Welcome back to the 44th annual TD Cowen Healthcare Conference. I'm Marc Frahm from the biotech team. We're really happy to have with us here the team from Blueprint. We have Kate Haviland, CEO; Fouad Namouni, President of R&D; and Christina Rossi, who's the COO. We'll get into mostly probably the AYVAKIT launch, but also a little bit in the pipeline as well. But maybe to start off with, Kate, do you want to just kind of give a brief status update, kind of level set people, and kind of what you view as the key issues for Blueprint kind of over the next six, 12 months? And then we can dive into discussing some of those issues, probably. Yeah, absolutely. So Marc, first of all, to the whole Cowen team and Marc and Ernie in particular, thank you for having us here. We really appreciate it. This is always one of our favorite conferences of the year. In terms of kind of what we think about for this year for Blueprint, we're just coming out of the AAAAI meeting. And I have to say that obviously we'll spend a lot of time talking about AYVAKIT launch. We're in a great spot there, really strong and steady growth, being predominantly driven by the launch in indolent systemic mastocytosis. I know we'll spend time talking through that today. But what I'd say was really notable coming out of AAAAI is the excitement around just mast cells and mast cells and their role in a broad range of allergy and inflammation diseases. It really feels like almost kind of a new age where the biology of mast cells has been somewhat underappreciated. What we see is key opinion leaders and physicians broadly, actually, engaging on the idea that by targeting mast cells, particularly now with our wild-type KIT inhibitor, BLU-808, we have just a tremendous opportunity to drive impact in large patient populations. Just a lot of momentum coming out of that in terms of how we're thinking about both BLU-808 and other targets we're working on, honestly, in our discovery portfolio. So we look forward to talking more about that. Obviously there's a lot of focus on AYVAKIT, but I'd say it was kind of refreshing for us to see so much time and attention being spent on the near-term inflections in the pipeline. So I'm sure we'll talk about that today as well. Okay. Maybe just sticking on AAAAI just for a second within the AYVAKIT. What's the major feedback you were getting in the meetings with the physicians who have started using this commercially, but also you presented the long-term data? What were the kind of key salient points there that were resonating with those physicians? So I'll start, and then please, you guys should chime in too. But I think, first of all, when we think a year ago, we were presenting our registration data of the PIONEER study at AAAAI for the first time. And people were taking a look at the profile of AYVAKIT, particularly in ISM, and then also just understanding the mechanism of action, the first disease-modifying therapy that targets the source of the disease. So it was a conversation around, what does this profile look like? And then here now we were, a year later, having broad conversations with physicians who now have clinical experience and patients on commercial therapy and having this kind of impetus to go look for more patients and to do the right diagnostic workup and to think about the clinical science and symptoms that should lead them to think about SM. And so in just a kind of short period of time here, it really felt like a complete step change in terms of the levels of conversation we were having, the awareness, the enthusiasm, very broadly from physicians who are in community settings, obviously the people we work with from an investigational perspective, but a very broad set of conversations there. Yeah, I agree with that. I would say that the meeting also really highlighted the very broad leadership position that AYVAKIT now has in systemic mastocytosis and the fact that that position is not static, but it's moving, right? We showed long-term data both from a safety and efficacy perspective. I think showing very compelling, durable efficacy over time, as well as a safety profile now with a median follow-up out to 18 months just in ISM, where you really see very consistent safety over time. Both of those data points are very compelling to physicians. I think it just shows that the bar here is, it continues to move, and the leadership position that we have is one that I think is going to be very hard to touch. In terms of that kind of long-term follow-up, this is more of a Fouad question. Just ISM, some patients, that's the end state of their disease, but there's others who will kind of eventually progress to ASM or historically have, which of course gets even more severe and can have deficits on survival. Do you think this is disease-modifying enough that you can actually prevent that transition? And kind of when do you think you can is there a way to robustly show that from a potentially reimbursement perspective? Thank you, Mark. I think with all the data that we know from European registries, from our own data in the U.S., up to about 20% of patients are at risk of progressing from ISM to ASM. That's a good proportion of patients that needs to be taken care of earlier. I think our data from PIONEER continue to mature. I mean, the majority of patients are still on treatment in the study. And obviously, in order to see the impact on