MAP4K1 inhibitor, to advance into clinical development next year.

And a third area of strength is our current financial position, which as Mike will describe in more detail, enables us to drive revenue growth across multiple domains, invest in a range of high value R&D programs, and continue to build a world class company with integrated global capabilities.

For some time, we've talked about the promise of diverse revenue streams across the strategic pillars of our business. This diversity is now truly coming into view, as we're able to increase our full year revenue guidance based on activity throughout our portfolio, both independently-driven, and through our strategic collaborations.

Combining our prolific scientific platform and commercial execution, with the financial and organizational strength to bring in external assets, we're well positioned for Blueprint to be the leading driver of innovation in precision medicine for years to come. With that, I'll turn the call over to Christy to discuss our commercial efforts.

Christy?.

Thanks Jeff. Good morning, everyone. Let me start by sharing our third quarter results. Our AYVAKIT net product revenue was $17.3 million. Net and user sales of GAVRETO, as reported by Roche, were $5.5 million for the quarter. As a reminder, the booking of GAVRETO sales shifted to Roche at the beginning of the quarter.

Q3 was our first full quarter of the AYVAKIT US launch in advanced systemic mastocytosis, and the positive early trends we have been seeing, reinforce our view that SM across advanced and non-advanced forms of the disease, is the most significant near term opportunity that we are pursuing at Blueprint Medicines.

As I reflect on the launch dynamics to date, a key theme that gives me confidence is breadth, breadth of prescribers, accounts, and patient types. Let's start with the breadth of prescriber and account activity.

As I've shared previously, a key focus area for Blueprint, has been engaging with SM centers of excellence and key accounts where patients are more concentrated. Over the first few months of the launch, our efforts to engage these centers have gained good traction, with approximately two thirds now utilizing AYVAKIT commercially.

As we continue to focus here, we also know that many patients are cared for in a community setting, and that prescriber education and patient identification there, will be critical to the long term trajectory of the launch. With that in mind, I'm very encouraged that approximately half of our volume is coming from community prescribers and accounts.

Overall, through the end of Q3, we have had more than 100 new prescribers or accounts utilizing AYVAKIT for the first time since our approval in advanced SM. This prescriber breadth will catalyze our ongoing efforts to identify more advanced SM patients, and ensure they have access to AYVAKIT therapy.

We are also seeing breadth of AYVAKIT utilization by patients across their advanced SM treatment journey. We continue to see a fairly even mix of patients switching from other therapies, and those who have no indication of a prior advanced SM therapy.

We will gain additional insight into these patient dynamics as we move through the launch, but this early data suggests that AYVAKIT is being used among the prevalent pool of diagnosed advanced SM patients, as well as in newly diagnosed incident patients.

Finally, we are pleased that the demand we are seeing, has been supported by strong patient access to therapy, and a rapid time to fill prescriptions.

In total, this combination of increasing prescriber and account breadths, new patient starts, and the long durations of therapy we expect based on our clinical trial experience, form a foundation for longer term revenue growth.

As we continue to execute on our launch in advanced SM, we are also focused on building our leadership position in SM more broadly. A key priority is increasing disease education and patient identification so that more patients who are suffering from SM, can be diagnosed and offered appropriate treatment.

I'm very excited about progress we've made in the third quarter to increase access to testing, which is critical to achieve this goal. We've initiated a partnership with LabCorp to make highly sensitive blood-based KIT D816V testing available for patients across the United States.

Testing is now widely available and accessible through our sponsor testing program to qualifying patients where an SM diagnosis is suspected. We anticipate that the widespread availability of testing, will help to improve the rate of diagnosis in the US, and facilitate improved access to care for patients.

Overall, we've taken important steps this quarter towards realizing the potential we see to transform care for SM patients globally.

I'm excited about the road ahead as we continue to execute on the US launch and look to plan global launches in advanced SM, the readout of PIONEER next year, and the opportunity for AYVAKIT in non-advanced SM, and of course, our ongoing development of BLU-263. Let me now turn to GAVRETO.

As we've mentioned, a key strategic rationale for our collaboration with Roche and Genentech, was that it enhanced our ability to reach more patients globally. We're excited to begin to see this come to fruition.

In the US, we continue to focus our efforts on expanding the red inhibitor market through increasing comprehensive and actionable biomarker testing rates at diagnosis.

