Good afternoon, everyone. Thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Goldman, a biotech analyst, and it's my pleasure to introduce the team from Blueprint Medicines. To my immediate left is Christy Rossi, Chief Operating Officer, and on the far left is Fouad Namouni, President of R&D. Just as a reminder, our format for today is a fireside chat, but if anyone has a question, please feel free to raise your hand, and we'll add your question into the discussion. Before we get started, I just need to read a quick disclaimer. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. And with that, Christy and Fouad, thanks so much for joining us, and maybe I'll just hand it over to Christy real quick to do some introductory comments, and then we can get into the Q&A. Sure. First of all, thanks to Mike and to the Morgan Stanley team for having us. It's a pleasure to be here. Looking forward to the Q&A, but maybe just to sort of set the stage, Blueprint Medicines, for those who may not be quite as familiar with the story, is at an incredible point of growth and value creation for the company, and really focused on three key pillars this year. The first is our ongoing launch of Ayvakit in indolent systemic mastocytosis, and I'm sure we'll spend some time talking about that opportunity. It is, I think, one of the most exciting rare disease launches happening in the industry and one where we've seen incredibly strong growth and a peak of north of $2 billion. The second is the ongoing growth in our pipeline and portfolio, really centered around the capability and infrastructure that we've built in mast cell disorder. So anchored by our experience in Ayvakit, also with our next-generation asset, elenestinib, and then importantly, BLU-808, which is a wild-type KIT inhibitor, that we think has very broad potential in a number of very large patient populations, suffering from allergic and inflammatory disorders. We just moved that asset into the clinic, so we're very excited to continue to generate healthy volunteer data and then move that forward into patients. And finally, really a position of financial strength that is driven by our prioritization of key areas of investment. Again, mast cell disorders, our continued investment in our R&D engine, a very strong cash position coming out of the last quarter, and very much in a position to continue to inflect growth and value. All right. Well, great. Thanks for that introduction, Christy, and maybe we can start with the Ayvakit launch. Obviously, a lot of interest there. You've had some quite a bit of success. You're a little over a year into the launch now. So maybe just to start, if you could talk about what's driven your success so far. Yeah. You know, I would say the keys to the success of this launch are, first, systemic mastocytosis is one of the more compelling commercial opportunities that I've had the privilege to work on in my career. It is a disease that I think many of us, frankly, probably were not familiar with or hadn't heard of before, you know, avapritinib was really being developed in this space. It's a prevalent rare disease, so one where, you know, originally we thought there were about thirty-two thousand patients in the U.S. Now it seems like the estimates are much larger than that. So more common than you might think. Patients suffering from a chronic lifelong illness that can be very, very debilitating and have long-term impact because essentially, they have mutated cells in their bodies that they're living with over time. These patients have had really nothing available to treat their disease until now, and now we have really the second pillar of what I would say is the successes, is the profile of avapritinib. You know, a very, you know, compelling therapy that addresses the underlying driver of the disease. We saw powerful efficacy across every measure in our PIONEER study, a very well-tolerated safety profile that looked very similar to placebo, and supports chronic long-term treatment in a once-daily pill. And so the combination of a high unmet need, a significant patient population, and a therapy that really provides transformational benefit in those patients, it's you know, that is a recipe, I think, for really having very substantial impact. Yeah. And maybe you can talk about some of the feedback you've gotten from patients and their experiences on treatment. Yeah. You know, I think one of the most interesting things about SM is that it can be a heterogeneous disease, and patients often are searching for a long time to get to a diagnosis, to really understand, you know, why they've been living with the constellation of symptoms that they have been living with. You know, we know that Ayvakit has a very powerful clinical benefit. We know that from the PIONEER study, where we saw impact on objective measures of disease, on clinical outcomes, and on quality of life. I think the most compelling feedback that I have heard from patients is the benefits that they see from therapy that are not captured from the clinical data. Many times, a sentiment that we hear over and over again is that patients don't realize how sick they were even until they're on therapy and really understand the impact that Ayvakit can have, on their day-to-day lives in ways that, frankly, are not even captured by something like a total symptom score. Yep. Makes sense. Maybe just talk about some of the metrics you provide on sort of every earnings call and kind of what are