progression, it's going to need really a few years of follow-up because when these patients progress, it's between five to 10 years. So we continue actually to report safety data, and we continue to follow these patients as much as we can in the context of this study. We believe in the mechanism of action, given the fact that we are really dealing with the root cause of the disease by really tackling the KIT-mutated mast cell. There is potential for patients to not progress to ASM, and we need to follow up on that. Okay. Now, maybe turning back to the launch itself, you recently put out guidance for the first time that includes ISM of $360-$390 million for the year. Just maybe walk through, Kate, the kind of major pushes and pulls there when you were kind of coming up with what's the right number to put out there. And kind of what is the factor that you think you have the kind of greatest uncertainty on when you were doing that analysis? I'll start, and Christina can chime in too. What I think is really important to note is we haven't had a year yet of experience with ISM in the market. So we haven't seen the four quarters and the different dynamics that you traditionally see in various quarters from just any pharmaceutical perspective. And so we are really happy with the opportunity to put out $360-$390 in guidance. And importantly, that puts us on a trajectory of really notable other medicines that have had deep and important impacts in patients like Soliris and Jakafi, right? So I think that the fact that we feel that we're on this current path is just really a phenomenal place for us to be in this point in time with AYVAKIT. I mean, Christina, do you want to talk about how we thought about some of the puts and takes in the guidance? Yeah, absolutely. So as Kate said, I mean, the midpoint of that guidance range represents more than 8% year-on-year growth and very much demonstrates the trajectory that we've been saying we see for AYVAKIT towards that more than $2 billion peak. To set the range, we really looked at our experience over the first two full quarters of launch. Some of the key variables we are thinking about were new patient starts, persistence or duration of therapy, which again, in a chronic indication like this, becomes very meaningful over time as you start to build a base of patients on therapy, factors like compliance, as well as percent of free drug, which we talked about in Q4 having come down to around 25%. Marc, I wouldn't say there's necessarily one or another where we have more uncertainty. It's more that there's obviously a range around each of these variables two quarters in. And so we really kind of looked at the likely set of outcomes there and tried to set a guidance range that we felt was realistic to really help people think about the forward trajectory of the launch. The other factor, again, as Kate mentioned, we're not a full calendar year into this launch. And so really thinking about quarterly dynamics and taking account of that as well, right? So traditionally, Q1 can be one that is challenging. We have not gone through a Q1 in ISM yet, so trying to understand what that would look like, etc. And so thinking about the quarterly phasing, and that's how we got to the range. Okay. I mean, you mentioned some of the kind of step change you're seeing at AAAAI of kind of acceptance of testing and doing the right work. I mean, should we think so kind of taking these pieces of guidance one at a time? We'll start with the new patient ads. Just should we think of that as steady, or because of these step changes that are happening, should we be or is it more of an acceleration that we should be thinking of through the year and into the future years? Yeah, we have looked at new patient starts and new patient adds as being very much a kind of steady part of the launch. And that is that we are gaining great awareness. People are starting to look for patients. But there's just a natural cadence of patient visits that is going to very much dictate when patients will come in and have their first conversation around AYVAKIT as an opportunity and then eventually come onto therapy. And I think that for us, as we've been talking about that for some time, I think that is just what kind of makes that kind of strong and steady view that we'll continue to add patients. We are absolutely growing this opportunity, but we expect that to be something that kind of moderates that pace of patient adds. As more physicians become aware, this is an opportunity that's 15 times the size of the advanced SM opportunity. But nonetheless, this is still a rare disease, right? And it's great that physicians are out there looking for patients now as well. And their clinical suspicion of SM is very much higher on their radar. But we, again, expect that this will be kind of that strong and steady cadence of patient adds. Okay. And in terms of persistence, I mean, obviously you have the clinical trial data where most patients stayed on for, well, essentially as long as you followed them so far. But Christina, what are you starting to see in the commercial setting? How are physicians actually evaluating whether the patient's having a good outcome or not and making those decisions of whether to stay on and keep for the patient to keep paying copays and all that? Yeah. So all signs thus far have been very positive and that the real-world experience with AYVAKIT looks