We were pleased with the continued growth we saw during Q3, bolstered by strong momentum coming out of ASCO, where we shared updated data on treatment-naïve patient from the ARROW study. During the third quarter, we also received a positive CHMP opinion for GAVRETO in a line agnostic non-small cell lung cancer setting.

An approval in this indication would be a competitive advantage in the EU territory for GAVRETO. This, combined with the multiple planned regulatory applications that Roche is pursuing in additional geographies, and the ongoing strong launch of GAVRETO in China by our partners at CStone, provides a clear roadmap for global revenue growth.

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

Thanks, Christy, and good morning, everyone. Earlier this year, I shared the broad R&D vision to position Blueprint Medicines as the world's leading precision therapy company.

This included three areas of focus, therapeutic area leadership in precision oncology and hematology, with a near term focus on systemic mastocytosis and lung cancer, innovative drug development, including the creative use of trial designs, translational data, and regulatory strategies, to bring our therapies to patients faster, and continue with scientific leadership through the productivity and the expansion of our research platform.

I'm excited to update you today on the very good progress that our R&D team has made towards realizing the vision across our portfolio. First, we continue to expand our leadership in systemic mastocytosis through robust execution of our KIT programs.

For AYVAKIT, our registration directed PIONEER study in non-advanced SM, is on track to deliver topline results in the middle of next year. For BLU-263, our next generation KIT inhibitor, the Phase 2, 3 HARBOR study, also in non-advanced systemic mastocytosis, is now underway.

In the third quarter, we began patient screening in the Phase 2 portion of the study, carrying forward momentum as we wind down PIONEER enrollment. As a reminder, HARBOR is enrolling a broad population of patients with non-advanced SM, including patients with milder forms of the disease.

Combined with the encouraging commercial launch of AYVAKIT in advanced SM, these studies position us to dramatically improve the standard of care across all forms of systemic mastocytosis. Second, we have significantly advanced our clinical program in EGFR positive lung cancer.

For BLU-945, patients enrollment in the SYMPHONY trial is accelerating, with significant and growing demand at multiple clinical sites. As the dose escalation phase of the study is moving rapidly, we are now planning combination expansion with third generation EGFR inhibitors, such as osimertinib next year.

This approach will accelerate and extend our development effort across multiple patient populations. We are also happy to report that we expanded the trials of global scope, with now a clinical trial agreement in place for Japan. This represents an important milestone towards building a robust trial footprint for our EGFR therapies in Asia.

For BLU-701, we have submitted an I&D application to the FDA, and we are on track to initiate a Phase 1, 2 study in the fourth quarter. Similar to the SYMPHONY study, we plan to explore combination development early in this study, including with BLU-945. Furthermore, pre-clinical data continued to support our clinical development strategy.

We have recently completed studies generating compelling data on the potential of a BLU-945 and BLU-701 combination, which we are submitting for presentation at a scientific meeting in early 2022. Finally, our early stage research pipeline continues to flourish.

In recent months, we have rapidly progressed BLU-222, our selective CDK2 inhibitor through I&D enabling work, and we now anticipate it will enter the clinic in the first quarter of 2022, earlier than previously expected. More broadly, we have also nominated multiple undisclosed research programs this year.

These include a number of exciting targets, with the potential to further extend our scientific leadership in precision oncology and hematology. As these programs progress through discovery research, we look forward to sharing more information on another wave of therapeutic candidates.

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

Thanks, Fouad. Earlier this morning, we reported detailed third quarter financial results in our press release. For today's call, I'll touch on a few highlights from the quarter. But first, as we head into the fourth quarter, Blueprint continues to build on our strong foundation - strong financial foundation through a range of revenue sources.

In addition to our growing base of global revenues from AYVAKIT and GAVRETO sales, progress across our multiple strategic collaborations is expected to meaningfully contribute to our fourth quarter revenues.

Based on increased anticipated milestone and other collaboration payments, including the acceleration of potential milestone achievements into the fourth quarter, we are raising our annual revenue guidance for 2021 to between $170 million and $180 million.

In the third quarter, total revenues were $24.2 million, including $17.3 million of net product revenues from sales of AYVAKIT, and $6.9 million in collaboration revenue.

