Blueprint Medicines Corporation

Good morning, everyone. My name is Seb, and I will be your conference operator for today. At this time, I would like to welcome everyone to the Blueprint Medicine's second quarter 2021 financial results conference call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, please press star followed by two. please plan to limit yourself to one question at a time. Thank you. I will now hand the floor to Kristin Hodes of Blueprint Medicines. Please go ahead.

Thank you, operator. Good morning, everyone, and welcome to Blueprint Medicine's second 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 investor section of our website at www.blueprintmedicines.com. Today on our call, Jeff Albers, our Chief Executive Officer, will discuss Blueprint Medicine's second quarter 2021 business highlights. Christy Rossi, our Chief Commercial Officer, will provide a commercial update. Becker Hughes, Chief Medical Officer, will review our recent clinical progress. and Mike Lansdell, our Chief Financial Officer, will review our second 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 factor 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, Kristen, and good morning, everyone. Thanks for joining us today to review our second quarter performance. The progress made across our portfolio in the second quarter puts us in the strongest position we've ever been in as a company. In January, we laid out our strategic priorities for 2021, which were one, to accelerate the global adoption of Avakit and Gavaretto. Two, to advance the next wave of therapeutic candidates into the clinic. And three, to further expand our precision therapy research pipeline. Underlying these three pillars is a single ambition. to build the world's leading precision medicine company and make real the promise of precision therapy to improve the lives of people with cancer and hematologic disorders. In June, we received US FDA approval of Avakit for the treatment of advanced systemic mastocytosis, or FM. This was a significant achievement for Blueprint and the culmination of nearly a decade of hard work from our team in partnership with the medical and patient communities. Systemic massive cytosis is a classic example of a rare disease, with a clear genetic driver that has been historically difficult to target. With AvaKit's approval, we're ushering in a new era of care for these patients with advanced SM, offering them the first targeted therapy designed to potently and selectively inhibit DA16B mutant kit, the central driver of their disease. As Christy will review shortly, we're seeing very encouraging early momentum across all aspects of the launch as we work to drive patient identification and access to treatment. It's particularly rewarding to see the momentum and efficiencies being realized as we deliver Avakit and Gavaretto to patients globally, both independently and through our partnerships. In parallel to the launch of Avakit and Advance-SM, we're making important progress across our clinical stage portfolio, as Becker will discuss later in the call. We now have six programs progressing through registration-enabling trials or into proof-of-concept studies. Our two product candidates for non-advanced SM, two product candidates for treatment-resistant EGFR-driven non-small-cell lung cancer, blue 222, our CDK2 inhibitor, and Blue 852, a MAP4K1 inhibitor developed under our cancer immunotherapy collaboration with Roche. What's exciting is that each of these programs could bring important innovation and improved outcomes for a large number of patients with significant medical need. Underpinning the promising scientific, clinical, and commercial execution is a very strong financial position, as Mike will discuss. Through our product launches and a purposeful mix of collaborations, we've enabled a diversified revenue stream that will further strengthen Blueprint and allow for meaningful across our business and portfolio as we continue our efforts to deliver transformative benefit to patients. So with that, I'll turn the call over to Christy to provide an update on our commercial efforts. Christy?