very similar to what we saw in PIONEER, which again was very positive, where we saw incredibly high levels of persistence, 96% of patients rolling into part two for the open-label extension, which I think speaks to the patient experience on the drug. Physicians are evaluating this, and patients are evaluating, I think, in much the same way that they parse the clinical data, right? So we got the question a lot when we had the PIONEER data set, "Is this clinically meaningful? How do I think about all these different endpoints?" And I think the data speaks to the totality of the impact that AYVAKIT can have across symptoms. And that's what we see in the real world. Patients are very heterogeneous, but what is uniform is that we hear about patients really feeling better and having aspects of their lives impacted in ways that maybe they didn't realize how much they were suffering before they started therapy, the ability to exercise, to go out, etc. So all of those pieces are part of that equation as the physician and patient kind of assess benefit. One thing just to kind of point out, you mentioned copays. That's really not a factor for our patient population. We have a very robust patient support program so that patients who are on commercial therapy generally are not paying out of pocket. And so that's not a barrier that we see. As the launch keeps progressing, I guess, how are you thinking of payer coverage? Just early on, it's a new market. They're not used to it. Is there some risk here as the launch is going pretty well that you start seeing a little bit more management coming in? Yeah. I mean, I think I've said sort of tongue-in-cheek that the more payer push we get on this, I think it'll be a good sign in terms of how well the launch is going. But when we think about payer management, at least in the U.S., it's generally a function of willingness and ability to manage a category. In terms of ability here, again, it's a very small patient population, very clinically heterogeneous, difficult to manage in a way that's sort of easy for a payer. And there's not other approved options, right? So where you start to see, I would say, heavier payer management tends to be in therapeutic areas where you have multiple options and can kind of play manufacturers off of one another. That's not something that we see here. That being said, certainly as utilization of AYVAKIT grows, it would not surprise me if we start seeing questions around this. I don't see it becoming really a major factor in how we think about things like revenue gross to net, at least in the sort of short to medium term. The other piece on gross to net, it often is kind of the payer mix, right? How is that evolving, particularly as the franchise becomes more and more dominated by ISM sales versus some of the other indications? So the ISM patient population is a bit younger than advanced SM. And so certainly, as ISM has become a bigger proportion of our patient population, we're seeing that favorability come through as we expected. And where that really shows up is in the percent of Medicare patients that we see, where we also are more likely to see patients on free drug due to copay issues. And so we mentioned in Q4 that our free drug percent had come down to about 25%. As we think about this year, I think, again, a range around that point estimate as being one that we looked at to set guidance. But certainly, the Medicare proportion of ISM is more in that sort of 20%-25% range. I think on the free drug piece, a year ago, you kind of had a bolus of patients able to access some programs that they haven't always been able to access that brought that down for Q1. Have you seen that again this year now that we're a good chunk of way through the quarter? Yeah. I mean, we'll obviously have more commentary on kind of the full Q1 dynamics when we get on a quarterly call. But that dynamic was very much a unique one where there happened to be external funding available for our advanced SM patient population that provided them with the ability to have a certain number of commercial fills that we set unwound. And that really explained a little bit of the Q1-Q2 revenue dynamics last year. So I wouldn't expect that same factor to kind of be in play as we think about quarter-over-quarter this year. Okay. And then maybe turning a little bit longer term for AYVAKIT, you've also put out peak sales guidance that you think the kind of now existing label can support at least $2 billion in sales. Just kind of what are the major factors there? Is that really just the people under care? How much do you have to access some of these larger numbers that you've also kind of predicted are out there based on your AI models of claims databases and things like that? Yeah, that's a great question. I mean, what we had been saying before we had approval for AYVAKIT in ISM was that we believe the AYVAKIT peak opportunity was going to be greater than $1.5 billion. And what we've seen since the approval is a couple of things. First of all, when we got the approval, we were very happy to get a label from the FDA that was a very broad indication, right? So we got an indication for all adults. And what we've seen is that we were talking quite a bit about 7,500 patients kind of leading into the approval that we could see in claims data who were diagnosed with SM and who were moderate to severe based on the kind of pharmaceutical