Collaboration revenue for the quarter was primarily driven by commercial supply shipments to our partners, CStone and Roche, as well as royalty revenue for sales of GAVRETO and AYVAKIT by CStone in China. As a reminder, US GAVRETO sales are now being booked by Roche, with our share of profit or loss appearing on our income statement.

Our total operating expenses in the third quarter increased slightly compared to the second quarter of 2021, driven by continued growth in R&D expenses, as we bring multiple programs into clinical development.

Over the next few quarters, we anticipate that investment in our promising early stage programs, as well as our commercial efforts with the ongoing launch of AYVAKIT in advanced SM, will continue quarter-over-quarter operating expense growth.

Finally, we ended the third quarter with nearly $1.3 billion in cash on hand, ensuring we have sufficient resources to invest in our pipeline.

Overall, this combination of growing product revenues and progress through our collaborations, fortifies our exceptionally strong financial position, allowing us to focus on execution across our portfolio as we enter another transformative period of growth for the company. I would now like to turn the call over to the operator for questions operator.

Our first question that comes from Salveen Richter from Goldman Sachs. Your line is now open..

Hi, everyone. Thanks for taking the question. This is Andrea on for Salveen. Congratulations on the quarter. Christy, maybe a question for you. Just wondering if you could speak a bit more on your partnership with LabCorp and how you expect this to expand the potential addressable population.

And then very quickly, if you're seeing any utilization in non-advanced patients at these centers of excellence. .

Sure. So, we're quite excited about the partnership with LabCorp. Throughout this year, building capability and making highly sensitive blood-based KIT D816V testing available in the US, has been a key strategic focus of ours.

And as I've discussed before, we believe blood-based testing will greatly facilitate access to diagnosis for patients, particularly for non-advanced SM patients where that diagnosis may be suspected. And so, the partnership with LabCorp, LabCorp has this testing available commercially.

So, that, in and of itself, will be very helpful for prescribers who use LabCorp nationally. We will have a - we have a sponsored testing program that is available where if a patient is suspected of having an SM diagnosis, they can receive access to testing through Blueprint.

And so, we believe that this will reduce the potential barriers and hurdles for patients to access testing, and also ensure that if a provider suspects SM, they utilize the appropriate type of testing so that the results that they get can be trusted. And so, we're really excited about this as a step forward.

In terms of utilization of AYVAKIT, our best understanding continues to be that patients who are being prescribed right now, are advanced SM patients, by and large. We, of course, don't have perfect visibility into every patient.

And as I said before, the diagnosis and subtyping in SM is complex, to say the least, but certainly that's our understanding based on the intelligence we have from speaking to healthcare providers. .

Great. Thanks so much..

Our next question comes from Reni Benjamin from JMP Securities. Your line is now open..

Hey, thanks guys for taking the questions, and congratulations on a great quarter.

Can you just give us a breakdown of maybe GIST versus SM in terms of the KIT revenues? And can you just also give us an update on the TAPESTRY study and if PIONEER enrollment is completed? Because I think to meet this deadline, at least by our calculations and the follow-up that's required, I would think enrollment had to have completed in the third quarter, but I'm not too sure.

I might have a calculation off here. Thanks very much. .

Yes.

So, Christy, why don't you take the first half, and Becker, take the second half?.

So, in terms of revenue, we obviously do not provide a formal breakdown in terms of indication split, but as you've seen, if you kind of look historically and as we've discussed, GIST has been, I would say, relatively consistent revenue stream for Blueprint at this point.

And so, when we look at quarter-on-quarter growth, it's really coming from advanced SM primarily, as well as a little bit of international as well, but advanced SM is really the key driver, if you look on quarter-on-quarter growth,.

And then with respect to the two trials, you mentioned TAPESTRY, again, we're transitioning to Roche, and there continues to be enthusiastic interest in getting multiple tumor types into this study.

With respect to PIONEER, we have - as I mentioned on the last call, the processes to screen patients and make sure that the patients with the right PFS score severity of disease are enrolled in the study, we've actually stopped the pre-screening.

And so, we filled our screening group of patients, and we're converting those into patients enrolled in the study, and we are looking forward to revealing topline data in the middle of next year..

Got it. Thanks for taking the question..

I just want to also - I'll also mention that we're taking that momentum and we're shifting it over to BLU-263. The HARBOR trial has an even more extensive site list. We discovered a lot more interest and really enthusiastic about this next generation KIT inhibitor moving into the treatment. .

