Perfect. Great. Thanks everyone. My name is Bradley Canino, Senior Biotech Analyst here at Stifel. Thanks for joining us after lunch for the fireside sessions for the rest of our last day of the Stifel Healthcare Conference. I'm really happy to be sharing the stage with Kate Haviland, CEO of Blueprint, and Christy Rossi as well, the CEO, COO, excuse me. Thanks so much for joining us. Kate, maybe I'll have you do some intro comments, but I wanted to frame this because last year when we shared the stage at this conference, you were just beginning to talk about the precision medicine at scale vision for Blueprint. You know, and over the past few quarters, if people have been listening to the quarterly calls, you've made some significant comments about the bar you're setting for clinical stage- Yeah ... drugs in your pipeline. So, you know, do the intro comments, but also let us know what should investors be prepared for in 2024 for Blueprint? Yeah. Thank you. Thank you, Brad. So first of all, thank you for having us back. We really appreciate both yourself and the whole Stifel team. It's been a great meeting for us. So for those of you who are less familiar with Blueprint Medicines, we are leaders in precision medicine, and we are now a fully integrated commercial global company that are bringing our commercial product AYVAKIT to patients around the world. And we are focused in the areas of mast cell diseases and cancer. And I think, you know, where we sit today is we have our approved medicine, AYVAKIT, that has now been approved across the spectrum of SM, with the most recent approval in the U.S. for the 95% of that population, which is the indolent form of SM. As you mentioned, Brad, you know, we just had our first full quarter of launch and, you know, we're really pleased with how the launch is progressing with $54.2 million in revenue for the first full quarter. We're just seeing great metrics across the board in terms of the breadth and depth of prescribing, the payer receptivity and patient receptivity, and the impact that the drug is having. So we're in a great spot from that perspective. I'm sure we'll talk more about that today. To your question on pipeline, I think we are also in a really excellent place in the sense that about 18-24 months ago, we put a number of investigational new compounds in the clinic, and we are bringing those through to their phase I dose escalation completions right now. We're gonna be in a place where we can look at that data and decide what does it-- where does it make sense for us as Blueprint to move something forward? What is better maybe- better possibly in the hands of a strategic partner, and through strategic business development, and what maybe hasn't met the bar in the patient population that has the most meaningful opportunity to bring it forward? And so we're gonna be sharpening our focus in terms of what we'll be investing in going forward and how we think about that, both from a data perspective and strategically as we kick off next year. Yeah. And so we look forward to talking more about that, for sure. Okay. I think you've always had a pretty large number around what you think AYVAKIT can sell. Mm-hmm. I guess, is there any change in that confidence one way or another, now that we've gone through that first full quarter of sales in the U.S.? Yeah. So if anything, I would say our confidence in the opportunity continues to increase as we get further down the road. So to take a step back, as Kate said, ISM is the most prevalent form of SM. There are probably about 30,000 of these patients in the United States. We're seeing increasing diagnosis rates, and we've talked about targeting patients who are uncontrolled and have said that we see about 7,500 of those diagnosed, uncontrolled patients in the United States. And so when we've talked about AYVAKIT having blockbuster potential, you can clearly see a path to that just in penetrating that 7,500 patient population in the US alone. Getting to half of that gets you to $1 billion in revenue. What has evolved, I would say, over the last, you know, year, and in particular, as we've seen the PIONEER data read out and then gone through label negotiations with the FDA, we have an incredible profile in AYVAKIT. Incredible risk-benefit profile, very active therapy against, you know, the full range of symptoms that ISM patients experience, with an incredibly clean safety profile that looks, you know, frankly, better than placebo, based on that data. Then we got to a labeled indication for all ISM patients. Not just these sort of uncontrolled or moderate to severe patients, but every ISM patient, which I think is a testament to the need in this patient population and frankly, the really compelling clinical profile that AYVAKIT has. And so what that opens up is the potential to really go beyond that 7,500 sort of moderate to severe patient population that we see, as we really redefine what it means to be well-controlled in this disease, and then we see that patient population