burden and healthcare burden that they had. So these are patients taking H1, H2 blockers, cromolyn, steroids, clearly symptom-directed therapies to help manage their SM. And we've seen that grow from 7,500 patients now to 9,500 patients in that claims database. And then I think it's what we've talked about, which is the market receptivity to AYVAKIT's clinical profile. So we're seeing incredibly strong receptivity from healthcare providers, from patients, and from payers. And so I think you bring those three pieces together. And as we look at that opportunity, we clearly see it, and this is predominantly driven in the U.S. and Europe, as being an opportunity that's greater than $2 billion for AYVAKIT at peak. And if you think about those 9,500 patients, if you get 3,500-4,000 of those patients on therapy at any one given moment, that's $1 billion in and of itself, so. Okay. That's assuming kind of flat pricing from here on out, or often there are some, at least on a WAC basis, price increases over time in the U.S. Is that built into that $2 billion, or would that be on top of the? It's how we think about the overall model for the opportunity, which will take into account some modest price increases. I think the days of significant price increasing is somewhat over, but we certainly do try to stay current with inflation as we think about the value of the medicine. Maybe on the pushes and pulls there, I mean, I guess what kind of needs to happen to make it not just something over $2 billion, but maybe it's $3 billion on the positive side or vice versa? What would go wrong that would make this actually more like the $1.5 billion, the old guidance, right? Is it competition? Is it something else? I think as we look at this, we think about it, it's not an if, it's more of a when. So how long does it take us to get there? Listen, we know that when you have a greater than $2 billion market opportunity, that there will be competition that will come. We don't see anything on the horizon right now that we think is commercially relevant from that perspective. And what we have additional work that we're doing with our next-gen molecule and ISM, as well as other targets actually that we're looking at, which we haven't disclosed yet, we're going to continue to push the innovation in this space. And we anticipate that we'll continue being those leaders from the innovation perspective. So I think one of the things that I think on the positive side is we've seen this in other disease categories. I think Soliris is a great example, where you watch kind of the market and the patients in need build underneath a really impactful and effective therapy. So it becomes bigger than anyone expected, right? I think that could absolutely be the case here. I think we are having conversations with people around all sorts of different kind of patients who may be considered MCAS right now. And are they SM? And how do we think about where that epidemiology will or potentially could go? And I think there's a real opportunity for the market to continue to grow underneath the therapy like Ayvakit. You mentioned other mechanisms that might be coming. Is that SM-specific mechanisms or just other kind of broad ways to target mast cells that might happen to work in SM but are kind of more broader applications? I think systemic mastocytosis is a mast cell-driven disease because of the D816V mutation. That is the root cause of the disease. However, I mean, it's a complex disease where there is an inflammatory process in addition to mast cells being abnormally activated and releasing their mediators. So I think a lot of research our teams are doing in that space and more to come in the future, hopefully. But I think it's a very complex disease. In a leadership position, I think we owe patients really to look at all the aspects of this disease and try to hope for future cure for the disease. Are those things we should be expecting to see enter the clinic near term, or is that kind of a long-term research project still? I mean, it's a research that we are doing. We actually have gathered a good amount of data from PIONEER study, from real-world evidence. We have a very good understanding of the biology of the disease, what the mast cell does, and how it interacts with the inflammatory system. So more to come in the future. Obviously, we'll talk when we are ready to talk about the market. But I really think this disease for us is one of the most complex things. And we are at the forefront of really unlocking the issues that patients are facing in this disease. Okay. Most of the discussion has been U.S. focus here. You're approved in Europe now. Maybe just kind of the status there and how we should think of that rollout. Obviously, you have to go through the negotiation periods with each individual country. But just as each country launches, should we kind of think of it as very similar to the U.S. trajectory, or are there other dynamics there that make it faster or slower within a country? Yeah. So we received approval in Europe right before the end of 2023. So we had our first patients treated in Germany before the end of the year and are rolling out primarily in Germany and ISM. As a reminder, we are already approved in advanced SM in Europe and just. So I would expect to see those launches. This year will primarily be Germany, just given the pricing dynamics. It takes a little longer