Great. Thank you..

Our next question comes from Dane Leone from Raymond James. Please proceed with your question..

Hi. Thank you for taking the questions. I'll keep it to two for me. Firstly, could you comment at all in terms of the progress with the BLU-945 Phase 1 enrollment in treatment? Anecdotal evidence that I think most us have seen at this point, does suggest you're getting a mix of patients that do and do not have a T790M mutation.

So, be curious about your thoughts around the complexion of the patients getting treated in that dose ascending study, and kind of the implications for evaluation of the therapeutic index and what's going to be effective for those patients with T790M.

And then secondly for me, could you just maybe comment a little bit more in terms of the treatment center utilization around ASM now.

for those treatment centers open, where do you think the percentage of docs and patients being treated now that would qualify for avapritinib, are getting the drug and just some of the hurdles that your team's trying to get over now to increase that utilization rate heading into 2022. Thank you. .

All right. So, Fouad, why don't you take the 945 study question, and Becker can add color as necessary. .

Thank you, Dane. For 945 in the SYMPHONY trial, we are very happy with the way it is progressing in the dose escalation phase. And we have - four months in the Phase 1, we have seen really a good momentum.

We are also very happy that our use by the investigator of tumor and CT DNA, is able really to pick on a variety of mutation, TM mutation, CS mutation, double mutation, and triple mutation, all this information.

And with the profile of 945, would allow us in the next months to have a much better understanding of the safety profile, and also be able to see detection of clinical signals. We will be sharing data next year on the first part of 945. .

All right.

And Christy, don't you take the breakdown of where we're seeing activity in ASM?.

Yes. So, I think your question sort of speaks to, I think, what the opportunity is going forward in terms of additional opportunity at centers, as well as beyond that.

So, as I said, we're pleased to see that we've had engagement and utilization by two thirds of sort of the accounts that we consider to be key accounts in centers of excellence, which is great. But I'm also very happy that we've got a significant amount of utilization coming outside of those accounts in the community.

I think there is additional opportunity within key accounts. I think what's interesting about SM is that it is still an immature market in many ways.

And so, unlike other diseases where you may have one specialist at a center that tends to have every patient funneled to that person, what we see in advanced SM is that these patients at a center, may be maybe seen by multiple providers.

And so, one trend that I've been watching and interested to see is that we're starting to see more than one prescriber at a given account utilizing AYVAKIT. And that deepening within accounts is something that we're going to continue to focus on as we go forward.

But long term, I think the key driver for us of additional patient identification and growth will be also really getting out into the community where we have that tale of patients that are presenting, and again, really happy with what we're seeing.

Certainly looking forward to having additional catalysts going forward as our data gets out and we continue to educate and identify more patients there..

Thank you..

And the next question comes from Marc Frahm from Cowen. Your line is now open..

Hi. Thanks for taking my questions and congrats on the quarter.

Hey, Christy, just to follow up on the last points about physician use and who they are, when you are seeing use in the community, is that still just with community-based oncologists, or are you seeing some use in other places like allergist office and things like that that may have broader populations than just ASM within their practice? And then for the - and then also to follow up on Dane's question on the different types of patients enrolling in 945, would you expect to ultimately have expansion cohorts that are broader than just C797S or some of these other resistance mutations, or is C797S really the main focus?.

Sure. So, I can start with your first question. So, in terms of the mix of prescriber types that we're seeing, the vast majority of utilization right now is coming from hematology, whether that's at a center of excellence or in the community. We have seen some utilization by allergy.

I think what's important to keep in mind is that allergists play a role in the management of advanced SM patients, and certainly are a critical point in the pathway to diagnosis for many of these patients, and will often be involved in co-managing patients with hematologists.

And so, we've seen some utilization coming from allergy, but again, the vast majority coming from hematology at this point..

And for your second question, Marc, for 945, 945 is our triple mutant agent covers the drivers with also T790M and C797S. The way the SYMPHONY Phase 1 trial was designed is to expand in all subgroups of mutations. So, we'll be expanding in triple mutation. We’ll be expanding also in CS double mutation and in TM double mutation.

So, we'll have really a very good understanding across a broad spectrum of these combinations of mutations. .

