All right, welcome back to the 45th Annual TD Cowen Healthcare Conference. Next up, we're really excited to have the team, really, from Blueprint up here. But maybe to start off, so I'm Marc Frahm from the biotech team, but maybe to start off with, Kate, we'll have you give the high-level overview. Sure. And then we'll get into some of the specific questions. But also, the audience, feel free to raise your hand. We will try to bring you into the conversation if you have your own questions, but I do have a list to go through with them if not. OK, well, first of all, Marc, and for the whole TD Cowen team, thank you so much for having us here. We really, really appreciate it. I'm here joined by my colleagues, Christy Rossi, our COO, and Fouad Namouni, our President of R&D. And to Marc's point, maybe we'll just kick off where we stand. So really, the fundamentals of Blueprint's business, both our commercial business and kind of what's coming through our pipeline, are an incredibly strong place. And so I think what we were able to kick off the year with is an understanding of our Ayvakit opportunity and the overall ISM market, which is bigger than we thought it was, and it's growing faster than we expected. So that's a great place to be. The fundamentals of the product itself in terms of the receptivity to patients, patients staying on therapy for a very long time. You know some of the other dynamics I'm sure we'll talk about around access and the launch have just been going very well. And so we're looking forward to another great year in terms of Ayvakit revenue growth. And then what we have is a pipeline of pretty exciting assets, including our next generation D816V Inhibitor, Elenestinib, which is going into its phase III registrational study. We can talk more about how that fits in, but really, it's Elenestinib and the opportunity that asset brings for us to drive innovation in the treatment of patients with SM and really extend our SM franchise on the backdrop of what we know is a growing and large opportunity from ISM perspective. And then BLU-808, which is our wild-type KIT inhibitor. I'm sure we'll talk about that today as well. We had our first data from that at J.P. Morgan this year from the healthy volunteer study, so early clinical data. And I think what we see is BLU-808 is certainly a best-in-class and likely first-in-class oral wild-type KIT inhibitor that has the opportunity to impact a large groups of patients across numerous different diseases. And so as we kick off 2025, we're in a very strong place between our commercial execution and our really the next growth drivers of the company very much coming into focus here at Blueprint. OK, maybe this is a bit for you as well as Christy. Just you did issue guidance on the earnings call the other day you know at $680-$710. But how did your kind of approach to coming up with your guidance differ this year versus a year ago, you know given the kind of experience base that you now have in this market? Christy, do you want to talk about this? Sure. So you know our approach to to setting guidance hasn't changed. What has changed, to your point, is that we have a much larger business that we are now sitting on top of this year than we did last year. When we set guidance, we're always aiming to provide you know our best view of how we think the time period will evolve. And then we want to set guidance that's informative, as well as guidance that we feel confident about. Last year, when we issued guidance, we had, I think, two quarters of launch experience under our belts in a you know new market that we were building for the first time. So clearly, error bars around guidance are going to be wide in that situation. You know w e ended up, to your point, beating and raising guidance several times through the year. Although at the end of the year, we were able to set a range that we felt very confident in a very tight guidance range and landed within that range. As we think about the guide this year, you know we are aiming to, again, provide our best view of where we think things will evolve, and underpinning that you know are some of the factors that are driving our confidence in the long-term opportunity. When I think about what's going to get us to our $2 billion by 2030, our $4 billion franchise peak over time, it's really the fundamentals that are very strong around you know more and more patients starting on therapy, where we're seeing growth and breadth and depth of prescribing, a widening lens of sort of who is an appropriate Ayvakit patient, as well as just a growing base of patients that we're penetrating into. So we have a market that's growing as well. And then once these patients start on therapy, we're finding them to be highly compliant, and they stay on therapy. So that is a consistent theme that runs through the year. We're also accounting for some of the factors that will impact quarter-to-quarter revenue, right? So certainly, you know impacts around, for example, Q1, gross-to-net Dynamics, et cetera. And so as we think about how the year will evolve, our guidance accounts for sort of some of those shorter-term revenue factors