All right, so welcome to this Fireside Chat with Blueprint Medicines. It is my great pleasure to welcome Kate Haviland, CEO, and Fouad Namouni, President of R&D. Welcome, and thanks for joining us today. Thank you for having us, Michael. We appreciate the invite from you and the entire Guggenheim team. Thank you. So why don't we jump right into Q&A? I think most people are very familiar with Blueprint Medicines. And starting out with a few commercial questions initially. So AYVAKIT obviously had a very strong launch in ISM. Now it's been a year and a half or so since the label expansion, and the product's really expanded its commercial presence. How are you thinking about the overall market opportunity in ISM at this point, having, again, 18 months under your belt, and any key learnings from the launch so far? Yeah, absolutely. So I think, as you mentioned, Michael, we just reported our Q3 earnings, and we're really pleased to be on a run rate of about $0.5 billion in revenue here for our first full year of launch of AYVAKIT and ISM. And I think that really puts this launch into pretty rarified air, as you think about the opportunity to change the disease treatment paradigm in a rare disease like ISM. And so as we've kind of been building this market, as AYVAKIT is the first and only therapy approved for patients with indolent systemic mastocytosis, this is a disease that is characterized by a significant burden of symptomatology across a wide range of symptoms in patients who really have to kind of make their lives smaller. So they have to kind of control, even with symptomatic therapy, they've had to control their disease symptoms by altering how they live, where if they go to work, how they engage with family, how they are able to travel, if at all. And so what we've been able to see with AYVAKIT is the opportunity, by addressing the source of the disease, which is the mutation, the KIT D816V mutation in KIT that is on the mast cells, that we can have this broad symptomatic impact that is deep and durable, and with a very well-tolerated medicine that patients can this conducive to chronic treatment. And so to the point you've made, I mean, I think what we expected to see and what we have seen is that we've seen a really nice growth in patients on therapy. So a steady stream of new patients who are starting the medicine and patients staying on therapy for long periods of time, again, conducive to what we expect to be a multi-year treatment regimen for these patients. And so as we've kind of continued to build this market, I think a few interesting things. One is that with advanced diagnostics and greater clinical suspicion, we're starting to see updated epidemiology studies come out. And there was one published in February out of Sweden, and there's been some others that really talk about the fact that likely the prevalence of this disease is larger than we expected. And so that's one piece of information that's interesting to us. The other is we've just continued to see a growth in the number of patients who are diagnosed, and we can see that in claims data in the U.S. in particular. We've seen a really nice growth in the number of diagnosed patients. Last year, at the beginning of the year, as we kicked off, or sorry, in 2024, beginning of this year, as we kicked off 2024, we could see about 22,000 patients in U.S. claims data. That number has been growing. That is also a very key point for us to think about how big this market could be. Importantly, we have been very much focused on hematology, oncology, and allergy immunology as the primary places where our field teams are going. We have started to see patients come out of other specialties. We think that there is a more prominent role for patients from medical dermatology, for instance. So we're starting to see those prescribers kind of come on board and actually prescribe AYVAKIT, as well as seeing some patients who were thought to have irritable bowel syndrome or IBS now having a differential diagnosis to ISM, and so I think if you kind of triangulate all three of both our own field experience, what we're seeing in the diagnosis rates and diagnosed population and claims data, as well as epidemiology, our expectations of this market is larger than we expected when we first set out to launch AYVAKIT, and we'll be spending time early next year kind of putting a finer point on that for everybody. Sounds good. And then maybe just diving a little bit more into detail on your most recent earnings report, where you've again raised 2024 guidance to $475 million-$480 million now. So we always like those launch dynamics of any product launch, which is great to see. And so anything that has been the primary driver of growth beyond your initial expectations, especially this summer, has there been one factor that's been driving that in sort of finer detail? Yeah, it's been the constellation of factors. I mean, I think the most important factors, again, for the launch are patients starting therapy and patients staying on therapy. So growth in that pool of patients on therapy is really the foundational what's foundationally important to the overall growth of AYVAKIT. I think we've also seen in the beginning part of the year, we saw favorability in terms of the free good commercial mix, and we expected to see favorability over time with fewer patients on free goods and more on paid commercial therapy. That happened very quickly in the beginning of the year, and partially that is payer mix, but as well as the dynamics with the IRA. So that gave us some tailwinds on that. But that was predominantly seen in the first half of the year. We've continued to see high compliance rates. Our launch in Europe has been going well, and so that's important as well, in that we are in the free pricing window for ISM in Germany, which is the biggest portion of our European sales to date, although we are expanding into many other countries right now, and so there's a lot of different factors we look at. There's none of them that have been the most important driver, but