I just wanted to add one thing. Marc, the 945 compound is optimized to hit the triple mutation, but it is a compound with a really large winded wild-type. So, we expect extraordinary safety. That really plays into our plan to combine these molecules and move to earlier lines of therapy.

And we're really open to all levels of activity for this compound, just given how safe we expect it to be..

Okay. Thanks. Very helpful..

Our next question comes from Andrew Berens from SVB Leerink. Your line is now open..

Thanks. Let me also add my congratulations on the great execution this quarter. Just a few for me. I'm trying to get a sense for how excited we should be about these results being sustainable.

Were there a meaningful percentage of patients using AYVAKIT this quarter from the expanded access program? Do you guys have any color on how many lines of therapy they had seen previously on the average or how long ago the patients had been diagnosed? And then a question on GAVRETO for Christy.

I didn't hear you give a percentage of new patient starts like in prior quarters, and just wanted to see if I had missed that. And again, wondering why the 40% you saw in Q2 and the 25% in Q1, doesn't seem to be translating to revenues.

Is it really just that the rep market is not that large?.

So, I think all those are for me. So, happy to start with the SM color. So, in terms of patient dynamics in the quarter, we did have some patients who were on access programs prior. It's the minority certainly of the patients that we saw coming onto AYVAKIT through the quarter.

I think your patient - your question sort of speaks a little bit to, is this a bolus? And I think what we've seen certainly is that there were patients who were frankly waiting for AYVAKIT approval. There was a lot of excitement from the centers that know AYVAKIT well, and have experience waiting for the drug to become available commercially.

So, certainly, we're pleased that we were able to pull those patients on and offer them treatment upon approval. What we now see and what I think will be sort of offsetting that and continuing to drive growth, is the rate of new prescribers and accounts that continue to come on board.

And so, I'm really excited about just the breadth, again, of prescribing. I see that as a critical indicator of long-term growth potential, and pleased to see that we've continued to really add new prescribers and accounts at a very steady clip as we've moved through the quarter.

In terms of lines of therapy, as I said, our best data right now suggests that we're seeing a pretty even split in terms of patients who've been on a prior therapy versus those who say that they do not have indication of a prior therapy. Our visibility into that right now is limited.

And as we start to see our own patients through claims data, we'll have a better sense, frankly, of exactly what we think that mix looks like. And so, I would say that we'll gain insight to that as we continue to move through the launch.

In terms of GAVRETO, the question about sort of how do we think about new starts and then kind of moving through to revenue? So, with the transition to Genentech, our level of sort of individual patient visibility is simply different. They have a different distribution model than we do.

And so, really, we're looking at prescriber level demand now as kind of the best indicator of growth, and had our strongest quarter this - to date essentially in Q3. And so, we're excited about that and that it speaks to, I think, the ongoing growth of the market, which we're seeing across both Blueprint and Lilly.

It will take time, as I've said before, between new products, new patient starts or transitioning into revenue. New share is a leading indicator of total share, which then will translate into revenue over time. And of course, our quarter-on-quarter revenue growth continues to be really strong..

Okay. Thank you..

Our next question comes from Avatar Jones from Morgan Stanley. Your line is now open..

Thank you for taking my questions. Many have been answered, but I have one question on AYVAKIT. Do you have any visibility into the average duration of therapy to date? And moving forward, how would you suspect this will evolve? Thank you..

Sure. So, duration of therapy is one of the aspects of the AYVAKIT opportunity in advanced SM that I think is most exciting, and certainly will be a critical driver of growth, particularly as we get further into the launch and can see patients sort of accumulating, because they can stay on therapy.

I also think it's exciting because we have the potential, I think, to really impact how long patients are living well with advanced SM, which I think is a really exciting clinical opportunity.

At this point in the launch, it is just - it's too early to really have any meaningful insight into duration of therapy, right? We’re a couple of - a few months onto the market at this point. Certainly, our clinical data suggests that patients may be on for years.

And so, I think we'll have better insight as we go through over the next year to two to really understand what we’re seeing in terms of what that looks like..

Okay. Thank you..

Our next question comes from Arlinda Lee from Canaccord. Your line is now open. Please proceed with your question..

Hi guys. Congratulations on the quarter and the launch. I had maybe an additional follow up on additional color that you might be able to provide on the breakdown of newly diagnosed patients versus those that were already known.