that you know we deal with, as well as anyone else does as well. For this year, I mean, you mentioned the Q1 gross-to-net. What are kind of the major factors that are going to influence whether ultimately you end up at the low end of the range, the high end of the range, or maybe even get beyond the range? Yeah, I think, again, you know we're still in the context of a rare disease market. Our fundamental view here is that we're going to see more and more patients initiating therapy as we move through the year, right? So that is something where we have a very good view now on how this market is evolving, which is when we bring a prescriber on for the first time and we see that breadth grow, depth is following in a pretty predictable way, and in our view is that we'll continue to see more and more patients starting on therapy. Again, we have better insight now into duration of therapy, which is a really important driver. That is trending towards a multi-year duration. As we continue to go forward to the launch, it's possible that will that will look even better, right? It's something we saw with advanced SM, where the further we got into our launch and commercial experience, our duration of therapy trends improved. Other factors that will influence the year are you know things like, for example, free drug rate, right, where we are projecting you know from a place now that is incredibly strong in terms of our free commercial mix. We saw a lot of improvement in that throughout 2024. We now have a baseline, but you know small variability there, a point or two on free drug can have pretty significant impact, given the size of the revenue line this year, and other factors like compliance, et cetera. One you know additional driver as we think about the year is certainly our international business. We have our head of international joining us at this meeting. We've been really pleased to see growth there through 2024. We have additional launch coming online this year. Obviously, the timing around that will be whether another factor that will you know impact how one quarter may look versus another. OK. And now a year plus into the launch, what do you find has resonated the most with patients in deciding to start therapy or stay on? And maybe conversely, you know what are kind of the reasons that some patients maybe choose to hold off and opt not to use it? And may bring Fouad into the conversation too, how some of the presentations this weekend at Quad AI may kind of speak to these points. Yeah, so maybe I'll start, and then you can come in. We understand this market really well. We've been working in SM for years now with providers, as well as with advocacy and patient organizations. ISM is fundamentally a disease about lack of control. Patients you know have a very hard time sort of controlling their day-to-day, predicting how the disease will impact them. And so the decision to start a therapy is a big one for these patients. Often, they have really limited any variables in their life, and they live in a more sort of contained way. And so you know they need to be confident in that decision to start. A lot of what resonates, I think, is the experience that they hear both from their health care provider as well as from other patients about what the true impact of a treatment can be for these patients. We hear again and again that patients didn't realize how sick they were until they started therapy, that some of the impact of the disease in terms of how a patient feels goes well beyond what can be captured in, for example, a symptom score that we use in clinical studies. And so really understanding that and bringing that to life has been incredibly impactful for patients. That is you know more about sort of how a patient feels in the here and now. I think another piece that is becoming more and more relevant within the SM therapeutic area generally is the longer-term implications of living with ISM. And we know that you know treating the disease is much more than just relieving symptoms day to day. You know and I don't know if you want to talk a little bit about, for example, impact on bone and some of the places we're going. Yeah, I mean, in addition to the long-term safety data that we reported Yeah. at Quad AI that shows that over the years, continuing to be a well-tolerated medicine, helping a lot of patients with continuous efficacy over time, we were able really to show that beyond improving the symptoms, we go to asking the question, can we heal the organs? Bone health is a major concern in ISM. In fact, it affects probably more than 50% of patients with osteopenia, osteoporosis. Even younger patients have fractures sometimes when they fall down or so. So we did a retrospective analysis. This question was not prospectively asked in the Ayvakit PIONEER Part II study. We did a retrospective analysis to look at bone health evolution over time in subgroup patients where the DEXA scans and the data were available. And we reported this. We clearly demonstrate that Ayvakit impacts bone health and improves the quality of the bone over time, means lowering the risk of fractures and so on. And as