As we head deeper into 2025. Great. Thank you. Thank you, Andres, and thank you to H.C. Wainwright for having us. Blueprint Medicines is a growing independent biotech company with a leadership position in mast cell biology that we are leveraging first to drive a really compelling commercial opportunity in a disease called systemic mastocytosis through the launch of AYVAKIT, which is our flagship medicine that was approved for indolent systemic mastocytosis about 18 months ago. We are in the middle of a compelling launch where we've been driving significant revenue growth. We achieved $479 million in revenue last year and have guided to $680-$710 million in revenue this year against what we see as an opportunity that will get AYVAKIT to $2 billion in revenue by 2030 and an overall peak opportunity across our franchise of $4 billion. We think the first value driver is really around our launch in systemic mastocytosis and continued commercial execution with AYVAKIT. We have a next-generation product for systemic mastocytosis, elenestinib, which we are also bringing forward and have just initiated a registration-enabling study called Harbor. We are bringing that forward to really expand and extend our franchise into the next decade and beyond. We will continue to deliver innovation in SM. Beyond that, we have leveraged our capability in mast cell biology and the experience that we have built over several years to develop BLU-808, which is an oral wild-type KIT inhibitor, which has the potential to address a really broad range of highly prevalent diseases that are driven by mast cells. BLU-808, we just reported healthy volunteer data at the beginning of this year where the profile really started to demonstrate our hypothesis, which was that we could develop a highly tunable, potent, selective oral wild-type KIT inhibitor where we could really tune dosing to be able to address symptoms and also manage on-target side effects. We are looking forward to continuing to bring BLU-808 forward. We have several proof-of-concept studies planned this year to better understand the profile of the therapy as well as the role that mast cells play in disease biology and several important allergic and inflammatory conditions. Of course, beyond BLU-808, we have a robust pipeline. I'm joined by Percy Carter, who's our CSO. We have a long track record of delivering scientific innovation through our discovery engine. We continue to invest in that innovation and look forward to bringing other potential therapies forward beyond 808. The last point I would make is that our successful launch of AYVAKIT, along with a really disciplined approach to capital allocation, has put us in a very, very strong financial position where our operating cash burn has been coming down substantially. We are really in a position where we control our own destiny in terms of being self-sustaining and able to advance our priorities forward based on the strong financial profile that we have. Great. Thank you for that great overview. Thank you. Starting with AYVAKIT, maybe one question on the U.S. market growth strategy. With prescriber-based breadth increasing, is the next phase of growth focused on expanding to new prescribers or deepening of utilization? How should investors be thinking about that opportunity there? Yes. I think there's substantial opportunity on both fronts. What we have seen through the launch of AYVAKIT is very steady growth in first breadth of prescribers. New prescribers coming on board, treating their first ISM patient, getting experience with the profile of AYVAKIT. This is on the backdrop of a rapidly expanding patient base and market opportunity where we've seen the number of diagnosed patients continue to grow at double-digit rates. The market is growing as we launch the drug. Prescribers are having more and more patients coming into their offices. Growing breadth is something that we think is going to continue to be important in the near term. We've seen growth both in hematology as well as, importantly, in allergy. Our initial strategy was very much focused on those two specialties, which tend to play an important role in managing indolent systemic mastocytosis. What we have seen in a very, I would say, consistent way is that with breadth then comes depth. Depth follows breadth. Once somebody has their first prescription, they tend to find more patients and prescribe more deeply within their practice. There are really two factors that drive that. One is increasing comfort with the profile, increasing comfort managing ISM, which leads to a widening lens on who an appropriate AYVAKIT patient is. We see prescribers looking within their existing pool of patients and going deeper in terms of who they initiate therapy with. We also see that, again, because more of these patients are being diagnosed and patients are finding their way to experienced providers, that patient pools are broadening within healthcare providers who have experience treating ISM. I would expect both breadth and depth to continue to grow. One important strategy for us as we go forward is, in addition to continuing to drive that growth in breadth and depth within allergy, particularly, as well as hematology, we are increasingly seeing other specialists who see these patients and manage them expressing an interest in prescribing. Dermatology is an example that we've used recently. We've engaged with that specialty much more significantly over the past year. We're expanding our field footprint this year to enable us to go even deeper there. They tend to play a role diagnosing these patients and have expressed interest in managing. We think that's a really compelling opportunity for us to continue to drive growth over the long term. Great. Very helpful. Regarding the experience you have garnered in the United States with the successful launch in both of these indications, how should investors be thinking about ex-US growth? How can you leverage what you've learned here in