CHRISTY PAMBIANCHI- Thank you, Jeff. Good morning, everyone. In the second quarter, we generated total net product revenue of $11.4 million, including $8.5 million in sales of Avakit and $2.9 million in sales of Gavretto. The second quarter marked a significant inflection point for Blueprint, and we are now beginning to realize the enormous potential we see to change the lives of patients living with SM. The approval of Avakit for Advanced SM came just a few weeks ago, and we are already off to a strong start executing against our three launch priorities, identifying patients, providing disease and product education, and ensuring best-in-class support. Immediately upon approval, we've seen a high level of engagement and interest from healthcare providers and patients. We received our first prescription request just hours after announcing the approval. And over the past few weeks, we have already seen utilization of Avakit by 40% of our 70 key target centers, which we believe treat about half of all SM patients in the United States. Importantly, we are seeing significant demand from community-based physicians including those who have no previous experience with Avakit in the clinical setting. We've also been encouraged by feedback we've heard from healthcare providers on the differentiated profile and robust clinical data package supporting the launch. We are hearing that Avakit will set a new standard in the treatment of advanced SM and healthcare providers are excited to have this option available for their patients. We were especially pleased to see Avakit added to the NCCN guidelines as a preferred agent for the treatment of advanced SM. Our early data suggests that Avakit is being used broadly across advanced SM patient types, including patients switching from other therapies, such as Midostorin, and patients with no indication of a prior advanced SM therapy. These are promising indicators of the current breadth of demand and the potential for market growth over time. As more patients are treated, we will gain more insight into these dynamics and the role that Avakit is playing in revolutionizing the treatment paradigm. We've also been encouraged by early indicators of strong patient access, as well as the support we are offering to patients with advanced SM. Payer approvals for our initial prescriptions have come fast, and initial payer policies appear to be in line with our label. Leveraging our expertise and existing infrastructure from previous launches, our goal remains to help every patient who is a prescribed advocate to start on therapy quickly and have continued access as long as it is clinically indicated. I'm thrilled to see our strong early execution in this area. While Advanced SM was a smaller part of our recognized revenue in QQ because of the timing of the approval, I expect it to be the primary driver of Avakit revenue growth going forward. We view SM as a potential blockbuster opportunity, and I look forward to continuing to update you on our progress as we advance the launch. In PDGF for AlphaGist, we anticipate more incremental growth with additional launches outside the US over time. Let me turn now to Gavretto. We continue to see good progress in growing our share of new patients who are starting on a selective red inhibitor. Since launch, our share of new patient starts has steadily increased and now exceeds 40%. Growing the red inhibitor market overall remains a key focus as well. We were encouraged to see an uptick in demand following ASCO this year, where we showcased updated data from the ARROW study that included an 88% overall response rate in the treatment-naive setting. Continued multidisciplinary education on the compelling clinical data supporting Gavretto aids our broader efforts to increase comprehensive and actionable biomarker testing rates at diagnosis. Importantly, we reached a milestone with our partners at Roche and Genentech at the end of Q2. Going forward, in the United States, Genentech will now be booking end-user sales with Gabretto and, as a result, will also assume responsibility for product distribution. We are confident that our joint efforts will drive ongoing growth in the number of patients who are identified and treated in the United States. and we expect further revenue growth from ongoing launches outside of the US, driven by our partners, Roche and Seastone. Before I turn the call over to Becker, I wanted to come back to the opportunity in front of us to transform the treatment of all patients with SM, which starts with the launch of Avakit and Advanced SM, and will expand through the ongoing development of Avakit and Blue263 in non-advanced disease. Earlier, I mentioned that we had our first advanced SM prescriptions within a few hours of approval. As it happens, our first request came from a center that had advanced SM patients identified. And the team there also told us that they had multiple non-advanced patients that they were interested in enrolling in Pioneer. This demonstrates the power of the leadership position we have built in partnership with the SM community. The patient need across subtypes of SM is acute, and I could not be more excited about the opportunity we have to impact patients with a best-in-class portfolio of treatments for this debilitating disease. With that, I would now like to turn the call over to Becker to talk more about our clinical portfolio.