And if you can maybe talk a little bit about the turnaround time for the LabCorp tests and what kinds of - you said that it would be available to patients that were eligible. Could you provide additional information on who might be available? Thanks. .

Sure. So, again, in terms of the splits of patients that we're seeing, right now, we're really relying on the feedback we hear from patients and prescribers directly, which is how we understand that mix of about half saying they do not have prior therapy versus half saying coming from a variety of other therapies that are being used.

No indication of prior therapy does not necessarily mean that they’re newly diagnosed. And so, we will continue to gain insight to that as I said, as we start to kind of see claims data and other sources that will help inform our understanding.

Our expectation, certainly, is that as we move through the launch, we will shift from being utilized primarily in prevalent patients who are already diagnosed, to newly diagnosed incident patients. And so, that's a dynamic I would anticipate we will be, but again, it's just too early to really know what we're seeing.

In terms of the LabCorp test, the turnaround time is fairly quick. I believe it's something on the order of less than a week. And the eligibility criteria, essentially we ask physicians to fill out a form where they have to specify one or two of a couple of different symptoms that are often hallmarks of a potential SM diagnosis.

So, essentially what we're looking for is suspicion, clinical suspicion of SM in order to be eligible for the test. .

Great. Thank you, and congratulations again..

The next question comes from Michael Schmidt from Guggenheim. Your line is now open. Please go ahead..

Hi. This is Paul on for Michael. Thanks for taking our question. Just one from us on the CDK2 program. Can you provide your thoughts on how to potentially compare it with other CDK2 approaches in development, for instance like are included in triple inhibition of DDA 2.6 that are being explored. Just hoping to see your early read there on the landscape.

Thanks..

So, Fouad, why don’t you start maybe Becker can add color if needed?.

Thank you. Our CDK2 inhibitor that is entering the clinic early next year, as I mentioned earlier, is a selective one. It has been developed as a validated target, a regulatory partner of CCNE1, with particular selectivity over CDK1, CDK4, CDK6, and others.

This allows our CDK2 inhibitor to be selective, leading to efficacy and potentially in very favorable safety profile. When you look at the entire landscape, one of the challenges the landscape faces in developing CDK2 inhibitor is selectivity over CDK1, but also over CDK6.

So, we do believe that our CDK2, with its very selective profile, is also a very good partner for combination with CDK4/6. We believe the strategy of developing a selective sole CDK2 inhibitor is a good strategy that gives us the ability to combine different doses with CDK4/6.

Our development strategy targets two major areas, CCNE driven cancers, where we believe that tumor addicted to the pathway, ovarian cancer, endometrial cancer, so CDK2 will be developed in combination with standard of care and the diseases.

The other part of the development of CDK2 will focus on the emerging issue of resistance to CDK4/6 in breast cancer. We know today that CCNE1 over-expression is behind the resistance to CDK4/6 in breast cancer.

So, we'll be looking to really contribute to reverse this resistance, not only in the late stage by combining CDK4/6 in breast cancer, but also in the early stage..

Great. Thank you..

Our next question comes in Joel Beatty from Baird. Your line is now open..

Hello. This is Benjamin Kallo on for Joel. Two questions for us, one on AYVAKIT, and then one on the pipeline.

As far as AYVAKIT, do you have a sense, I'm not sure if I missed it or not, but the number of repeat prescriptions? And then on the pipeline, I'm just curious if you could maybe put into context the relative risk of the different plan initiations for 701, 222 and 852. Do you see one as more highly risky or less risky than the others? Thank you..

Sure. This is Christy. I can take them. The first one on repeat prescriptions. So, again, we're early on in the launch. We’ve seen nothing that would be any different than what we would expect, which is in terms of we expect patients will be refilling.

Certainly, we do know that often, if patients are going to find their right dose, that is the dynamic that happens early on. And so, dose modifications, et cetera, tend to be occurring in the first few months. Our strategy around flat pricing, et cetera, really mitigates a lot of the impact that we would expect to see from that.

But that's a trend we'll continue to watch, but so far, we’re seeing everything essentially in line with what we would expect..

Sure.

Then in terms of the relative risk, maybe Fouad, I'll have you start, but yes, I think it's a question we look at all of our programs in terms of going after known oncogenic drivers of disease where there should be a higher probability of success in cases where we can get to clinical proof of concept as quickly as possible, remains a hallmark of our portfolio selection priority or our process.