I'd say that when we think about the foundation, it's really growing that number of patients on therapy that is what's going to be critically important to the success of this continued commercial launch. Yeah. And when you think about sort of the opportunity to reach more patients relative to what the population is on drug right now, and I know you talked about perhaps expanding, targeting, or reaching other specialties beyond the Hem/Onc and allergist initially. Where do you see the sort of near and midterm opportunity in this area? Is it expanding more on existing prescriber base? Is it adding different specialties to the mix? And then also, is there active promotion necessary, perhaps an increase in your efforts there to drive some of that? Yeah, so I think in terms of how do we think about growth, and this is a very promotionally sensitive therapeutic area. So in other therapeutic areas, it's more kind of long-term data-driven, and this is a very promotionally sensitive therapeutic area. I think we continue to see a really nice breadth and depth in our current kind of call points with hematology/oncology and allergy/immunology growing. So we've kind of shown this chart every quarter, and you continue to see people prescribing for the first time, as well as the kinetics, where as a physician has a first one or two patients on therapy, they tend to then prescribe the drug for more patients, I think, when they see what AYVAKIT can do for their patients with ISM. And so we see that kinetics of the deepening as well. Really, we're really just scratching the surface on that. We expect that out of the current call points, we'll continue to see really nice, steady growth. Physicians are also out there looking for patients, and we know that patients are sitting with misdiagnoses in places, but also just need to get the official workup done for ISM. That will happen. We'll continue to be part of what our team does over the year. Then I think we are, and we'll have more time to talk about this at the beginning of the year, because it is promotionally sensitive. We are looking to expand where we call. So our MSL team has done a nice job of being kind of the forward group to be engaging with other specialties, and that gives us a really good sense of how we want to think about continuing to investing to drive AYVAKIT growth. I think what's critically important is we're in the very early innings of a rare disease launch where we are going to be kind of in the driver's seat of innovation here for multiple years to come, and we expect this market to be growing well into the next decade. Great. So maybe just one more as we think about 2025. So IRA tailwinds have helped this year, it sounds like, or this year, and also you had a reduction in free drug supply. So how much additional help, I guess, or how much additional tailwind should we think about in early 2025, especially from the IRA dynamics? Yeah, so from the IRA perspective, as you mentioned, Michael, in 2024, what we saw is a pocket of out of, sorry, a capping of out-of-pocket expenses at a certain level. That certainly has helped in terms of patients being able to go on paid therapy rather than being on free drug. Next year, I'm already in 2025 in my mind. Next year in 2025, what we'll start to see is the smoothing. Obviously, the cap comes down, and then there's a smoothing, which should just make it even more affordable for patients with Part D coverage. From our perspective, we've gotten this year to a really great place versus free drug versus commercial. It's a very optimized mix at this point. So what we'll be looking to do is all those patients reset as of January, and we'll move them back through that process of kind of determining whether they'll be on commercial or free drug. Our expectation was that we'll continue to be in a similar place, but we're going to need to see how that comes through in January, February of next year. Okay. And then maybe just one more. So treatment duration, how has that panned out relative to expectations now that the drug's been on the market for some time? Yeah, so what's great about indolent systemic mastocytosis is a chronic disease. And what we've seen is very, very low discontinuation rates. Even though we've been on the market for 18 months, given that it is a chronic disease, it's going to take us some time before we can get to average treatment durations in the sense that patients are staying on therapy. We do expect this to be a multi-year course of therapy. We did say this year we were able to put out the fact that we're at 25 months average treatment duration in advanced systemic mastocytosis. So these are patients with an aggressive hematologic neoplasm, and we're seeing patients already out on that side of the business out to 25 months. So I think that bodes very well for what we hopefully will continue to see in ISM. And we think that's, I think that's been an underappreciated yet critically important part of the overall value story for AYVAKIT and ISM. Okay, great. So maybe then a couple of questions for Fouad. As we think about elenestinib and sort of the Harbor study, which is starting to enroll the randomized portion soon, again, how should investors think about the opportunity for elenestinib to perhaps further expand your presence in ISM? The development strategy for elenestinib will be very different in many ways than avapritinib. We learned over the last many years from the Pioneer study, but also from now the data we have from real-world as we commercialize avapritinib, what are the next key questions to ask to develop a medicine for this population of patients. So we will be obviously sharing more about it soon, but I think people will see how we are targeting the SM patient of four or five years from now, not the SM patients of 2016 and 2017 when we started the Pioneer work. I think we are working on starting the study before the year-end, as we mentioned. We are on track of that, and we will have the opportunity to share more soon. I think just adding to what Fouad was saying