Thank you, Christy, and good morning, everyone. Let's start with the pioneer trial of Avakit and non-advanced disease. As we celebrate Avakit's approval for advanced SM, We're eager to expand our impact to non-advanced disease, which comprises the overwhelming majority of SM patients. Pioneer is the first large global registrational study ever conducted in non-advanced SM and has required a complex operational effort, especially during this global pandemic. In part two of the trial, we've activated nearly 40 sites across 12 countries and screened well over 200 patients. We've also worked carefully with sites to transition patients with consistently evaluable moderate to severe disease into the treatment phase of the site. As the trial's momentum has increased and with AvaKIP's recent approval for advanced disease, the investigator and patient enthusiasm has reinforced for us the breadth of need in this population. Now, as we begin to plan the wind down of screening and enrollment efforts at clinical sites, we're focused on driving toward top line data which we're looking forward to reporting in mid-2022 with potential regulatory filings following thereafter. Importantly, we're also applying the learnings and these learnings and carrying this trial momentum to Blue263, our next generation kit, the 816V inhibitor. Recently, we initiated the HARBOR study, which is evaluating Blue263 in non-advanced SM, including in patients with milder disease, with the goal of expanding our reach to an even broader SM population. As Pioneer winds down, we expect Harbor to ramp up and benefit from our expertise and deep engagement with the global SM community. We look forward to providing updates on the Harbor trial next year. Shifting to EGFR mutant lung cancer. In the second quarter, we initiated the Phase 1-2 trial of BLU945, our triple mutant inhibitor. This study includes a dose escalation portion in patients with EGFR mutant non-small cell lung cancer who previously received at least one prior EGFR-targeted tyrosine kinase inhibitor, followed by expansion in groups of patients with tumors harboring specific mutation profiles. Later this year, we plan to bring blue 701, our double mutant inhibitor, into the clinic as well. For both programs, we'll rapidly evaluate both single agent activity and both agents in combination with each other and other EGFR-targeted therapies. In addition, we continue to advance our newest development candidate, BLU222, the CDK2 inhibitor targeting cyclin E aberrant cancers. She's expected to enter the clinic in the first half of next year. Yesterday, we announced a strategic research collaboration with MD Anderson, well known for their expertise in translational medicine. The collaboration is designed to enhance the program by identifying novel methods to select tumors likely to be responsive to a selective CDK2 inhibitor as both mono and combination therapy. With this robust list of drug candidates advancing toward proof of concept data, all homegrown from our prolific and proven scientific engine, we're excited to keep you updated on our progress in the months ahead. I'd now like to turn it over to Mike to discuss financial updates.

Thanks, Becker. Earlier this morning, we reported detailed second quarter financial results in our press release. And for today's call, I'll just touch on a few highlights from the quarter. Total revenues for the quarter were $27.3 million, highlighting our growing diversity of our global revenue base and positioning us for strong future growth. This included $11.4 million in net product revenues, as Christy discussed, and $15.9 million in collaboration revenue. Collaboration revenue was primarily driven by commercial supply shipments to our partners, Seastone and Roche, to support our broadening geographic approvals. Collaboration revenue also included royalty revenue for sales of Avakit and Gavretto by Seastone and Greater China. Our total costs and operating expenses in the second quarter increased moderately compared to the first quarter of 2021. We saw an increase in cost of sales related to drug product shipments to our partners, In addition, SG&A expenses increased, driven by our commercial infrastructure expansion. As we increase investment in our promising early-stage programs over the next few quarters and expand our commercial efforts with the launch of Avakit and Advanced SM, we expect to see continued increases in future quarter-over-quarter R&D and SG&A operating expenses. We ended the second quarter with nearly $1.4 billion in cash on hand, ensuring that we have sufficient resources to invest in our growing pipeline of wholly owned drug candidates. Overall, with the recent approval of Avakit and Advanced SM, strong collaboration execution, and a deepening pipeline, we have a solid foundation from which to drive future revenue growth. anchored by sales of Avakit and the potential for several meaningful collaboration milestones, we anticipate that our second half revenue will more than double over the first half, which positions us to meet our 2021 revenue guidance of $150 million for the full year. This second half financial momentum will then set us up for a series of important clinical catalysts in 2022 as we continue to build the world's leading precision medicine company. So with that, I'd now like to turn the call over to the operator for questions. Operator?

Thank you. At this time, I would like to remind everyone, in order to ask a question, please press star and then the number one on your telephone keypad. Our first question comes from the line of Salveen Richter from Goldman Sachs. Please go ahead.