the key ones and how have those sort of evolved, you know, through the launch? Yeah, so we've been obviously focused. I mean, the number that everybody's looking at, I think, quarter on quarter is revenue, right? So we've seen really compelling quarterly revenue growth. We have now raised guidance twice on the year. We started with a guide of $360 million-$390 million for sales for this year, and are now at $435 million-$450 million. So it's been really nice to see revenue really continue to perform. But it's really what's underneath that, right, that I think drives our conviction in the long-term trajectory of the brand, and again, in that peak revenue opportunity. We've talked about the large patient pool that's out there and the growth in diagnosed patients that we have seen, frankly, even before Ayvakit was approved, but certainly with the approval, we've seen that continue. So we have a large patient population that we are just beginning to penetrate into. At J.P. Morgan last year, we talked about 21,000 diagnosed patients in the United States. That number continues to grow, so we have you know a very significant patient opportunity. We're seeing growing breadth and depth of physician prescribing. So the kinetics of prescribing in this disease are, we're continuing to see first-time prescribers come on board, treat their first patient, and on the back of having a positive outcome and a positive experience with those patients, find additional patients in their practice, and so we see deepening. And so we've continued to see that, and I you know expect that that will continue, and that's really where we can start to see you know growth off of a very strong foundation in this launch. We talked about duration of therapy as being, you know, a really positive driver, where patients are having good experiences, and we expect staying on for chronic durations of treatment. We've seen that even in advanced SM, and we expect ISM durations to be even longer. We've seen strong patient compliance. And the last thing I would highlight is access. So, you know, reimbursement, the ability to get therapy for patients has been very, very smooth. We've had really outstanding coverage and, you know, are able to get really any appropriate patient started on therapy quickly. You mentioned duration of time on treatment. I don't know if you can share this, but just the average duration so far, and where that could go in the future. Yeah. So we don't have an average yet, right? Because we've been on the market, you know, for over a year, but we expect our medians to be well beyond that. As I said, in advanced SM, when we first launched there, we talked about a projected commercial duration of therapy of around eighteen months, and that's now grown to more than two years. Our trends for indolent SM suggest that our duration should be well beyond that, so we would expect a multi-year duration of therapy. Obviously, until we're actually on the market commercially for longer we'll have better insight into that. But as we look at patient trends early on, it's very consistent with a long duration of therapy. So again, that's consistent also with what we saw in the PIONEER study, where, you know, we had a very good, you know, duration on treatment, in the study, and good rollover into the extension portion of that study. Yep. You also talked about diagnosis rates and sort of the addressable patient pool continuing to expand, and maybe it's even bigger than, than you think it is. I guess, what types of things can you do to help drive that as well? This is an area that we have been focused on at Blueprint for quite some time, and certainly predating the approval of Ayvakit in ISM. Systemic mastocytosis is a disease where, you know, disease awareness, education, not only of hematologists, but particularly of allergists, who are really seeing a lot of these patients and managing them, making sure they know what to look for. And then once they have a patient that they suspect may have SM, we've tried to make the process of actually getting to a diagnosis smoother. Certainly, the availability of high-sensitivity testing for patients to pick up the KIT D816V mutation is one, you know, avenue that certainly makes that a bit easier for physicians. We're also very focused on patient education. You know, this is a very motivated, active patient population. There's advocacy groups, like Mastocytosis Society, which has grown really exponentially in terms of the number of patients that are a part of that. And so patients, we want them to be empowered to sort of self-advocate, recognize their symptoms, and then seek a diagnosis, and so we've certainly been focused there as well. Gotcha. And can you talk about the mix of, you know, sort of moderate to severe patients? I think in the past you've suggested it's been more on maybe the severe spectrum, but are you starting to gain more traction, you know, for maybe less severe patients? Yeah, I've seen that, and Fouad can probably comment on this as well from his discussion with physicians. You know, we first, I think it's important to remember that the indication for Ayvakit is very broad, right? It's really any patient with ISM is a potential Ayvakit patient. Certainly, when we launched, we expected that our initial uptake was going to be in what we consider to be uncontrolled patients or more symptomatic, moderate to severe patients. We estimated that was about 50% of the diagnosed patient population