is, as our view of this overall SM opportunity has grown, and we'll talk more about that in more specifics, I think e lenestinib plays an even more important role for us, which is the fact that we think this overall SM franchise is quite substantial. And when we think about driving innovation in this space, we're really in the driver's seat of that. I think this is a market that no one really understood, which is why there's not a lot of competition, to be honest with you. I'm sure it'll come. But I think where we sit is that we have the opportunity to not only have AYVAKIT be a really substantial multi-billion dollar product, but to drive a branded franchise kind of beyond that by having a next-gen product with a longer kind of patent life and our ability and our knowledge set now to really bring more innovation based on what we've learned to patients and physicians to give them a really compelling choice that would kind of that will put a tail on beyond AYVAKIT. Right. And obviously, as you mentioned, elenestinib's IP runway is much longer than AYVAKIT, but it'll presumably reach the market long before AYVAKIT goes off patent, I would assume. So can you talk a little bit about its positioning relative to AYVAKIT? Is there a lot of overlap in target market? Are there complementary areas? How should we think about that? I think the value proposition that elenestinib will offer, once on the market, would be differentiated from AYVAKIT. First, AYVAKIT 25 milligrams is a very good drug helping patients. I mean, you guys just described it all, how it is impacting the disease natural history and the patient journey has changed over the last two or three years. Patients will have the opportunity, will have the option to continue avapritinib or switch to a different value proposition with different types of data and different types of information. And that's what the period of time that will overlap is the necessary period of time to be able to extend the lifecycle of ava over time. I think the timing is perfect, and I believe our strategy of development will also answer the question that will allow patients and their physicians to understand why they should be switching to elenestinib at the right time. And I think that is that kind of value proposition to move from symptomatic control by addressing the source of disease to really start putting more kind of efficacy parameters around disease modification. We're looking for the same kind of safety profile. AYVAKIT, again, at 25 and 50 milligrams, we now have patients who've been on the therapy. We reported median two years follow-up and Pioneer, but some patients have been on four years, right? And the safety profile, it's hard to improve on AYVAKIT's safety profile. So what we hope to do is recapitulate that and then really to build on the efficacy story with additional ways of measuring impact of the therapeutic intervention. Right. And then just one more. So when we look at elenestinib data that you have generated so far, so what are its most attractive intrinsic features of the molecule relative to AYVAKIT? I think a few key things. I mean, the molecule was developed initially to not be a brain penetrant molecule. However, all the data and what we are learning from the studies and from the clinical and the medical practice on avapritinib, that may be not that relevant feature, to be honest, Michael, for elenestinib. But elenestinib also will apply all the learnings, for example, dosing strategies, multiple strengths, things like this that we learned from ava, and we may have not fully done it for avapritinib. There's an opportunity to do all the things that in hindsight, you go back in time and say, maybe these are could have been a lot of key things done for ava. But Ava is treating patients and improving the disease in many ways. I think adding on top of that more key information to Kate's point, I think will really help physicians have an opportunity to understand much the value proposition of elenestinib and understand what's the best for their patients. Okay. So looking forward to learning more about the Harbor study, probably sounds like soon. Yes. And then perhaps just switching over to BLU-808. So lots of interest here, obviously, given the market opportunity. So just to set the stage, can you talk about sort of the potential opportunity in chronic urticaria for your wild-type KIT inhibitors? And then we can dive into some more details. Yeah. I I think, I mean, first, I mean, I would just say that the targeted mast cell has really been a key target in the industry for quite some time, and how to do it was really the question. I think now with POC done by other manufacturers showing, clinically validating, the role of mast cell in chronic urticaria as an example is key. So now how are we going to continue to improve the treatment of chronic urticaria? We're bringing options that can build on this POC for wild-type KIT and take it to the next level, and we can really talk about how to do that, how we think of it. I think we see chronic urticaria as one of the key indications that we plan to develop for BLU-808, but we see the opportunity for BLU-808 way broader than chronic urticaria. It is a molecule assuming success could go to a number of Type 2 inflammatory diseases. In fact, we will be this Thursday hosting a webinar where we'll be talking about our approach to these diseases and what are the POCs that will be starting next year. For chronic urticaria, we believe that mast cell and BLU-808 targeting will be one of the key indications. So, yeah, not to preempt your event on Thursday, but yeah, I mean, there are different opportunities for wild-type KIT. Yeah, how do you plan on prioritizing those? That's a great question. We are conducting for now the SAD and MAD study that we anticipate to report early next year. After that, I think our teams are innovating in a way to really start running multiple POCs of a variety of Type 2 inflammatory diseases within the same period of time. And that will really allow us to understand the impact