Good morning. Congratulations on the launch. What are your thoughts here on the trajectory of the advanced SM launch? Is there an initial bolus given the demand you mentioned? And then at the 70 hematological centers, what is the overlap there with the non-advanced SM total opportunity? And then separately, if you could just comment on the accounting mechanics for next quarter when Roche takes over booking of reto sales. Thank you.

Great. I can start. This is Christy, and then I'll let Mike chime in on the accounting. So, you know, we've been really excited to see the initial feedback and interest we're seeing around the Advanced SM launch. I think what, you know, the thing that is particularly notable has been that, yes, we're seeing interest certainly among those 70 key centers, but also seeing a lot of organic interest in the community setting, which I think is a really good indicator of the potential for future growth. It's early, obviously. So, you know, understanding exactly the dynamics around bolus versus not, et cetera, are, you know, I think we'll have more clarity on that as we emerge over time. But I'm excited about the potential for ongoing growth here, given that we are seeing broad interest. And in my experience, you know, the breadth of interest and breadth of prescribing is often limited. really a key driver of ongoing demand growth over time. We're also seeing utilization amongst patients that look like they've been previously diagnosed and treated, but also some uptake amongst patients with no indicators, at least, of another advanced system therapy in their history, which suggest that we're seeing, you know, prevalent patients, but potentially some newly diagnosed patients coming on to therapy over time. So, you know, we look forward to seeing how that continues to emerge as we go forward from here. The overlap amongst the centers, you know, the 70 centers are critical for treatment of advanced system patients. Certainly, if we get into the non-advanced setting, we will be broadening out into the allergy setting to a greater extent. But those centers are going to be critical for both indications. As I said before, SM is very much one disease with a common driver, a common mutation. And hematology can play a critical role in the diagnosis of non-advanced patients as well. So certainly getting established with advanced disease in these centers is going to be a critical part of setting us up for the non-advanced indication that we expect to receive over time. Maybe I'll let Mike comment on the accounting.

Yeah, so for the accounting, just as a reminder, in Q2, we recognized end-user sales of Gavaretto as product revenue, and then there was a true-up to the profit sharing for the U.S. that flowed through SCNA. Starting in Q3, as Christy mentioned, Roche will be booking end-user sales under the collaboration. And what we'll do is we'll record our share of the collaboration profit or loss as one line item on our income statement. It'll either show up in the revenue section if the collaboration is profitable or in the expenses if the collaboration is in a loss position. We're also intending to continue to provide transparency on our global product sales at the end-user level going forward.

Thank you.

Our next question comes from the line of Mark Fram from Cowen. Please go ahead.

Hi, thanks for taking my questions. One on, to start with, on Avakit, was there any kind of stocking impact from the launch of the new dose strength in the quarter or, you know, kind of all demand?

Yeah, so very minimal. You know, the advanced system dose, as you know, starting dose was 200, and we already had 300, 200, 100 milligram dose in the channel. So, you know, there's minimal 25 and 50 in the channel, obviously, to be available if patients need it as part of their ongoing treatment, but we haven't seen a lot of utilization of those strengths, and that wasn't a huge driver of what we saw in K2.

Okay. Thanks. That's helpful. And then maybe looking to the pipeline, just for RET, you were able to kind of report initial data about a year after initiating the trial. Do you think that's still a reasonable expectation for 945 monotherapy data, or do you think we should maybe expect you to wait a little bit longer for maybe combo data to kind of mature before you start reporting data out of the EGFR program?

So, you know, as we do every year, at the beginning of 2022, we'll lay out guidance in terms of sharing data and expectations, more specifically around timing. You know, as Becker highlighted, we think we're really well positioned now with this wave of new programs having either recently entered a clinic or soon entered a clinic. And so, to me, I think the company fundamentally feels different now than it did, say, a year ago. You know, getting the breadth of development candidates that we had pulled through and the quality of those candidates late last year, early this year, this advanced SM approval and the early indications, as Christy's highlighted, that we're seeing in terms of uptake and giving us a better sense of the magnitude of that opportunity. You know, I thought Mike said it well with the, We'll ride the launch into next year, but then we're looking to sort of lay out a series of clinical updates across these programs. So I don't think we're at the point where we'll specifically guide to any one of those, but the breadth of those clinical trials is what, for me, is really exciting.