as we're sure we'll talk about it later, we're prospectively studying this with Elenestinib in Harbor. All these data that we showed are showing that Ayvakit over the years is something that is helping patients with a very good level of compliance. Speaking about Quad AI, I mean, this is not Blueprint, a real-world report by investigators, a study called AVATAR that was published, real-world data from patients receiving Ayva commercially. And the efficacy actually starts to appear in real world pretty early from that publication, while the overall profile of the drug is really maintained very well, as part of what we have seen in clinical trials. So the real world data is really catching up with the clinical trials now, creating more confidence in the profile of AVA when used by practitioners. I would just add, I think you know to Christy's point and Fouad's point, as we've gotten to know these patients and this patient community, the first part of their decision-making is the tolerability of the drug. So as they've worked really, really hard to try to get some stability, they're on a series of kind of symptomatic-directed therapies. So as they sit down and they talk with us, or we hear from advocacy and some of our now prescribing physicians, the first thing they want to understand is what are the side effects and how can they think about that? And then they'll say, OK, now what's the impact it's going to have on my disease? And so I'd say for the vast majority of ISM patients, which is a little bit different than advanced SM, it leads with what is the safety profile? And then second, OK, what can I expect from the breadth of impact that I'm going to have on my disease? OK. You mentioned a minute ago on the longer-term guidance, the 2030 $2 billion, and then $4 billion plus a peak for the Mastocytosis franchise. Just what are the key assumptions there? And I think you've talked about kind of patient numbers being higher than you thought they were originally. So what really gets you to that $2 billion first, but also, as importantly, to the $4 billion? Yeah, you know the $2 billion is something that you know we think is is very achievable, if not even a conservative view of how the market may evolve over the next several years. $2 billion, you can get to a $2 billion run rate by assuming something on the order of 6,000 patients on therapy in the US, right, with some ex-US contribution there as well. You know that is still a minority of the patients that we see diagnosed even today, right, where we now see 25,000 plus diagnosed SM patients in the US. We've seen diagnosis rates growing at a double-digit clip. And so the market is continuing to grow. And we now have evidence that suggests that the prevalence of the disease is probably somewhere in the order of 60,000-65,000 patients in the US. And so our expectation is that the market is going to continue to grow. So by the time we get to 2030, I expect we'll see many more than 25,000 diagnosed patients in the US. And again, that you know kind of penetration, I think, is a very reasonable one. And at that point, we will still be you know used in a minority of SM patients. And so when we think about a franchise opportunity of $4 billion, you know the idea there is that we expect that this market is going to continue to grow and that our penetration can continue to grow across the franchise beyond, we don't see a peak of you know $2 billion in 2030. Maybe are there some, thinking through the severity of disease, the kind of the efficacy safety profile, are there some drugs that you look at as, hey, this is a good proxy for kind of what peak penetration can look at can look l ike in this type of patient population? I think every you know there's never a perfect analog there. What I think maybe I would think about is that you know you see many therapies where a first-in-class therapy continues to grow penetration over the long term, right? I think you know Dupixent is a great example, where you can continue to see growth there you know over many years. HAE is one that's in the allergy space, where I think you've seen more and more patients being treated as that market has developed over time. I think about multiple sclerosis, where if I think back to when the first disease-modifying therapies were launched, you're continuing to have more and more patients being treated over many, many years as that market continues to develop. So every therapeutic category is unique. But I think the message is that there's many examples where you know you don't get up to a peak penetration five years after after a first therapy is approved. Yeah. How much of this increasing patient numbers is coming from the MCAS population who, with your more sensitive Yeah. tests you're now discovering, really aren't MCAS Right or are actually SM? It's really not. I think that's another untapped source, potentially, of additional market growth. So when we think about you know when we put out a number saying 60,000 to 65,000 patients in the US, that's based on epidemiology that has been done recently, really taking you know kind of the current standard view of diagnosing systemic