of 808 strategy in terms of how we give it and how we do it for a few different or variety of different Type 2 inflammatory diseases. And from there, understand what is the most impactful, what are the most impactful data, how to prioritize, how to resource allocate over time, and how to understand at the end of the day the scope of the opportunity of what 808 could bring to patients. And I think one of the things we talk about a lot is we often, as an industry, kind of throw around the term pipeline in a pill. And we truly believe that 808 has that opportunity. So how do we early on kind of establish a clinical footprint across disease states and organ systems there where we know mast cells are really important that help guide that view in the world we live in today, right? An IRA type world where you can really then figure out how does your development then proceed from there. And I think establishing the footprint opportunity for 808 fairly broadly early is going to be an important part of that. Makes a lot of sense. And then obviously before that will happen, you're obviously in your healthy volunteer study right now, right? SAD, MAD study. So what are you hoping to learn from this initial human trial experience? And to what degree will the data inform opportunity for clinical differentiation of your molecule? Given that targeting the mast cell in terms of proof of concept in, let's say, chronic urticaria has already been demonstrated, I think the data from 808 or BLU-808 will be a major inflection point for patients, for Blueprint, for all of us. We will be looking at the safety profile of this small oral molecule in healthy volunteers. We'll be looking at the pharmacology and how it behaves pharmacologically. We'll be looking at pharmacodynamic marker and understanding across doses how these pharmacodynamic markers vary. And all that information will help us really decide on how are we designing therapy in terms of dose and schedule going into the POC studies. What PD markers are important and how predictive are they for clinical activity? So we're looking at many PD markers. The one we have been talking about was tryptase, but there are others. I think tryptase is a very good pharmacodynamic marker, and it shows how hard you are hitting the target. How important it is to the disease. It varies from a disease to another. I would say it is a necessary pharmacodynamic marker to see across a range of doses how you hit the target. It's not a sufficient marker from our decade base experience in the mast cell universe that can predict the exact activity in a variety of diseases because we know that in this Type 2 inflammation, diseases are very complex, and the mast cell is the key effector and blocking the mast cell is important, but we know the inflammation is there. We learned over the years from our experience with AYVAKIT. This This because of the inflammatory process that exists and has built over the years in these diseases, just counting on tryptase alone is necessary, but not enough. We have proven this in SM. We'll report this marker across doses, and we will see how it varies across a range of doses. It will inform our selection of dose and schedule strategy for the POCs. Makes sense. And then there's been investor and investigator focus on the side effect profile of KIT antibodies recently, especially. And so there's some on-target side effects, perhaps some off-target side effects. So how do you think that will play into your strategy for 808? As you probably know, Michael, historically, mast cell has already been sought after as a key target because really it's a key effector of allergy. It's the first cell involved in the allergy and inflammation process. But the on-target toxicity has been holding people from going into that development. Building on our real experience in the mast cell world, starting with systemic mast cell diseases, we really learned a lot about the biology of the mast cell and the importance of KIT to the mast cell, not only from a survival perspective, but also from a function perspective. And we learned how to fine-tune the inhibition of mast cells to achieve a specific effect on the mast cells. And it goes from very low concentrations of inhibitor to levels where you inhibit the activation and the degranulation without a full depletion to levels where you fully deplete. And then if you take it to the very high exposure level over time, you are not only fully depleting the pool of mast cells, but you are going deep enough into the myeloid progenitor, for example, to generate hematological toxicity. So with a small molecule and a shorter half-life than what typically we see with monoclonal antibodies, I think we believe we can have a titratable, tunable strategy to offer to these patients. On one hand, you keep very good efficacy, and on the other hand, you keep patients on treatment because they are not discontinuing because of toxicities. Great. I know we're at time, but I want to slip one more in. A question we get a lot is there are a few other inhibitors in development targeting MRGPRX2. I hope I got that right. How would you contrast that approach relative to the wild-type KIT approach? I think our teams really have a very good knowledge of what are the variety of targets you can find on a mast cell. I would say if you want MRGPRX2 has been reported to be skin-restricted, mast cell skin-restricted targets. So something go for diseases, allergy, and inflammation diseases specific to the skin. Targeting wild-type KIT will really target all types of mast cells. And we know there are three major systems where you find the mast cell: the respiratory system, the GI, and the skin. So it's really much broader application than just targeting one organ. I look forward to seeing more data actually on MRGPRX2 in the future. Okay. Sounds good. Well, I think we're being signaled to end. So really appreciate the insights. And then we'll look forward to hearing more this Thursday. Thursday. Yeah, please. Thanks, Kate, and Fouad. Thanks, Michael. Appreciate it.