Okay. Thank you. Our next question is from Dane Leon from Raymond James. Please go ahead.

Thank you for taking the questions and congratulations on all the updates and launch in ASM. Just one question for me following up on the EGFR question Mark asked. Could you just maybe elaborate a little bit more in terms of the clinical strategy here, what you need to see out of the phase ones to then move into combination studies, which I think a lot of us think is the end game here. And again, you know, as much as I can push you to give some idea of timelines on that effort, it would be appreciated. Thank you.

Yeah, first, Becker, I'll take that. With respect to the overall strategy, you hit the nail on the head. The combinations are the key to providing the most benefit with these compounds to patients. um we are going to explore as i said single agent activity of both and we will start combinations um before we finish exploring single agent activity combinations both with blue 945 and 701 together and then with each of those with other third generation tyrosine kinase inhibitors for egfr mutant lung cancer so i think what you'll see is a number of different experiments going on simultaneously in different patient populations we're also learning more about the mutation profile of the patients um how they present either alone or in combinations that is the mutation and so we'll refine our strategy as we understand the biology more and the our ability to combine these compounds during the um during the trials with respect to timing um as we've previously reported we started the 945 There's escalation recently, and we expect to enter blue 701 by the end of this year. And, you know, the extent to which, as Jeff said, rather than releasing data piecemeal, we have so much data coming out next year that there will be periodic updates. But I hesitate to speculate or guide about any specific thing individually.

This is Jeff. Maybe just combining the comments from Mark and Dane and comparing them to Rhett. All of us, when you're thinking about forward-looking statements, are speculating on when we'll have data, how quickly you'll move through the dose escalation to get to an effective dose. As Becker just highlighted, understanding the biology and where there's likely to be the greatest benefit of early signs are encouraging on this end. The fact that with the first couple of sites activated, we're already seeing patients lined up with some of those sites, patients willing to travel. So the first marker is, are the patients there? Can you identify them? And we're moving through that nicely. And then for 701, as Becker said, we're looking at moving into the clinic by the end of this year. The enthusiasm from investigators and potential investigators there to get that up and running is just one more of those markers. And so, you know, tied together is why, you know, I think we're collectively so optimistic about those two programs together.

Great. Thank you, guys. Congratulations on all the updates.

The next question comes from Rennie Benjamin from JMP Securities. Please go ahead.

Good morning, guys. Thanks for taking the questions and congratulations as well. This is one question. I'm going to give us a status update of what's happening with the application there and kind of importantly, what's the rest of the world filing strategy for 2021 in terms of other geographies to look at? And just as a follow-up, I know Christy talks about patient identification, and I thought in the past we talked about digital PCR, NGS, and then, you know, your own sort of test. I think Seastone is coming up with their own test as well. Can you just give us an update as to what's happening with your own testing product? Thanks.

Maybe, Becker, you take the first part of that with Roche's efforts outside the U.S., and then Christy is talking a little bit about patient identification.

Yeah, so as you all remember, this data outside the US is owned by Roche and they're leading the filing. We've guided to having filed that and that's well under review right now. With respect to the strategy in other regions, they have a number of other regions lined up to shortly follow the European evaluation of the dossier.

And then I can pick up the thread on patient identification. I think you might have been asking around advanced SM, but let me know if I'm picking in a different direction than what you were asking.

I thought it was Gavretto.

Are you asking about Gavretto?

No, no, no, advanced SM. Sorry. Yeah, switched on you.