continuing to grow as well. Diagnosis rates have been growing at quite a clip. We've seen about, you know, 50% growth in the diagnosed patient population over the past several years. So we are incredibly excited, and really just at the beginning stages of penetrating into this opportunity. Yeah. Now, if I'm to combine those two comments there, driving towards profitability with AYVAKIT, that's being helped potentially by some of the- Mm ... portfolio decisions that will be made. So now, how do you build Blueprint for 2025 and beyond? Yeah. What do you invest those AYVAKIT generator resources into? Yeah, so I think, you know, we have had a history of just incredible productivity coming from our discovery engine. Our discovery engine is unique and differentiated, and I would point to just this year alone, we announced a development candidate for wild-type KIT in BLU-808. And so we've had the great fortune of being able to grow the company organically through our own research and development or through our own research platform and our team, and that team, you know, continues to enable us to bring new and interesting compounds forward. And in fact, in the past, we have done so in such a way that, you know, we can't bring them all forward ourselves. And so again, we've always used strategic business development to maximize the value of the innovation that our discovery team has pushed forward. But going back to BLU-808, we're really excited about that compound and that opportunity. So now we have our foothold with AYVAKIT. We have a next generation program there for the mutated form of KIT, which we can talk about. And then we have what we think is going to be a best and first-in-class oral wild-type KIT inhibitor that has numerous possible, you know, indications. We'll start with urticaria. We've seen nice proof of concept there, but we see multiple ways that that can be a pipeline in a program, and that could expand very rapidly. And then, again, our discovery team continues to drive innovation, and we look forward to talking about the programs that they push forward next year and beyond, which we are really excited about. Okay. Now, you've given us very granular details on the quarters for the launch. Stuff like the number of AYVAKIT patient additions QoQ, which is super helpful in my seat, but, yeah, sometimes dangerous. Is it reasonable to think that you continue to achieve what you reported last quarter, which was about +215 patients quarterly throughout the next year, or is there something else to consider there? Yeah, so we have been very clear that what we expect from this launch is strong and steady growth in patients on therapy, and that's what we're seeing. You know, there is no indication that what we have seen is a bolus, for example, which is a question we sometimes get. The patient demand that we're seeing is driven by, you know, new and existing prescribers finding patients. We did not have patients transitioning onto therapy from clinical trials. We didn't necessarily see warehousing. So we're really excited about the organic demand that we're seeing as we continue to build prescriber breadth, and then we start to see depth in prescribing. So strong and steady growth of patients on therapy in the context of a chronic disease, which I think is an aspect of this launch that maybe, you know, is not fully appreciated. We've historically launched into oncology indications, where duration of therapy tends to be limited, and clearly, that impacts revenue growth. This is a chronic market. It's a chronic immunology market, and so we will see, you know, strong and steady growth of new patients in the context of an existing patient base that will continue to grow, and that's really what adds to revenue scale. We will be guiding on revenue next year, likely on our Q4 call, and that will, I think, help everyone think about how best to model this as we go into next year. Yeah. Are you learning anything yet about potential treatment durations in the real world? I mean, you've made comments that are very helpful in the past about the proportion that stayed on the trial to the open label. Yep. I think it was, like, 97%. You know, I'm traditionally spending most of my time in oncology. I was just having a conversation today about, you know, when a PFS is six months, the Q3 into a launch can sometimes be a little volatile- Mm-hmm. As you get that initial wave that falls off. I think you mentioned that for some of your own products. What have we learned so far? Early experience has been very positive and very consistent with our belief that we'll see extended treatment duration on the order of years for these patients. The fact that we're not seeing anything early is a very good sign, right? Yeah. So it's early days. Really not seeing any evidence of discontinuations. We wouldn't expect that based on the PIONEER data. So clearly, we will learn more as we get further into this, but, you know, we know enough from our clinical trial experience and from the profile