We do always take into account as well, though, the size of the opportunity, the relative opportunity.

So, right before you enter the clinic, it's almost an impossible exercise, but Fouad, why don’t you take a stab?.

The only thing I would add, Jeff, to our answer is, Blueprint as a leading precision medicine company, has really one of the strongest expertise in rationally designing molecules that are selective against targets that we would like to use as treatment. To Jeff's point, these targets are well-validated and are important for the treatment of cancer.

It's now taken Blueprint to a next level of targets with a broader scope of the opportunity, whether you think about it from EGFR mutated lung cancer, or breast cancer resistance to CDK4, as an example, for CDK2. Obviously, these studies are either in Phase 1 or entering the Phase 1 clinical trials in the next weeks or months.

So, we would have more information to determine really the profile of these agents.

But I think with responder hypothesis as a part of the development, with selectivity, with windows of data or with therapeutic indexes in the development of this compound, I'm confident that we will run these compounds very efficiently, and the data will tell us what we - when we see it from the Phase 1..

Yes. And maybe I'll circle back. It's interesting.

Kate Haviland, our Chief Operating Officer, often talks about the idea that, how do we get better with subsequent programs over our first wave of programs? And it has always been a cornerstone of our strategy to develop molecules that can be combined with other effective therapies, if we really want to change course of disease.

And so, as Becker noted earlier on 945, that was part of the target product profile, that to reach the full potential was to focus on the window of a wild-type so that you could see various combinations expanding the opportunity over time.

Similarly, I'd say that's true for BLU-222, our CDK2 program, that we will certainly be looking for single agent activity, but the true opportunity comes in how you combine over time. And so, that selectivity that Fouad talked about with respect to BLU-222, is really critical to what we hope to see as we move into the clinic..

Got it. Thank you so much for those insights..

The next question comes from Peter Lawson from Barclays. Your line is now open..

Great. Thanks. Thanks so much for taking the question.

Just kind of thinking about the GIST and the ASM revenues underlying this, is there any way - is there any point where you'd break out those revenues and or would you kind of break out when GIST or rather ASM kind of exceeds the GIST revenues? Just your thoughts there, and if that happened this quarter.

And then A second question for Mike, just sort of breakout of the guidance. How much is that milestone driven? Should we think about a milestone number as a $75 million or a $50 million number? Thank you..

Okay. So, maybe I'll start. We don't have perfect visibility into every patient. So, the effort of trying to break out exactly where each of them sits, will probably be difficult. So, I don't think it'll be a focus. I mean, based on the data we see, as Christy has already highlighted, the growth is clearly coming from ASM.

But exactly where that line is, I don't think we have that degree of detail. And then maybe, Mike, you ….

Yes. So, just a little bit more color on the revenue guidance. I think maybe backtracking a little bit, like early in the year, we guided to the fact that we might have $80 million in potential milestone payments.

What we've seen - we've recognized a little bit of that today, but what we've seen is primarily a lot of potential milestones are now concentrating in Q4. And that also includes the acceleration of potential milestones that were originally, I’d say, forecast for 2022.

So, as those come together and come to fruition in Q4, the bulk of the revenue guidance raise that we're seeing is driven by milestone revenue that we anticipated, as well as other collaboration payments, supply payments, and royalty payments. .

Yes. And maybe I'll add to that. I mean, that's - I think that's a over and underappreciated aspect of our current position, is that we've always focused on retaining meaningful commercial rights and bringing therapies to patients on our own. But we also have looked at collaboration as an opportunity to either accelerate or expand our reach.

And the breadth of collaborations we now have in place is truly differentiating our revenue streams, and what is in exactly quarter-over-quarter, maybe a little bit lumpier than revenue growth, with end user revenue growth. But we're seeing a mix of milestone payments, royalties, and other payments from partners.

That is going to continue on as we go forward. So, I would say in my seat, I don't really care where the revenue comes from. It’s meaningful and it allows us to continue to invest in our research platform, which is the way we're going to drive long-term shareholder value. .

Thanks for that. Just to follow up on Christy’s comments about ASM.

Are the majority of patients going to come from the heme or the allergy side for ASM eventually?.