to work through pricing and reimbursement with some of the other major markets, but we'll see those come online. The overall market dynamics, obviously, there's puts and takes in each country in terms of who's the primary treater, etc. But in terms of how patients are managed, the overall EPI, a lot of that is very similar. Clearly, the biggest difference in Europe over time is price and where that lands. I think from a modeling perspective, when we think about the opportunity, Europe or international has been running at about 10%-ish ± of our revenue. I think this year, that's not a bad assumption. Over time, I would expect the U.S. still to represent the majority of the opportunity at peak, whether that's 70% ± 80%. We'll see where that nets out. But the lion's share will be in the U.S. But international will increasingly become an important part of the growth of the overall top line. Briefly brought up Elenestinib to avapritinib. Just maybe Fouad, review kind of the data that you've presented and just the clinical profile. I guess what can point you to kind of how it differentiates from avapritinib and avapritinib so far? Yeah. Elenestinib, from the data we presented last year, the ASH shows really a very good benefit-risk profile, very good efficacy, very good safety and tolerability profile. And it is looking like something that could be like avapritinib, a treatment directed towards a chronic disease. Now, what is going to make the difference more than any profile for Elenestinib is the way we think about developing it, taking advantage of all that we learned and we are learning from SM patients in PIONEER, from the biology, from all patients' groups, and the complexity, as I mentioned earlier, of the disease and think about how we bring Elenestinib to patients to really do even better in the life cycle of the systemic mastocytosis franchise. In the phase III portion of HARBOR, I guess when should we expect that to open? And maybe how will it actually differ from what was done with PIONEER? Yeah. I think by year, and we will be able to share the development strategy and the thinking for Elenestinib and how we are going about it. And right after the programs will start. AYVAKIT sets a very high bar. I think we're fortunate to understand kind of the depth of the data that we have and be able to look at opportunities to bring Elenestinib forward in a differentiated way from AYVAKIT. We certainly don't want to just replicate what we've done. We want to really push the innovation forward. Honestly, we could do that work with AYVAKIT if we wanted to, some of the places where we may think about continuing to drive innovation in SM. Elenestinib for us is really a life cycle management strategy. Here we have what is a $2 billion-plus franchise. We certainly want to continue to bring an innovative branded adoption forward when we're at that point in the life cycle of AYVAKIT. It sets a high bar. It's not a straightforward thing to solve for. Okay. In order to kind of unveil to us the full what that phase III plan looks like, is there more data that you're going to need to show us? Is it just the trial design? How should we think about that update? The way to think about it is what is going to be behind the way we will be setting or we are setting our development strategy. That will be informed by data we are gathering from our experience with avapritinib in ISM from the study and other data. That will really help us when we start talking about this and help the community understand what are the issues in SM beyond what we have been doing so far and how we are thinking about tackling these issues. Okay. Maybe we'll leave SM now, but not mast cells, and turn to 808, which you unveiled kind of the main preclinical data sets that caught eye. Just maybe, Fouad, high level, just describe this molecule, kind of what are the key takeaways that investors should take from those presentations? Yeah. Definitely. So let me start by saying the role of mast cell in inflammation and allergy has been probably theoretically known from a biology perspective, but pretty much underappreciated in our industry overall. And I think it's time now, building on the knowledge we brought through likes of SM and other hematological diseases, that we are going to modulate the mast cell in inflammation and allergy. And there are a number of diseases to tackle there by inhibiting wild-type KIT. So we made, over the last two years, this BLU-808, which is a wild-type KIT inhibitor, probably the most selective and best in class and probably the first in class tyrosine kinase inhibitor for a wild-type KIT. I think we shared the preclinical data at AAAAI. We are in the IND-enabling work, and we are targeting an IND by the second quarter of this year. Right after that, we start the healthy volunteer study. I think one of the things that we showed in the poster at AAAAI that was notable and actually got a lot of conversations with KOLs, but also with some of you all, was that 808, we can modulate the activity of the mast cell and yet not actually kill the mast cell. You saw that. We had this really cool poster, if you haven't seen it, with a QR code where you can look at some videos. Then we have assays where we can dial it up as high as actually killing the mast cell. We think that the opportunity with a small molecule to be able to tune that activity between just calming or not the