in the U.S. But again, any patient can be treated with Ayvakit. Importantly, and, and Fouad may want to talk about this a bit more, we've had a lot of research and collaboration with the community over the last few years that really shows that this is a long-term disease process, which may have long-term consequences. So beyond treating symptoms, you know, there. This is a disease that can potentially progress in patients, and so there is benefit in really addressing the underlying driver of the disease. We've seen physicians widen their aperture in terms of who they think about treating with experience. I was just talking in a one-on-one recently about being in the field a week ago and talking to somebody about treating a patient who was a younger man whose primary symptom was skin. You know, despite that being really the primary bothersome symptom for that patient, it was bothersome enough that, you know, the physician wanted to treat with Ayvakit. He already had a lot of experience, and so he was very comfortable using the drug in that patient. And if you want to. The only thing I would add, Christy, is, for a long period of time, this disease was seen as a symptomatic allergic disease, skin, you know, rash some GI symptoms, some brain fog, and so on. There was really not a very good understanding by the patient community, not by the physician. The underlying root cause is a KIT-mutated mast cell. It is a neoplasm. These mast cells in patient ISM proliferate at a high rate and migrate to organs where they're not supposed to be, like bone marrow, for example. And that leads to the generation of good amount of inflammation and so on. So there is an underlying disease, no matter how controlled are the symptom or no matter how mild are the symptom are, that is over time and over the years could become a problem. Last year at ASH, Dr. Sudipto Mukherjee from Cleveland Clinic reported from an analysis he did on claims data, that the rate of progression from ISM to ASM, which is basically a leukemia state of the disease, was around, I think, 18 or 20%. It is a really serious disease, no matter how mild or, you know, moderate the symptom people see on the outside, that needs some really root-cause treatments. Yep. And Christy, you've mentioned sort of what the guidance... You know, you've raised guidance twice this year. I guess, any additional comments on recent trends, just given if you kind of do the math on guidance, it seems like there might be a little bit of a slowing in the second half. You know, any drivers of that or how to think about that? Yeah. So, you know, when we issue guidance, our goal is to, you know, do our best to really help frame what we think reasonable expectations are. That's always been the goal. We have been in a position now where we've, you know, we've beat and raised twice. That was largely because as we thought about framing guidance for the year, we've always been focused on a few key variables that are sort of underpinning performance, right? And I talked about a lot of those already. We're looking at new patient starts, which have been very strong and steady. We're looking at trends around duration of therapy, which have been really good. Patient compliance, free drug versus commercial, which is obviously a very important factor because that impacts top line in a very direct way. And then, you know, performance of our international business as it continues to launch. Yep. And we're actually joined at this meeting by our head of international, who's with us as well, has been talking about that in some of our one-on-ones, so as we thought about the second half of the year, you know, first half, we really saw incredible strength across really all of those variables, which is great. In particular, I would say perhaps to the upside and a bit unexpected, the free commercial mix came down in ISM much more rapidly than what we had thought when we started the year, and so we saw a lot of growth that came from that success, really, in being able to get patients onto paid therapy, where previously they may not have been. As we think about the second half of the year, you know, we're continuing to look at those same variables. We expect strong and steady growth in patient starts. We expect to continue to see good trends in duration of therapy. We are not expecting to see favorability in free goods, right? We think we've probably gotten that to a place where it's about as good as it's gonna be. We may sort of bounce around an average there, so we have to think about puts and takes on that. The international business is continuing to perform, but we'll have some pricing impact coming in as we start to negotiate prices in ISM that we need to account for. And then I mentioned on the call, you know, really wanting to just make sure we are accounting for potential seasonal impacts. We don't know, right? Mm-hmm. We have not been through a full normal calendar year of this launch. It's still very early days. We know last year in Q4 that we saw some seasonal impacts of patients starting therapy around holidays. It's something you often see in a chronic market. So, you know, wanna just be prepared that we could see that again during holiday vacation times. Sometimes you also see that impact on compliance. So, you know, really factoring in all those variables, and then again, we're honing in now on two quarters of performance to get to the end of the year, and so, trying to kind of inform what we think