Yes. Advanced SM certainly will be majority of hematologists. That’s the specialty that tends to primarily manage. As I said, allergy certainly can be involved. Sometimes they're involved in co-management, but we expect hematology to continue to be the primary driver for advanced SM..

Brilliant. Okay. Thanks so much..

Our next question comes from David Nierengarten from Wedbush. Your line is now open..

Hey, thanks for taking a question. I'll skip any commercial questions that often beaten to death. On the pipeline for 701 and 945, maybe if you could help us out with the ultimate goal.

Is it to have a combination therapy with 701 and 945 in that setting and say second line mutated - EGFR mutated lung cancer? And then if that's the ultimate goal, what do we need to see from these single agent studies to accelerate your entry into the clinic with a combo? Thanks..

Thank you, David. 945 and 701, our fourth EGFR - a fourth generation EGFR agent, have been developed with combination in mind, and have been designed with combination in mind. So, very quickly, 945, as Becker mentioned earlier, has one of the widest selectivity profiles over wild-type EGFR.

And that allows this compound, not only to be developed as a same agent, but also to be developed in combination with other agents. As I mentioned earlier, we'll be starting next year combination with third generation EGFRs and 945.

701 has been also developed as a single agent, highly potent on CS mutation, on driver mutation, more (indiscernible), highly brain penetrant, but also developed towards combinations with other agents. So, for the on-target combination strategy, we would like to see each agent developed as a single and in combination in the late stage.

But our ultimate goal is to move these two agents together to the frontline treatment of EGFR positive non-small cell lung cancer. And that's because of the profile of both agents, the potential synergy and combinability in terms of being able to displace and do better than standard of care.

We will also be looking, in addition to the combination of 701 when it's ready and 945, to combination with other agents. I talked about EGF, third-generation such as osimertinib, but we will also be looking at combination with off-target agents, just given the profile and the selectivity of these compounds.

Off-target agents can include a variety of things. It could be med inhibitor. It could be RAS. It could be chemotherapy and others. I do believe that these four generation agents developed together, could become transformational in the treatment of EGFR mutant non-small cell lung cancer..

Thanks. And maybe just a quick follow-up on the other potentially off-targets agents. Again, I guess, I'm curious how far you might look into those before, again, focusing on 945, 701, or is it going to be just a broader basket study and open to just interpreting the results as they come? Thanks..

Sure. So, this is Becker. I'll take that. With respect to combining with agents that have other mechanisms of action and address resistance or potential resistance for other targets such as MAT or RAS inhibitors, initially we need to get the tolerability and dosing information for our single agents, but I don't see it as a sequential development.

We tend to do these things in parallel. we're quickly adding combinations to our ongoing studies, and the - we'll let the pre-clinical data guide us to an extent, but emerging data on resistance and trying to get in front of resistance, is really where we're going with this program in a broad fashion.

Got it. Thanks..

Our final question for today comes from Brad Canino from Stifel. Your line is now open..

Great. Thanks for fitting me in, and great launch and execution here. I mean, just one more for me on the EGFR trial. And again, specifically on that cohort, that T790M, but not C797s. it looks like per the protocol, they're going to go first gen to OSI to 945.

And like we talked about previously on the call, likely cancer there is driven by something other than T790M, like MAT.

So, are you expecting to see, and should we be looking for monotherapy 945 efficacy in this specific cohort because you've been talking about the higher therapeutic window and wild-type sparing, or is this really the focus safety on this cohort? Thanks..

This is Becker. I mean, obviously in Phase 1, safety is the initial focus and the main focus of this study. However, just a reminder, 945 will inhibit very strongly any protein that has the T790M mutation on it. We are trying to understand better the heterogeneity of this cancer.

There are patients where we believe that there - the EGFR mutations or the EGFR protein is still the primary driver. And the more we look, the more patients that seems to be the case. There are other patients where it's more heterogeneous and you have multiple populations of cells or even multiple drivers within a single cell.

And so, as we understand the biology, we'll have a better sense of where to expect single agent activity. So, that's an emerging story that we'll speak to later when we have more data. .

With that, I'll hand the call back to Mr. Albers for closing remarks..

Thank you, Operator, and thanks to all of you for taking time to join us today and for your continued support of Blueprint Medicines. And we look forward to updating you again soon, and hope you all stay well. Goodbye..

Ladies and gentlemen, this concludes today's call. Thank you for joining. You may now disconnect your lines..