the United States to really expand that global footprint in the years to come? Yeah. We're continuing to grow the footprint of AYVAKIT and ISM globally. I do think our international expansion is an important driver of top-line revenue growth as we continue to go forward. Right now, AYVAKIT is approved and reimbursed, obviously, in the United States and then Germany, where we have reimbursement in ISM. We have reimbursement in advanced SM and a number of other markets that are still executing launches outside the U.S. in advanced SM. ISM, we expect to have additional markets coming online this year, mostly in Western Europe, some of the other major EU markets as we work through pricing and reimbursement negotiations. The market dynamics obviously vary from market to market, but there are some things that are pretty consistent. The epidemiology looks similar as we think about Europe versus the United States. Patient opportunity as you normalize for the population looks similar and is significant outside the U.S. Treatment approaches are more similar than different. There is a lot of our learning in the United States that we can leverage as we launch outside the U.S. Our international business in 2024 contributed roughly was sort of in that 10%-15% of top-line revenue depending on the quarter. As we think about this year, I would expect it to continue to sort of be in that range. We are growing revenue globally. We are growing it in the U.S. Then outside the U.S., we expect to see additional growth as well. Very helpful. One question on competitive positioning and the future differentiation. As new therapies enter the SM market, could you highlight for investors how AYVAKIT's, how are you planning on sustaining AYVAKIT's leadership position in this market? What are the key drivers for maintaining that long-term growth? Yes. We are at the very beginning stages of penetrating the ISM opportunity. We have still a minority of patients being treated. As I mentioned, the market itself is growing underneath the launch, which is in some ways what you would hope and expect to see with a rare disease like this where the advent of effective therapy catalyzes diagnosis and treatment. Our focus and objective this year, and I suspect that will be the case for several years to come, is to continue to catalyze treatment with disease-modifying therapy. The biggest competition to AYVAKIT is symptom-directed therapy only. That is really the discussion that we're having, the benefits of treating with a disease-modifying therapy. AYVAKIT has a profile that sets an incredibly high bar. We had very compelling efficacy in Pioneer. We've seen that efficacy sustained as we've followed patients out now over the long term. We just presented data recently at QuAD AI with a median of three years of follow-up with some patients significantly longer than that, where we're seeing sustained efficacy. What's really, really important in this market is safety and being able to see very consistent safety tolerability, no adverse events coming up for the first time that are different. The profile has very much held. As we've talked to particularly community allergists who are seeing the majority of these patients, that is such an important driver. We think we're really well-positioned there. When patients start on AYVAKIT, we're seeing very positive trends in terms of staying on therapy. Also, patients are very, very compliant. Again, I think the bar we're setting is high. I think it's going to take the differentiated strategy that we're bringing forward with elenestinib, frankly, to challenge AYVAKIT's sort of position on the market. Absolutely. That's a perfect segue to my next question. Wanted to highlight to investors, surprise, surprise, it's not all about AYVAKIT. The company has a robust pipeline. Moving on to maybe elenestinib, which is the next-generation KIT inhibitor. It would be great to set a baseline about some of the critical differences between elenestinib and AYVAKIT for investors in terms of efficacy and safety profiles that we should expect and maybe even a comment or two on patient selection, how certain populations might be more amenable here. Great. Happy to start. Percy, may you want to chime in on this one as well? From a chemical matter perspective, elenestinib is also a very highly potent selective KIT D816V inhibitor. We are starting with raw material that I think gives us a lot of optionality to be able to develop this in the right way to impact the disease. As we have developed AYVAKIT, learned a lot about ISM, we really challenged ourselves to think about how to develop elenestinib in a way that is differentiated. As I said before, the bar that AYVAKIT's setting from a product profile perspective is a very high bar. We need to think about innovation in terms of how to impact the disease. We know a lot more about ISM now than we did when we first started Pioneer. The way that we're thinking about development for elenestinib is to really shift the narrative from addressing symptoms, which is incredibly important. Of course, these patients need a therapy that can effectively address symptoms, but also modify the longer-term course of the disease. What we know is that ISM can have really significant impact on patient morbidity, in some cases, mortality over time. Some of the endpoints that we're exploring with Harbor are really providing a solid base of evidence around the ability to impact that over the long term. Bone health is one aspect of this disease that has become really, really important for providers and patients. 