is reasonable as we think about the remainder of the year. The bottom line message is, you know, the growth this year has been incredible. I think the launch is in a really strong place. You know, we have, you know, more conviction, I would say, standing here today than we ever have had in terms of what that peak opportunity looks like. And if you look at how this launch is evolving from a revenue growth perspective, we're in a really great spot. Yep. Makes sense. You mentioned just the European launch, and that's going well. Maybe just expand on that a little bit. Yeah But maybe also talk about some of the key differences between Europe and the U.S. market. Yeah. You know, it's been great to see the European launch. I mean, first of all, Europe has been launching even in an advanced ISM, right? So, you know, the biggest difference in Europe versus the U.S., frankly, is access, right? That is, you know, a difference. It tends to be much more gating to unlocking the commercial opportunity as you negotiate pricing and reimbursement, and so we're still seeing advanced ISM launches really kind of come online in some of the key markets there. Germany is the only market that's commercially launched in ISM. It's been going really, really well and looking very similar to the U.S. in terms of, you know, underlying trends and demand, patients being treated, et cetera. We will, as I said, have to negotiate new pricing around ISM. Anytime you add an indication, you need to renegotiate prices. Unfortunately, they only move in one direction, which is down, but, you know, we'll go through that process, and we're certainly on very strong footing, I think, based on the very compelling clinical data that we have in the PIONEER data set. So more to come there, but I think Europe will continue to be, and international, in general, will be an important source of growth for the brand as we continue to capture that peak. Makes sense. Maybe just talk also about, you know, potential competitor, you know, your thoughts on how you're positioned right now. Yeah, I mean, I think, one of the most exciting aspects of this opportunity is that we are building a market for the first time, and Ayvakit is really the first therapy, to address, the underlying cause of the disease in these patients. You know, I expect we will see competition at some point. Any attractive market opportunity, we always will see that, right? What that will look like, I think, is still a bit of a question in terms of what, you know, what competitors may ultimately get to market in SM. We'll see. Regardless of what that may be, what we know is that Ayvakit is building a very strong leadership position in SM. We're continuing to add patients on therapy with every passing, you know, month and quarter. Patients are staying on therapy. Their experiences are very, very positive. So I think, you know, the profile with Ayvakit is gonna be very, very difficult to top. And any therapy coming on is gonna have to have a pretty compelling value proposition because you're either gonna be competing for new patient starts who haven't been treated with Ayvakit at that point, or you're gonna be asking a patient who's doing really well to switch. Yep. Gotcha. And you mentioned, you know, peak sales, you're pretty confident in two billion plus. I don't know if you can sort of give us a sense of the sort of the breakdown between ASM and ISM and kind of what you're seeing right now in ASM in terms of level of growth or is that sort of flattening out? Yeah, it's interesting. I mean, we honestly model the SM opportunity as an SM opportunity, right? I mean, I really... This disease, I know we sort of built it through indications, but it is very much a spectrum of disease where you have patients kind of arrayed along that continuum. Again, that's one of the benefits of the profile of Ayvakit, where we have multiple dose strengths available and you know a lot of flexibility for providers to be able to customize clinically based on the needs of the patient. We know that ISM is the majority of the value, right? It's you know 95% of patients would be ISM patients. Certainly, duration of therapy in those patients is going to be extended. So, you know, the majority of the opportunity and the majority of that peak is certainly gonna come from, you know, ISM if you wanted to try to break it out. But again, there's a lot of synergy, and I think the bottom line is we are growing in SM across the board. We've put out data about new patient starts, you know, sort of 70%-75% of new starts coming at the 25-milligram dose, which means that we do see, you know, we continue to see patients coming on at higher doses, and a lot of those patients may have more advanced disease. Yep. Okay. Maybe we can move on to Elenestinib. You know, kind of related here, but maybe slightly different. So maybe remind us the key differences and kind of your thoughts on, you know, how that, how that fits in. I'll start, and maybe Fouad can join. You know, Elenestinib, again, is our next generation KIT D816V inhibitor. It's something we do at Blueprint across any target that we think is high value, really making sure we have next generation molecules that can go after that opportunity. From a chemotype perspective, Elenestinib is non-brain penetrant, but is a very potent selective KIT D816V inhibitor. We've shown some initial data that show that it is active, has a very favorable benefit-risk profile in ISM at a you know variety of