mastocytosis. And that's certainly the way that we're continuing to see patients diagnosed now. So it's with currently available technology, looking at you know patients who look like they may have ISM and then working them up. MCAS is a much broader population of patients who have mast cell activation symptoms, don't necessarily look like they have ISM or haven't been diagnosed as having ISM. I think traditionally have been thought of as really a separate seperate bucket of patients. And you know to your point, we now have much higher sensitivity testing on the horizon, not yet commercially available. But we can see a path to having that commercially available in the not-too-distant future. And we see that you know potentially 20% of those patients could have a mutated KIT at the sort of root of their disease, which could make the ISM patient population actually even larger than the numbers that we've been talking about. OK. And briefly on Europe, since those countries are more meaningfully going to be starting to come online this year, how should we think about the adoption curves in these countries? Many, not all, but many have centers of excellence that are really capturing these patients. Should we think of, at a country-by-country level, the adoption curve being faster than the US, or is that not appropriate? You know it is. It It depends. It's probably not a satisfying answer, right? I mean, one thing I've learned is that we talk about Europe like it's a monolith. But in reality, each market has its own characteristics. We were talking earlier about how you know there's aspects of Germany that seem very similar to the US, that you see patients sort of at centers. You see them in the community. I think one of our first prescribers in Germany was a community prescriber, which was exactly what we saw in the US I think about a market like France, where these patients are much better identified even now and sitting kind of in a place where we can see them. Obviously, a big driver of European performance is also price. And so we're going through kind of that process as we continue to bring additional markets online, although are very, very pleased with where we ended up in Germany, which I think is a nice recognition of the value. And some of that complexity, honestly, is why we've been kind of giving these rules of thumb to say you know revenue ex-US may comprise, you know we're saying, 10%-15% maybe of the top line this year. I would expect it to tick up over time. Of course, the US will continue to be you know the driver of the lion's share of the opportunity. But I think thinking about it that way may be may be easier. OK. Maybe starting to transition to Elenestinib, just with that $4 billion kind of peak for the franchise, does that rely on Elenestinib meaningfully extending the franchise, or could Ayvakit get there on its own? Yeah. Maybe Maybe I'll start, and then Christy. I mean, so what we know is that you know Ayvakit will continue to grow beyond 2030. And where that that kind of branded opportunity for Ayvakit lands will depend a lot about its its competition matters 2034. We'll see how that kind of plays its way through. I think what we're doing with Elenestinib is enabling us, as Christy was just mentioning, this market is larger and growing faster than we expected. We expect it to be growing like other rare disease markets well through the next decade. And what Elenestinib does is allow us to, first and foremost, drive innovation in the treatment of these patients based on the body of knowledge we've kind of gained through our entire Ayvakit development program in SM. And what we know is, where Fouad was talking about bone and some of these other really important impacts on the disease for these patients, is that we can impact those and measure that in a way that that you know continues to drive treatment innovation for these patients and enables Blueprint to continue to benefit from a growing market over you know well into the next decade. And so Elenestinib is absolutely part of that equation. And what's really great for us is, strategically, as we have both of these programs within the same company, we can watch that profile come through. We can continue to see the Ayvakit data. And we can really make some good strategic decisions with both you know the plan would be to have both Elenestinib and Ayvakit on the market for some set of years together, as we then kind of migrate towards an Elenestinib-driven opportunity set in the latter half of next decade. So at Quad AI, presented some bone data for Ayvakit. That's also been part of the kind of nuances of the Elenestinib trial that prospectively are measuring it. Do you expect Elenestinib to perform better on bone or some of these other you know more nuanced endpoints that you didn't have the first time around? Or is it merely just you're going to capture it for the first time on a prospective basis? That's a great question, Marc. And when we were working with the world experts on SM, trying to understand what is the next big thing for patients in a few years from now beyond improving the symptoms, which we do, it was really