Okay. So, yeah, so, you know, the most important, one of the most important patient ID levers across, you know, advanced and non-advanced disease, frankly, is testing for 5816B. In advanced disease, where I would say that becomes most important is in SMHN, where you're really trying to identify the SM component. But clearly, most advanced patients are diagnosed with something. In non-advanced disease, driving accessibility to you know, highly sensitive blood-based testing is really critical. And there, I think we've made, you know, we've made a lot of progress. So, you know, the goal is it's not so much our own assay. What we're trying to do is really enable capability amongst labs broadly in markets that we're going to be commercializing in. to have that available so that physicians and patients can access testing easily. Over the last six to nine months, I would say there's been good progress in terms of the number of commercially available, highly sensitive tests in the United States. And then we are working as well with a few large lab partners to further develop that capability and make sure that it's accessible and available to patients. And, you know, I'm expecting ongoing progress against that even as we go through the remainder of this year. So I would say, you know, generally speaking, we're in a much better spot even now than we were 12 months ago and would expect to see ongoing developments there from here.

Great. Thanks for taking the questions and congrats.

The next question is from Peter Lawson at Barclays. Please go ahead.

Hi. Thanks for taking the questions and thanks for the update. Just on the preclinical update for 945 and 701, just kind of perhaps walk through what we should expect to see and the potential venue for that in the second half.

So I assume what you're talking about is the combination of 701 and 945 in preclinical models. We haven't decided on a specific venue, but we are working on generating that data. Identifying the proper models and animal models for these complex mutation profiles is where we've gone, we are partnering in, we have internal models. So you should just look forward later this year for a couple of different looks at that.

Gotcha. Thank you so much.

The next question is from David LeBeau. It's from Morgan Stanley.

Please go ahead. Thank you very much for taking my question. In the early run of the Ibogaine launch in ASM, There's certainly been, sounds like there's been a lot of inquiries about patients with ISM that you end up referring to the Pioneer trial. Are any of the physicians actually trying to take these ISM patients and put them on drug now at this point, or certainly inquiring as to ways they might be able to get patients on drug? As you have elaborated on in the past, it is overall considered one disease.

Sure. You know, the data that we have right now suggests that the patients who are being prescribed Avakit are advanced system patients as diagnosed by their healthcare provider. Certainly, as you know, I mentioned anecdotally, and that's not the only site I will say where we have seen, you know, both advanced and non-advanced patients being treated. interest in um in pioneer also potentially interest in harbor down the road so i think it it uh just highlights you know again the synergy that we're seeing um in our engagement with with this community uh you're right sm is is absolutely one disease subtyping is complicated, you know, so, you know, I think we may see over time utilization, but I think what we've heard is that, you know, early on we expect utilization to be in advanced consent patients, and we have no data to suggest anything differently from what we're seeing.

Thanks for taking my question.

The next question is from Benjamin Pellock from Baird. Please go ahead.

Hello, this is Benjamin. I'm for Joel Beattie. Just a few questions for us, mainly on the advocate. I'm just wondering if there's a sense of the number of repeat scripts, potentially, and the number of new prescribers. And then I was wondering if you also could comment more on the demand from community physicians. Is it more demand, or is there interest, or is there maybe specific examples you might be able to point to to kind of provide a little bit of clarity on that? Thank you so much.

Sure. So, you know, we are, I guess at this point, like five weeks in or so, right? So we are, we are most, I mean, the majority of the demand that I've been commenting on is these new patients, you know, where we would certainly expect with an indication like this and given, you know, the incredible duration of therapy that we see with Avakid, which is, you know, I think one of the ways that it's really transforming care for these patients, we would expect long duration over time. And so certainly, you know, seeing that revenue build as we see refills as well as new patients coming in. But based on where we are in the calendar, we've barely even gotten to the point where you would see your first refill starting to come through. In terms of the community, again, it's early days, but I think the marker for us was that we saw interest really almost immediately coming from a broad number of stakeholders. And I would say a significant percent of our utilization already is coming from the community, which I think is a really good indicator. And I will likely be sharing more about that as we progress through the launch and continue to build that data. You know, this is a rare disease. And to me, what this suggests is, you know, we are often the launch of a transformational therapy catalyzes, you know, changes in the treatment paradigm as well. And so, you know, I would not be surprised to see that here and to see Avakit really enabling broader care of advanced system patients, both in centers as well as in community practices.