and based on what we're hearing from prescribers and patients, it's all very consistent with that. Okay. This might be a question for both. How frequently are you seeing any personalized dosing in ISM? So maybe a patient that is dosed up- Yeah ... a level based on tryptase or maybe symptoms. And with that happening, and with a competitor trailing you by a few years, does that hurt or help the AYVAKIT brand perception? So the fact that we have a range of doses for AYVAKIT on the market is a huge source of strength for this product profile. We did, on our Q3 call, talk about the fact that 70% of patients who had initiated in the quarter initiated a 25 mg dose. So we know that for the vast majority of ISM patients, 25 mg will be the dose that they start at and the right dose for those patients. We do see a small number of patients who are initiated at different doses. Advanced SM tends to start at 200 mg, but SM is a disease spectrum, right? We talk about these like they're two discrete indications. They're really not, right? We know that SM is a spectrum of disease. We have patients who are on the more severe end of ISM, smoldering SM, that, you know, really are kind of closer to that advanced stage. And so the fact that we have dosing flexibility that enables providers to customize dose, I think is a really huge strength, and it's an aspect of the profile that we get a lot of very positive- Mm ... feedback on. What we know is that in ISM, you know, the goal of therapy is primarily symptom control. And we know that there is not a dose-dependent effect on symptom control. We have seen this now through our own data and through other data as well. So 25 mg is gonna be the right dose for most ISM patients. It's when you're kind of in that, you know, stage where you're progressing towards advanced SM, that higher doses may be needed. Yep. Okay. And I think one of the things that, you know, we have learned through the PIONEER clinical trial, as well as our continued experience, both in the extension of that study and commercially, is that, you know, the historic view of the progression rate from ISM to advanced SM has been kind of in the single-digit range, you know, 5%, 6%. And we have now been working with KOLs and different big academic centers, and in fact, there'll be some data at ASH that in collaboration with the Cleveland Clinic, that we've put together, that really shows that actually, that progression from ISM to ASM over the lifetime of a patient is more like 20%. And so, as Christy was saying, we're starting to really understand the middle part of this phenotypic spectrum and understand who those patients are, who have risk factors. What are those risk factors? How do we monitor them, and how do we work with KOLs to think about kind of developing some additional evidence there? And to you know, as we said, like, the solution is on the market with AYVAKIT for those patients now. If they need a higher dose, they have availability. That's available for them, so. Okay. That blue sky opportunity that we referenced with that label indication, actually not including the words moderate to severe. Are you seeing that broadness of the current patient population that's being added now? And, you know, how do you really access that in earnest, the milder side of the population? I think what that question gets to is, is what does it really mean to be well-controlled if you're ISM? Certainly, what we see in terms of the patients that prescribers are choosing to start AYVAKIT on, typically they pick their first patient, and those patients will look similar broadly to what I would say we saw in PIONEER, right? So patients who maybe have tried some symptom-directed therapies, may have some of those therapies on board, but are still impacted by their ISM symptoms. And so that's often kind of the first patient that a prescriber will choose to use AYVAKIT in. What's been interesting is to hear the feedback that we're hearing from prescribers and patients when these patients come back in to be seen, and the kind of impact that they're experiencing. Things like, "I can exercise again, where I wasn't able to do that before." You know, very, you know, tangible impact in quality of life, and often it's in aspects of their lives that, you know, I think the patients hadn't even realized how impacted they were and how much better they could feel until they were on therapy. And so that is the way I think that we then open up the aperture, right? A prescriber will see that impact on a patient, and it causes them to reevaluate when they're having that discussion: What does doing fine really mean? What does doing fine mean if you're on, you know, four different drugs that, you know, make you feel really sluggish and sleepy? And, you know, there's... The impact of this disease day in and day out is pretty significant. I do think that broader opportunity is accessible, and that's, that's the, you know, the experience that we'll start to build in the community. Yeah. I think we even saw in