a consensus that it's a disease that manifests with symptoms because of a degeneration of mast cells, but it's a disease that really hit the organs, and you need, we need to heal the organs, and so it's really moving from improving symptoms to healing organs, and when you ask what is, in ISM, the first organ of concern, all experts talk about bone because of what I just said earlier. More than 50% of patients have bone disease, Osteopenia, Osteoporosis, fractures, and so the idea is really to get approved today, you have to use a validated TSS tool, which we do have. And that's how the primary endpoint of the study for HARBOR two is designed. But the study is powered in a way that we are able to prospectively compare Elenestinib versus Placebo in HARBOR Part II and seek for regulatory purposes, in other words, for labeling for that data, which we don't have. For Avapritinib, its you know we were learning about ISM. You know we captured some patients retrospectively who had some bone data because physicians sometimes capture, look at bone for these patients. But it was not embedded in the study in a way that is with that we can use as a company. So that's a big difference. We are also capturing in Elenestinib the prevention or reduction of serious anaphylactic reaction, which we described with AVA, but we did not capture prospectively on the study so we can hit the label. Obviously, the study is wide and broad. You have cohorts that are covering smoldering disease, cohorts that are covering post-TKI ISM patients. So it's probably, by far, from all that I have seen, the most comprehensive program in the development of a TKI in Systemic Mastocytosis. This is more of a Kate and Christy question. Just thinking through that ability to, over time, potentially transition the franchise to Elenestinib, the lifecycle there, are there examples of other therapies where the kind of primary differentiation is the endpoint you looked at, even if there are case reports out there and things like that that kind of show the first drug at least has some level of effect on that endpoint? Yeah. I mean, there's no kind of perfect analog here. But we certainly look at a range of different cases where we you see kind of some of these different dynamics playing out. Yeah. I mean, I think you know we've seen sort of management of a franchise at Alnylam. We've seen it at Vertex. I mean, there's many examples where you know you're not necessarily doing a direct head-to-head, but you're basically putting together a profile that you know the overall kind of benefit-risk is viewed to be you know really compelling based on the totality of the data. So in this case, you know we will be looking, obviously, at the same endpoint, right? So we will have data on the TSS, but we will have some of these other measures of you know clinical benefit beyond that. It's also worth noting you know we are looking at some additional cohorts within the study that I think will be informative to the overall clinical profile of Elenestinib. And we do believe that these additional endpoints, these more disease-modifying endpoints, are absolutely critical to achieving what we're trying to achieve with this franchise because this is like a few points difference on the TSS is not you know kind of clinically relevant. The TSS is really a regulatory tool. Physicians, in our experience, now at the table with thousands of them around the world, that's not a number they're hanging their hat on. It's really more about being able to say, hey, when you treat the underlying cause of disease, you can go beyond symptoms in terms of these long-term impacts on a patient's health and well-being. I In Prognostic, prognostic factors. I mean, we're hearing more and more about really, really young patients, both men and women, who have fractures. You know that's not a good place to be. And we're also understanding that physicians are finding even the little bit of data we have with Ayvakit on bone health motivating for that urgency to treat in these kind of younger, maybe less symptomatic patients as well. So that will continue to play out you know as we bring Elenestinib forward. OK. Maybe in the time we have left, we move to 808, where you showed healthy volunteer data earlier this year, and now are starting to open up some of the POC trials. Just can you walk through the process that you went through to choose those indications to go after because there's a number of different mast cell diseases you could go after? Yeah, absolutely. [audio distortion] And how to prioritize them? First, I mean, we are very happy with the data. We just reported, similar to J.P. Morgan, the data at Quad AI, a very wide therapeutic index for what looks like a very promising molecule. Our strategy, was given the quality of the molecule we have, is not to jump right away into registrational 2Bs and 3s. We know from a biology perspective, from what other molecules have derisked for wild-type KIT, that CSU is a derisked indication because the clinical data supports the inhibition of wild-type KIT. But then ASMA, allergic rhinitis, and allergic conjunctivitis, they are not derisked