doses. And so, we are planning on bringing it forward, really to differentiate and develop a data set that shows the clinical impact in ISM based on now what we understand about this disease and also what we think the bar is becoming in terms of really showing clinical impact, not just in symptoms, but in other measures of disease as well. How do you see it fitting relative to Ayvakit? Is there a specific patient population you think could be more suited for or? I think the way to think about the development strategy is really to answer questions that Ayvakit has not answered, given the way back in the day we designed the study, mostly focusing on improving symptoms. I really think there are parts of the disease that are important to study and answer for patients, and that could be impactful on really taking the practice to the next level. We said by the end of this year, around the end of this year, we will share our strategy of how the development of Elenestinib is very differentiated, in a robust way from the development of avapritinib, and thinking about what would be the population of patients of 2029 or 2028 looking for in terms of improvement of this very complex disease, where there is actually a neoproliferative process happening in the body. These are important questions that we will answer, and we'll answer the impact of that neoproliferation on patients with ISM. Yeah. I don't know if you can talk about it, but just like timelines, you know, when could we see sort of, I think you're gonna start another study, and then you might have some data roughly? I think by year-end, we will be initiating the registrational work, and we will share the overall strategy, as we, you know, mentioned earlier in this year. Gotcha. Maybe just talk about the broader strategy. Obviously, SM is an important pillar there. You know, you've made some adjustments recently as well in terms of where your focus is. So maybe just remind us, you know, how that bigger picture strategy looks. Yeah, absolutely. So at a company level, you know, we've been very clear that, particularly for our later stage portfolio, we really believe that we have built capability and scale in mast cell disorders that we can leverage in a very positive way. And so Ayvakit, you know, the success of Ayvakit is an opportunity for us, frankly, to really build on that. We're doing that with Elenestinib, and then again with BLU-808, which, you know, enables us to go quite a bit broader, frankly, than Ayvakit does, but has good overlap with, you know, a lot of the relationships and sort of scientific insights that we're generating from being present in allergy and, you know, building that capability. So that is really where our focus is for our sort of later-stage portfolio: continue to have a really robust discovery engine that is driving innovation both in allergy and inflammation, as well as in oncology. We have, you know, a platform now that has broadened out from kinases. We have, you know, a really, I think, exciting effort going on in targeted protein degradation under Percy Carter's leadership. So really, we'll continue to drive... I mean, our goal is to drive and bring forward innovation to patients that can impact large patient populations and that, you know, we can really bring forward in a way that's gonna deliver value. Yep. Maybe we can dig into BLU-808 a little bit, your wild-type KIT inhibitor. You know, maybe just give us a little bit of background on that program and maybe how it's, how it's differentiated. Yeah. I mean, let me start by just maybe going back to the mast cell as an immune cell. We have, I mean, as a scientific community, always known and believe that the mast cell as an immune cell is a major player in allergic inflammation or type two inflammation. And that has been really something that people have been looking at as the ultimate effector cell of the allergy and thinking about how to target and tackle this immune cell in type two inflammation, which has not been historically an easy thing. It turns out that at Blueprint, for the last many, many years, we have been working in the field of mast cell, and we developed a good understanding of c-KIT as a key gene for mast cell activation, release of mediators, and also survival. And that's where we're coming from, saying there are a lot of treatments in this type of inflammation, but none of which target the ultimate effector cell, the mast cell. So that's how the work started three years ago, making a wild-type KIT inhibitor, 808. And we really believe that there are a few targets you can see around the mast cells, but we believe the ultimate target, if you master the way to use it and to give it, is KIT, because you can modulate the activity, you can modulate the release of mediators, and you can go all the way to full depletion and killing the mast cell. And that's something that Blueprint is the leading house in making and studying this. Eight oh eight was developed as a small molecule targeting wild-type KIT with a high selectivity profile, very very potent molecule, and the preclinical data has actually been very very supportive of us moving into the clinic. Where we are today, we are in the midst of the SAD/MAD healthy volunteer phase I, that we can say we're tracking for data availability sometime early next year. We'll guide when we get closer to the data available from this study. And we see that, Mike, as an important set of data. We know today from, you know, other, you