the PIONEER study, I mean, we had numerous patients who screened, who screen failed because they didn't meet the score for moderate to severe- Yeah ...on the endpoint that we utilize, which is more of a regulatory endpoint than it was, like, it's not used in clinical practice, right? And so, and I think what we've seen, and we've heard from some prescribers, is some of those patients may have one really bothersome symptom, something that's really impacting their ability to go to work or leave their home. They wouldn't necessarily have been eligible for PIONEER. You usually need a broader set of symptoms, but they're going in and seeking out AYVAKIT. And because the label language is so broad, it's not a question in the prescriber's mind: is this drug indicated for this? It's more of a question of, you know: Is this an appropriate therapy for this patient? There's no limitation on that. Again, we haven't seen any—we've seen the access part of this launch, which has been incredibly smooth. So payers are covering the drug, no step edits. You know, it's really a PA to label. And so I think that just provides a very easy path for physicians and patients to give AYVAKIT a try. Yeah. Okay. You hinted at some additional studies that might be planned around ISM to ASM progression- Mm ...but you have the PIONEER open label extension ongoing now. I guess, what additional data should we expect to see reported- Yeah ...at medical meetings for that? And what of that do you expect to really continue to build the AYVAKIT perception in the community? Yeah, I was... You wanna start? Yeah. Sure, sure. So what I would say is, you know, if I think about long-term follow-up studies- Mm ...in indications like this, honestly, the most important data that people wanna see is, sort of patient experience, frankly. So safety, the fact that patients can stay on therapy over time. Clearly, we'll look for measures of clinical benefit as well, but it's really about adding evidence around the long-term benefit of staying on treatment for these patients, which is, what we expect to see. We expect to see patients treated chronically. Clearly from a data generation perspective, more broadly, you know, we're partnering with the community to really characterize aspects of this disease around progression, prognostic factors, et cetera. That's beyond PIONEER, right? So we have data sets that exist in the real world. We're partnering with key centers, et cetera, to generate some of that data. So we'll see more of that data coming out over time, and then, of course, we have, over the long term, elenestinib and the development we'll be doing there. So, you know, we really see our role as being leaders in the SM space, and that, you know, involves continuing to generate data around our own therapies, but also add to the body of evidence around the understanding of this disease more broadly. Yeah. Okay, and now at ASH, upcoming for the elenestinib data set, what should we expect from the level of disclosure? And what's the intent of this, I guess, from the investor community side? What do you hope we learn from it? I think what we want everyone to take away is that elenestinib is a safe and clinically active drug, and it's kind of worthy of continued development, right? And I think, you know, the goal of our HARBOR study, and you'll see the part one data from the HARBOR study, very similar design to AYVAKIT in PIONEER part one, is really about dose finding and figuring out, like, do we have a safe and clinically active molecule that then we wanna bring forward into a more registration-directed, pivotal, part two? So that's what we'll be showing at ASH. You'll see safety, you'll certainly see symptom, the overall symptom score by dose. That's the critical metric of whether or not a drug is active, and also if you can move it through, you know, regulatory processes, and then the quantitative measures, right? So those are kind of the key factors to understand the clinical profile of elenestinib. And so that's what we'll be looking to highlight at ASH, and then we'll spend some time next year talking about how are we thinking about that differential development. So as Christy mentioned, you know, elenestinib, for us, is really about extending our leadership life cycle in SM. So it has a longer patent life in terms of composition of matter than AYVAKIT, and it gives us that opportunity to think about a second molecule as it relates to even thinking about IRA strategies and/or life cycle extension. You're at a point in time when, you know, the franchise is most valuable, and so, we have a lot of flexibility there, and we'll be thinking about that differential development, about bringing elenestinib forward to where ISM needs to be in, you know, late 20, you know, 2030 or early 2030, like late 2028, 2029, right? And so it's not about recapitulating what we've seen with AYVAKIT. ... You've been very clear and consistent on your answer to questions around, would higher doses lead to better symptom reductions? You