biologies. The hypothesis is strong. The science is strong. We just reported the preclinical data in asthma at Quad AI. But we want to really look at the proof of concept in small studies that will allow us to better understand the scope of the opportunity with 808 and then decide, when the data will be available to us, how to prioritize the development across all these indications. We're adding to these type II inflammation diseases, MCAS, and I think Christy talked a little bit about MCAS. MCAS is something that is very much interesting to us for two reasons. It's an area that really we understand we've been working in mast cell disorders. First of them is ISM. But I tend to say, it is a disease that looks like ISM without the D816V mutation. We have the tools to develop, to jumpstart the POC in this disease. We're going to take the opportunity of all these CIndU, CSU, AR, AC, asthma, and MCAS to also develop our dosing and scheduling and regimen strategy, you know titration to effect, starting loading and maintaining, exploring multiple doses. And the idea is to develop 808 as a future medicine that captures the maximum efficacy while preventing in patients the on-target adverse effect. Or if we see them very early on, is to navigate smoothly through them so that they are not impactful for the patients. and you started touching on kind of potential for things like induction maintenance. Is that baked into these POC trials? Or is the goal here to show the kind of gross effect on symptoms and then go into refining dose schedule and things like that? Given the number of studies for POCs that I mean they just shared, I think we're baking this into these studies to really look at different ways to give the drug. And then we'll be able to look at the totality of the data and see you know what makes the most sense in terms of giving the maximum efficacy while avoiding the on-target AEs. OK. And just given I know you haven't fully disclosed trial designs yet. But just given that you have designed them internally and what you know about the indication in terms of patient numbers and maybe how active they are at certain sites, just how should investors think about the likely order of data readouts across these trials? It's very early. I mean, we will guide at the right time. I mean, the studies will be starting all of these studies will be starting this year. I think some of them are blinded and placebo-controlled. Some of them are open label. I think the open label studies will allow us to share information as soon as we are able to do so. The others will have to wait until unblinding. So as we get closer and we see a few, you will see us starting a few of them, then we'll start giving you more color on guidance for the timeline. OK. And maybe starting with CSU, CIndU, where we do have fair amount of proof of concept already from the wider field. Just what does POC look like for you guys? Is it do you need to have a dose and schedule that matches the antibodies? Is that not the goal in terms of efficacy? I think our goal is to do, in terms of benefit-risk, you know better than what exists today in terms of data, and that's because of the flexibility that small molecules will give us with shorter half-life than antibodies, with the ability to titrate to effect, to start high in short time and then go low, or to explore a couple of different doses, and I think CIndU and CSU are great opportunities to look at these strategies that I was just describing. I would just say, I mean, I think the key there is benefit-risk, right? Because you can knock someone's disease down, but if they can't stay on the medicine and they it's just not tolerable for them in a way that that benefit is worth it, then you're not achieving your goal, and I think we've learned a lot at ISM on this. As I said, ISM is very much a poster child where the safety is incredibly important, and having a benefit to patients in the context of really strong safety keeps them on the drug, and we've seen great compliance, great durations. That's what we want to see for 808 in these disease states where there is a body of data, is that symptoms get controlled in a way that is beneficial and meaningful to patients with a medicine that they can continue to take for long you know for many years. OK. And then rhinitis, asthma strike me as maybe potentially different pricing paradigms and things like that than a CSU, some much less common disease. If POC is established across it, should we expect additional molecules to go in to kind of manage some of that from a lifecycle perspective? I mean, kind of maybe not specific to that. We always have backup programs to all of our key programs, and we will continue to have that for wild-type KIT, and honestly, we're exploring actually a number of really interesting mast cell targets in our discovery team, and so we will [lock well on] in that space and that will be you know interesting future conversations for us all to have. OK. Unfortunately, that's all the time we have. So we're going to have to cut it off there. But thanks, everyone, for joining in the audience as well as the team up here. Thank you.