know, molecules that wild type KIT and the mast cell is a great target in some diseases, like, for example, chronic urticaria, whether it's spontaneous or cold-induced urticaria. So, the data that we will report from the healthy volunteer will be important because it will be the data that will not only inflect on what we do in terms of a key inflection point, but also increase the probability of technical success as the POC for wild-type KIT in chronic urticaria has already been shown by other modalities. Yep. We'll go beyond that, and we will study in some other type two inflammation a POC in, you know, the phase 1c, maybe 2, and we will be able at the right time, through this, you know, small POC that we will probably run in parallel, look at what is the impact on the population, how many populations of patients and diseases we can impact, and what that means for BLU-808 development. Yep. From there, obviously, we go through our leading indication. We continue to lead with the chronic urticaria as our lead indication. I think from a POC, once we pass the healthy volunteer data, I think the probability of technical success should be pretty high there. Yeah. We go from there. Any concerns on safety? I know there's been others who've hit some sort of tolerability issues and had to move to a second-gen program. Any concerns there at all? I think at Blueprint Medicines, we really have been studying KIT inhibition for probably more than eleven years now. You know, we make thousands of molecules or we study, you know, the blockade of KIT. We focused on the D816V mutated KIT for AVA and Elenestinib. We have been studying a number of molecules to really come up with the best profile that we can think of in terms of highly selective, very potent wild-type KIT inhibitor that will give us really a good window and a good therapeutic index, so we can tackle a variety of diseases, and we can combine with a variety of agents in the future. According to our preclinical data, we don't expect that we will s ee a safety concern that has been reported by other small molecules. But the study is up and running, and I think we'll know more early next year. Yep, makes sense. And when you share some of that initial data, what are some of the key data points? Obviously, safety, probably PK, any, any sort of biomarkers you'll be looking at that could be informative? Yeah. Safety obviously is key in this study. Pharmacology, I think we need to see early with PK profile as a compound we can dose in a variety of ways, and we can develop alone or in combination with other agents. Pharmacodynamic marker, showing us that we are not only hitting the mast cell, but we are having an effect that we would like to see on the mast cell. We talked about the tryptase as the quote, unquote, "obvious," and simplest PD marker. But at Blueprint Medicines, we are looking at other markers that I think we will share at the right moment when we report the data. Yep. Just on tryptase, is there any specific, you know, threshold of reduction that sort of can, you know, give you more confidence that you can have a translation into, like, a clinical effect, or is that unclear? I think tryptase is a marker that is telling us that we are hitting the mast cell, we're hitting the target. I think I would expect to see, you know, the decrease of tryptase with increase in exposure of dose, and it will give us optionality on dose selection, where we need to just inactivate the mast cell and prevent the release of mediator without going all the way to full depletion. And on the other side, we can go all the way to partial or full depletion, depletion of the mast cell. And I think our earlier preclinical observation shows us that there is proportionality in terms of how much dose we give and how much effect we see. And that's where the advantage of small molecule with really a much shorter, obviously, half-life compared to antibodies, allows us really to be able to dose, to work on the schedule in a variety of ways, so we can help a broader population of patients. Makes sense. Maybe just last minute, just quickly, two, and kind of the latest there. For BLU-222, our tyrosine kinase inhibitor, CDK2 tyrosine kinase inhibitor, I think that at Blueprint, we have been really pushing and leading work on this target as an important target, with the idea that in order to really improve the outcome of hormone-positive, HER2-negative breast cancer, in particular as an indication, a full inhibition of the cell cycle, not only CDK4, but also CDK2, are important. We made a compound that is highly selective over CDK1 and CDK6, and we have been seeing some really good data from a clinical and translational perspective in the clinic. Obviously, as we mentioned earlier, we have been talking about partnering this compound and through the discussions with pharmaceutical companies. We have also been studying, and I think we reported this at JP Morgan earlier this year, a CDK2 degrader from our degrader platform. So important target, we looked at it from an inhibition perspective, and the data actually are making a POC for it. We are looking at it from a degradation perspective. I think, clearly, this target obviously needs a CDK4 combination for the full and complete inhibition of the cycle, so we'll see more as we go down the road. Okay, great. I think we're out of time, so why don't we end it there? Thanks, Christy, thanks, Fouad. Really appreciate your time. Thanks, guys. Thank you.