Great, thank you. And then if I could say one more quick follow-up. On the underutilization of the 25 and 50 milligram dose, any thoughts there? Is that kind of surprising, or does that speak more to your comments earlier about the early in the launch?

Yeah, absolutely. So it's certainly not being underutilized in terms of what we would expect, right? I mean, the starting dose for advanced to some patients is 200 milligrams. You know, we expect the majority of patients to be treated at 200 milligrams, maybe 100 milligrams, 25 and 50 are there, certainly to enable appropriate dose adjustments and care on an individualized basis based on, you know, a patient and a provider. But I wouldn't expect to see broad use of those dose strengths in advance of them. So there's nothing that I've seen so far that is different than what we would have expected.

Got it. Thank you so much.

The next question is from Michael Schmidt at Guggenheim Partners. Please go ahead.

Hey, guys. Thanks for taking my question and congrats on the progress as well. I have a couple on your CDK2 inhibitor program. Just help us understand how your collaboration with MD Anderson actually accelerates development, as you mentioned. And then secondly, just mechanistically, how should we think about blue 222 activity perhaps PCNE-amplified or cytokine-amplified cancers relative to other potential mechanisms that include, for example, V1 inhibition or PKMYT1 inhibition in the same setting. Thanks so much.

Thanks, Michael. Let me start with MD Anderson. I think, as everyone knows, MD Anderson is really a powerhouse with respect to translational research. Just identifying a selective CDK2 inhibitor is really just the beginning of the journey. You've seen in CDK4-6 development that identifying signals often requires combinations, sophisticated preclinical models to understand how and when to use these drugs together. And in this case, we're looking at four, six inhibitors combined with two inhibitors and a number of other mechanisms, including those that you just mentioned, where novel combinations may really uncover amazing therapeutic advantage in different patient populations. The other place that they have quite an angle on the science is that there are so many patients that go through MD Anderson So their ability to query tumor banks and really deeply understand the biology of the indication such as ovarian and breast cancer and endometrial and beyond that we have identified and then pulling additional tumors off the shelf to understand where there's a vulnerability that might allow us to either use Blu222 or a combination that either we or they identify It's really unprecedented when you look at the breadth of the tumor banks that they have and the investigators that are involved. So we expect to enhance the iron-standing activity where we expect it. And what I'm really excited about is what we don't expect. This is what happened with Pfizer and CDK4-6, where UCLA identified a signal that really transformed breast cancer. This collaboration is one of the ones that I'm most excited about my entire career. With respect to the other modalities, it's really too soon to speculate about how the relative activity will compare. We're looking at cycling amplified cancers, expecting that a subset of these malignancies will be so dependent on the CDK2 pathway that we can see some apoptosis when we inhibit CDK2. The extent to which that's achievable through these other mechanisms, we're going to have to see. But as I said, as we go into novel parts of the tumor's biology, understanding how to combine novel compounds and the more standard care compounds is going to be something that we're really focused on. Great. Thank you.

The next question is from Andrew Behrens from SVB Lee Rink. Please go ahead.

Hi. Thanks, guys. A couple of questions for me on RET and then one on ASM. I just wanted to give us some color on the RET market. You guys are getting 45% of new patient starts, and I think previously you said it was around 25% in Q1. but we haven't seen that translated to the P and L yet. Is that because of sampling in the new patients or is it just not as many new patients as we had anticipated? And then what percentage of diagnosed patients are actually being treated with any RET inhibitor? And are you seeing any frontline usage or is usage predominantly after a Tevmo? And then just a question on the ASM launch, should we expect to see any change in the gross genetic adjustments Now that you're expanding into a larger opportunity.