mast cell down, but not actually killing it versus going all the way to potentially killing the mast cell is going to give us just a tremendous amount of flexibility to think about how to address, as Fouad said, chronic urticaria kind of coming out of the gate, but a range of other diseases. We'll be able to actually test that hypothesis clinically to say, where do you need to be in terms of inhibition to actually have a significant impact while striking on a really important risk-benefit profile for these patients with these diseases? I think it's a very exciting opportunity. Fouad, preclinically, where do you think you need to be ideally in terms of how much wild-type kinase inhibition? Is it IC50 24 hours a day? Is it more pulsing? Just how should we think about the kind of target inhibition? I think in terms of target inhibition, there is really a broad and this is a small molecule with hours of half-life, which is a big advantage in this area. So you may want to think about it like a range of doses we'll explore and see between what do we need in a given patient. There are maybe some patients; let's use chronic urticaria patients who are no longer responding to Xolair, for example, are candidates for cyclosporine in this country. This is a severe disease. Maybe for these patients, you need to go and really completely stop the mast cells. In other patients with less severe disease, you may not need to stop the mast cell or kill the mast cells, but just block the activation and the release of mediator by the mast cell. All these questions, we will look at them. This is what makes me think about probably major inflection for the value of this future medicine at Blueprint is the healthy volunteer and the PK data. Because the POC or the proof of concept for chronic urticaria with wild-type KIT blockade, we have seen the data. That has been proven and actually probably much better than other strategies like IgE and BTK inhibitors. I think now, do we have the right PK? We're going to look at serum tryptase in healthy volunteers and the very, very early safety signals that we look at. If that all are heading in the right direction, which is our prediction, then I think the POC is done and the move next year will be very quickly in terms of what is the work that we bring this to patients in terms of registrations. And give you serum tryptase as just a PD marker here. I mean, I know there's been a lot of debate about it on the SM side. Or is it a little bit more correlated with symptoms, do you think, in a setting like urticaria? It's a PD marker. It shows us, like in SM, as we have seen it, it shows us that we are hitting the mast cells and we are blocking the function of the mast cells. That's what it's telling us. How much of kind of where you're trying to dial in that inhibition is informed by the level of off-target inhibition that is happening in avapritinib? Can you already see what the safety profile is likely to be from your avapritinib experience? Yeah. I mean, obviously, here we are in a completely different disease. Sometimes we forget that ISM, even indolent SM or ASM, these are neoplastic processes. It's a neoplastic disease where we have mutated mast cells proliferating at a rate higher than what we would expect. And so in the case of CU or type 2 asthma or I mean, the list is long. These are not that these are normal mast cells that we are trying to block. And in patients where the molecule has to be the cleanest possible in terms of AEs. So I really think the work and it took a couple of years for our teams to do this, but the work our team did in terms of bringing 808 to IND is, in terms of selectivity profile, as I mentioned earlier, is the best. We'll have to see in the clinic, but we are not expecting major concerns with the molecule. Okay. I know we're running up on time, but maybe just real quickly, there's also a CDK2 update coming shortly. Fouad, do you want to kind of lay out just the scope of that update, how investors should think about it? CDK2, an important target in the cyclin-dependent kinase world, mostly for hormone-positive, HER2-negative breast cancer. It deals with the resistance to CDK4/6 and even preventing the resistance to CDK4/6 inhibitor combined with CDK4/6. We are in the phase I dose escalation of the combination. We'll be presenting early safety data from the phase I, as we mentioned in the previous meeting. That's where we are in terms of this. So far, the profile is consistent with what we are expecting from CDK2 initially. This is obviously a development that will be partnered with pharmaceutical because moving into registrational work in phase II, IIIs, and metastatic breast cancer, adjuvant breast cancer will need really a major partner to really be able to tackle this work. Okay. Unfortunately, that's all the time we have. So we're. Comment on your cash burn for this year? Yeah. So what we've said is with the growing revenue line and the kind of prioritization in terms of our R&D spend in particular, that we expect cash burn to be significantly lower than it was last year. We're getting full operating leverage off our SG&A investments. Actually, that's very flat for the year, and we're continuing to grow that top line off of that, so. Thank you. Yeah. Good. Unfortunately, that's all the time we have, but thanks for joining. And. Thank you. Thank you. Stay tuned for the next session. Okay. Thank you.