40%-60% of ISM patients, if not more, may have osteoporosis, osteopenia. These are often young patients. You hear stories of patients presenting with fractures where maybe the disease has not even been identified, and that can be the presenting symptom. Bone health in some ways is a marker for the impact that ISM can have really on patients' long-term health and wellness. Looking at the ability to impact that, we think, is going to be important. We have some data suggesting even AYVAKIT does impact bone. We presented that at QuAD AI, but we will be looking at this in a much more rigorous way with elenestinib again to really speak to that disease modification profile. We are looking at other endpoints around allergic reactions, et cetera. It is really about a differentiated clinical profile that we will bring forward versus redoing the Pioneer study and kind of coming out with a data set that we ultimately do not think is going to be enough to really differentiate over the long term. Great. Maybe digging into a little bit more of the nuance in elenestinib, could you maybe from a mechanistic perspective, maybe overview what's really driving that potential for improving bone turnover and anaphylaxis reduction compared to AYVAKIT? Yeah. That may be a good one for Percy. You want to speak too? Sure. Yeah. What I would highlight with the molecule is the excellent potency, very high selectivity, and excellent distribution properties, which we think give it the sort of fundamental characteristics in the patient context to cover the target safely and to allow us to see the effects that we believe will be driven by inhibiting this target. As Christina said at QuAD AI, with AYVAKIT, we've been able to see sort of initial views, for example, in these new endpoints that we're going to be studying now more rigorously in this trial. We are basically building on that foundational strength we have with AYVAKIT with a molecule that we think has the characteristics we need to demonstrate that in humans. Very helpful. One hypothetical for investors who are really projecting out the potential of elenestinib. If elenestinib does secure a broader label, do you expect it to primarily capture new patients, or will it drive switching from AYVAKIT? Can you highlight some of those dynamics that you're thinking about in this very early-stage program? Of course. As you would expect, as we get closer to actually having data available from Harbor, an approval launch, I'm sure we will be talking about all of these dynamics in a lot more detail. At a high level, our strategy allows us to have two options on the market for some period of time. We know that there's going to be a large base of patients on AYVAKIT who are doing really well, which is great. Elenestinib, I think, could be another option, certainly for new patients starting therapy. Over time, you may see migration of some of the business to AYVAKIT, really even just based on new patients coming in. Again, we'll be growing the market over this period of time. We talk about $2 billion for AYVAKIT in 2030. That, by my back-of-the-envelope math, is maybe 6,000 patients on therapy in the U.S. If you think about 25,000 patients diagnosed today, plus, we're talking about a minority of patients being treated with AYVAKIT even at that level. I think it will be continuing to grow the market, having new patients come on. It'll be another option, obviously, for patients who are on therapy as well. We will have, I think, a good amount of time where you'd have both options on the market together. Very well. Very helpful. Thank you for that clarity there. Moving on to BLU-808, Blueprint's wild-type KIT inhibitor for allergic and inflammatory diseases. It would be great to just get an overview of some of the insights you've generated from the phase one study that are shaping the dose selection and proof-of-concept trials and just an overall overview of 808 before we get into more of the nuances. Sure. I'll let Percy speak to this. I mean, at a very high level, what I'll just say is that as we set out to execute that phase one study, we obviously had sort of almost a set of attributes we were hoping to see from the molecule. In many ways, that data set exceeded what we were hoping to see. That initial phase one study, obviously, we need to continue to move it forward and look at further proof of concept studies in patients. Do you want to talk more about the profile? Yeah. No, that's great. We can just start out right there, actually, with Christy's comments. When we bring forward a program into the clinic, we have a target product profile. What we want the compound to do is to sort of achieve a certain set of results clinically. As Christy just said, I think BLU-808, really, the actual data sort of met all those criteria we had set out. What were we looking for specifically? I would call attention specifically to three things. The first was, of course, the fundamental pharmacokinetic profile. That was a crucial attribute in our optimization scheme. Because, as you know, in the context of wild-type KIT, given that there will be target-mediated impacts, we wanted to have as close as flat a pharmacokinetic profile as possible with once-daily oral dosing. The advantage that gives us is control over dose, dose regimen as we move forward into these clinical POCs. That just gives us a ton of flexibility in terms of how we conduct those trials and what doses we assess. That is exactly the PK profile that we showed at J.P. Morgan and then subsequently at QuAD AI. The second thing, of course, we were looking to see is to confirm our estimates of the potency of the molecule right on the target. Again, our pharmacodynamic readouts showed that unambiguously in a fashion that was well-aligned with exposure. Confirming what we had seen in in vivo preclinical studies and in vitro preclinical studies, that profile was borne out in human volunteers. The third aspect, of course, and a fundamental underpinning of any phase one study is to ensure that the tolerability of the molecule is where we expect it to be. This is something we spent a lot of time doing. I apologize for being late. In fact, the conversation we were just having was a very different program, but on this crucial topic. We were delighted to see that the tolerability profile of 808 was what we hoped for in volunteers, giving us the confidence to advance to