Great. Those are all for me. So I can start with Rhett. And actually, the questions that you asked are all related. So the way that we think about this market is, new patient starts being sort of the first indicator, total patient share, then following over time, and total patient share, you know, as total share approaches new share more quickly, obviously the faster the market grows. And so we know that, you know, Lilly had a bit of a time advantage on us in terms of being, you know, the only game in town for, you know, six months prior to having both indications available. And so as we've gained new patient share, we're seeing our total patient share grow, but it will take time for total share to catch up to where we see those new starts coming. So it's essentially thinking about like NRX versus TRX. And, you know, it's an indicator of revenue growth. And I think we've seen that. I mean, we're continuing to see really robust revenue growth relative to what we've seen from certainly Retevlo over the last period of time. You know, I think we would like to see the market growing more and growing faster, to your point, and I think, you know, that's really where we're spending a lot of time focusing with Genentech. You know, our best estimate right now is that, you know, it's maybe 20% of, maybe a little bit more than that, of potential RET patients are being diagnosed and then treated with a selective red inhibitor. And so there's certainly a lot of opportunity and we think to continue to really grow patient ID and expect . that the rebound post-COVID is happening in terms of testing, et cetera. So we're excited to see that pull through. And we're seeing use across lines of therapy right now, but certainly there's an opportunity to get to patients earlier upon diagnosis. And so that's something that, again, we're focused on. From a question at perspective, I wouldn't expect dramatic changes from where we were with Avakit. Certainly the strategy that we've been using to, you know, distribute the product in the United States is consistent, and our broad access strategy is consistent there. So I would not expect dramatic changes to the advanced system.

Okay. Thanks, Chris. We appreciate it.

Our next question comes from Arlinda Lee at Canaccord. Please go ahead.

Um, great. Thanks for taking my question. Um, I was interested in the overlap of in ISM versus ASM. Um, you mentioned, uh, how much you've been able to get into the key some centers. I'm wondering how much overlap do you think there is with, um, the pioneer and the harbor ISM populations? And then if you can maybe talk a little bit about judging these education efforts, have you been Is there any imbalance on ISM? And if you can maybe discuss if you've been seeing increases in D816Z testing. Thank you.

Sure. So as I said earlier, the 70 key centers are certainly where we see, you know, we think a lot of advanced to some patients being treated about half of the United States. They also play a key role for non-advanced patients. And I think that, you know, again, as I shared, we're seeing that in real time as we're out engaging with sites where we're seeing advanced to some patients being identified, but then also sites flagging non-advanced patients who are interested in treatment. Certainly our goal at this point is to facilitate enrollment in clinical studies for those patients, whether that be Pioneer or eventually Harbor. So, you know, we're going to be following up on that interest. And then as we get into the The ISM market more generally, allergy, as I said, becomes a broader, a more important call point. But I think these 70 centers still will help really, you know, they play a role in diagnosis certainly of many patients and I think will be a good sort of foothold for us as we broaden out into the non-adventure markets. great and then um is there a way for you guys to track the d816z testing that's kind of um you mentioned that that was the bottle neck or one of the main levers for patient identification yeah so this is something we will be um looking at over time i mean the difference uh you know i think a subtle difference here if i even compare to say gabaretto right where we're you know the the i think the um goal there is to get patients who are being diagnosed with lung cancer appropriately tested for a mutation Here, you know, our label is obviously not specific to a mutation, but we really see the testing as being kind of the key to facilitating increased diagnosis, particularly for non-advanced patients. So it's obviously early. We're just in the market commercially. So I think, you know, something we'll certainly have a sense of over time. And, you know, the way I think we'll see that play out is growth in the number of non-advanced patients. that we can really identify and see. And so that's a place that we will continue to focus in terms of disease education, market development, et cetera, you know, between now and when we have a completed approval there.

Great. Thank you very much.

There are no further questions at this time, so I'll hand the call back to Mr. Albers.

Thanks, operator, and thank you all for taking time to join us today and for your continued support of Blueprint Medicines. And look forward to updating you again soon. Have a great day. Bye-bye.

This concludes today's conference call. Thank you all for joining.