know, particularly if those doses showed better PD effects on lower tryptase, lower mutant mast cells. I think another way to ask a similar type question is, what's the working hypothesis for what might be driving the residual symptom of symptoms in the patients- Yeah. with a dose that doesn't fully clear those PD biomarkers? Yeah, so I think, so as you've, as you said, there is no correlation, even at baseline, in these patients between their symptom score and something like serum tryptase, right? So, you know, obviously, you know, mast cells do not circulate, you know, tryptase is a circulating broad marker. So, you know, there's a relationship, and you'd like to see both impacted, but it's not a one-to-one correlation, and that's why we can't use things like serum tryptase as regulatory endpoints. They can't be surrogate endpoints, right? Because they do not predict clinical benefit. I think what we have shown with AYVAKIT is that even with a 4x difference in dose, so 25 mg - 100 mg, and a 4x kind of impact on D816V, you do not see a difference in symptomatic impact, and that's because this is a chronic inflammatory condition. So clearly, the mutated KIT is the source of the disease, but patients have been living with this disease for decades. And so and we saw this even with our broad symptomatic impact; AYVAKIT impacted all symptoms and deepened some of them over time. But the kinetics of response in various symptoms is a bit different. So you think about skin symptoms. You know, clearly, like the flushing and the rash can resolve very quickly for patients, but the actual spots on the skin take time to remodel and to see a difference there. So, so you're, we are hitting the source of the disease, but it's an inflammatory complex condition, this, which is why you continue to see that impact in symptoms over time, and there's not that direct one-to-one correlation with quantitative measures. Got it. Okay. Maybe some questions to close out on the oncology pipeline. Really, I think most of the interest comes from investors, to me, in forms of questions around CDK2. Mm-hmm. And I'd love to ask you, where do you actually see the highest potential value for that target? And then specifically for Blueprint, what steps are you undertaking to generate data with the lens towards those high-value opportunities? Christy's team is leading the- Yeah ... the partnering efforts on CDK2. So this is one of the pipeline assets that we are most excited about in terms of, of broad potential. We reported some initial data at ASCO and as did a competitor, and so I think we're now in a place where this target is really viewed as a validated one and incredibly important. Clearly, the highest value opportunity is in breast cancer. You know, and I think as we are exploring combo strategies with CDK 4/6 inhibitors, that is data that is incredibly meaningful, primarily first, from just a safety perspective, and being able to show that you can safely combine, is really important and I think unlocks a significant amount of value as we think about this opportunity. We've also been really clear that, you know, the path here, because it is primarily in breast cancer and in these very large opportunities, is not one that Blueprint would pursue on our own. We don't feel that our capabilities and infrastructure really lie there. We know that there's gonna be significant, investment, frankly, required to get this to where it, it should go, which will be a very, very significant, revenue opportunity. And so we've been actively engaged in strategic conversations around the target, a lot of interest there, and so would expect to be pursuing that in the combination, or in the context of a partnership. Mm-hmm. Status on the combination study, and which CDK4/6s are you combining with? We're combining with ribo, and, you know, could look beyond that, but that is where we've chosen to start. You know, we're continuing to dose escalate in the combo, generating safety data and, you know, again, we'll report additional data as we get into next year. But, and clearly, in the context of discussions we're having, partners have, you know, potential partners have some visibility to that as well. Yeah. I guess, what extent of involvement do you want to maintain in both the clinical development and cost there? Yeah. The commercialization and revenue opportunity for CDK2, and is that dependent on data, or is that dependent on portfolio strategy? I think it's a strategic- Yeah Question more than anything else. Yeah. I mean, clearly, we see the CDK2 opportunity as a very significant one, so we wanna make sure that we can participate in the economics appropriately. There's ways to structure a transaction so that we have that, and certainly in the hands of the right partner. You know, we believe that having the right partner on board will certainly maximize the opportunity. Participating in it, clearly, you know, requires being able to shoulder some of the burden in terms of operations and expenses. We've just