patient studies for proof of concept. Very helpful and a perfect lead to my next question. My next question concerns with competitive positioning in the allergy market. With the caveat of all these studies are early-stage and cross-trial comparisons, you need to be very cautious. Can you help us understand how BLU-808 differentiates from other biologics and small molecules in the allergy and inflammation space to help us maybe sort of navigate some of those pitfalls of cross-trial comparisons at such an early stage? Sure. Maybe I'll start generally. We can definitely go into more specifics here. I think if you think about BLU-808, it really is, in my mind, an example of when people say pipeline in a product or pipeline in a pill, this is what we're dealing with, we think, here, where you've got a mechanism that could really apply quite broadly across a number of allergic and inflammatory diseases. We are learning more about the role of KIT as really the master control switch of the mast cell and sort of what the role of mast cells is in the biology of a number of these diseases. Part of our strategy with our proof-of-concept studies is to both learn more about the profile of 808, but also to learn more about the biology of the disease, particularly indications where we are still learning. I think about chronic urticaria as one where there is a lot of data already to suggest that KIT plays clearly an important role. Mast cells are obviously an important driver of disease there. We have data from antibodies targeting KIT that are further ahead. I think when we are comparing an oral agent versus maybe some of the biologics, there are obvious benefits to, first of all, having an oral therapy for some of these indications where patients are taking therapy chronically. Also importantly, I think the ability to tune is different with an oral. Percy can talk more about this. With a biologic, you are much more sort of in an on-or-off type of situation where we think with an oral small molecule, we can tune the profile. If you expand the lens beyond KIT and mast cells, obviously, there are other approaches targeting a number of these diseases. I think we'll see as the data plays out exactly how profiles differ. What you often see in large immunology markets is that some patients may respond differently to different mechanisms of action. We're dealing with very large patient populations, certainly multiple orders of magnitude what we're talking about with ISM. The commercial opportunity here is pretty compelling. I think there's going to be room for multiple approaches, particularly if you have a highly effective oral therapy that does have that balance of benefit-risk. I don't know if you want to talk more about the sort of KIT space specifically. No, if you'd like to add anything, that'd be great. I think Christy covered it very well. I mean, I think in brief, the only thing I'll add is just if we come back to a biologic versus a small molecule, we have the ability to explore three different sort of fundamental hypotheses about the relationship between exposure and benefit to patient. And for us, we can do that with a dose that allows us to cover the pharmacological activity of KIT, but not to the extent that would lead to the death of mast cells through apoptosis. We could alternatively go to a level of exposure that the biologics have achieved and, in fact, induce apoptosis of mast cells. We can do either of those. We can explore a unique hypothesis, or we could do sort of an oral biologic type approach if you wanted. The third thing we can do is to take a page out of sort of a more nuanced view here. You can imagine sort of an approach where we first initially explore a high dose or sort of a saturating dose with a molecule and then reduce that dose to spare the patient the target-mediated effects while benefiting from the induction of the mast cell killing. We can explore two unique hypotheses in addition to the sort of oral biologic profile. Great. Very helpful. In the absence of time, my last question. Beyond chronic urticaria, which is already in the crosshairs for 808, how should we be thinking about additional indications which offer kind of the best opportunity for demonstrating the breadth and the possibility of wild-type KIT inhibition moving forward? Yeah. We have four proof-of-concept studies that we've initially planned in the short term. We talked about urticaria. We're looking at allergic rhinitis and allergic conjunctivitis. We're looking at asthma. MCAS is a really interesting opportunity that I think Blueprint is uniquely positioned to pursue and has benefits across our portfolio, both our SM portfolio as well as potentially a new opportunity for 808. There are a number of additional indications beyond that where we think mast cells can play an important role. I'll give a little plug if anyone hasn't gone back. We did a few seminars last year where we explored some of the biology and potential indication opportunities. Those are available on our website if anybody's interested. We are planning another in the first half of this year. What we hope to do with the proof of concept data, as I said, is to get an initial read both on the profile as well as understanding biology and some of these indications. Then we'll have more to say in terms of how do we think about strategically bringing 808 forward. What indications do we prioritize? What do we do in parallel versus what do you do in sequence? There is obviously a lot of opportunity here for us to think about exploring. Great. No, this was very helpful. Thank you very much. That's all the time we have today. Obviously, we could continue talking for another couple of hours here. I really appreciate the insight that the team has given us. I really like to thank Percy, Christina, and again, Cassie for joining us today. Really looking forward to a great year for you guys and looking forward to future updates. Thank you so much. Thanks for having us. Thank you.