talked about the fact that this is, you know, gonna be a very significant investment to kind of get to that opportunity. And so I think a lot of it depends on, you know, leverage, frankly. A theme that we have been very focused on is how do we build and exploit leverage in our portfolio? Mm-hmm. When we think about what we are really focused on right now, it is driving AYVAKIT and SM. It is continuing to build that opportunity, and over time, build it with elenestinib as well. It is leveraging that for BLU-808, which gets us into broader mast cell disorders, and again, builds off of the clinical and commercial infrastructure that we have. So that is really where our primary focus is. I would say less so in terms of breast, where we don't really have, you know, sort of the balance of our portfolio headed in that direction. So, we're flexible on the specifics around deal structure, but really solving for having the right partner on board that can drive the economics. ... Okay. To continue on the theme of leverage in the portfolio, the EGFR inhibitors, you know, one of them homegrown, one of them insourced. Mm-hmm. really, at the time, the thesis was that would help broaden the potential commercial scale- Yes across multiple different mutations in EGFR. And you mentioned you've got some data in phase 1 that's nearly done, so you can make some decisions. Yes. Do you have to look at the EGFR portfolio as one, or do you now see the ability to have one of them continue if one of them doesn't? Yeah, I think that's a great question. I mean, I think to Christy's point, we always think about leverage and how do we think about leverage across. You know, the reason why we brought BLU-451, which is the exon 20 inhibitor that we brought in from a BD perspective, was because you know, we could leverage a broader development infrastructure than a you know, potential commercial infrastructure. I would say that the question about whether or not it, you know, they need to sit together can be independent, is really about the opportunity that sits beside each of these molecules and the target product profile that comes forward. So I think BLU-945, you know, we have shown really compelling data in combination with osimertinib in second-line-plus patients with EGFR-driven lung cancer. I mean, we're at a... I think at ASCO, I think we're in somewhere 55%-60% response rate. We're seeing some durability there. Really nice activity. That patient population is not big enough to stand on its own. And so what we're trying to do is understand, like, can we look at that data, and does that de-risk an investment to go into front line? EGFR-driven lung cancer, much larger opportunity, and then you can see how the investment gets you to a return there if you go into front line. I think similarly with exon 20, exon 20, you know, alone, would likely need to set, in our view, within a portfolio. Again, we're holding a very high bar on our exon 20. What we see as the medical need in exon 20 lung cancer, EGFR-driven lung cancer, is the CNS activity. So we are looking for a strong and durable response rate within the CNS to move that forward. And what we've also seen with exon 20 is that we are enrolling patients with atypical EGFR mutations, and we're seeing some nice activity there. So that, you know, exon 20 alone, again, would be hard to stand by itself. With the atypicals potentially pulling in, that becomes a much more substantive opportunity where you could move it forward itself. So I think the question, it's, it depends, and what does the data tell us? Where does the data lead us in terms of what is the opportunity in each of these compounds, and are they big enough alone to justify continued investment and/or together? And so that's kind of... We're coming to a place where we're gonna be able to answer those questions. Got it. Last for me, you've kind of talked for over a year now on the self-sustainable cash guidance. Yes. You know, we mentioned AYVAKIT growing nicely- Mm-hmm ... some potential portfolio decisions to reduce outyear spend. Yeah. What other levers are there to pull to maintain that guidance, if any, that you'd like to discuss? I mean, those are the two really key levers, right, is that continued revenue ramp, which we're, you know, we're on track to what we think is a blockbuster opportunity here. And then, you know, being strategic about where we invest our dollars for the longer term growth. I think, you know, we talked about BLU-222. We clearly believe that that strategically is better off in the hands of a partner, but with strategic business development comes capital as well. Now, I, you know, so I think you have all of these levers that all three of those are things that, you know, add into our view that we have a very durable financial and sustainable profile as a company. And we'll be able to talk more about that as well as we kick off next year. Okay. Yeah. Great. Christy, thank you so much- Thank you. And thanks, everyone, for listening in. Yeah. Thanks. Thanks, Brad.