Okay, great. Thanks, everyone, for joining the next session. My name is Brad Canino, healthcare analyst here. Happy to have Blueprint Medicines share the stage with us for the next fireside chat. We've got Christy Rossi, the COO, and Becker Hewes, CMO. Thanks so much for joining us. Thanks, Brad. Okay. Let's just start off with a quick intro to Blueprint, but I really want to focus on what the evolution of the company has been in 2024 and what the outlook is shaping up to be for 2025. Great. So thanks again, Brad, and to the Stifel team for having us. Blueprint Medicines has been around now for more than 13 years and has brought two therapies from lab all the way through to global approvals in that period of time. And to the question, over the last really few years, and in particular this year, the company profile has evolved substantially so that we now have a significant footprint in the allergy immunology space, anchored by the ongoing global launch of Ayvakit in systemic Mastocytosis, which has been an incredibly successful launch, I think one of the most interesting rare disease launches going at the moment, where we are now at a run rate exceeding $500 million in revenue and looking forward to continued growth against a multi-billion-dollar peak opportunity in SM. We also have brought forward some pipeline assets in the allergy immunology space, a next-generation KIT inhibitor, which will be a lifecycle extension on AyvaKIT and enable us to continue to drive growth in systemic mastocytosis over the long term, and importantly, BLU-808, which is a wild-type KIT inhibitor, which is currently in phase one studies. We see this as pipeline and appeal potential that could address a number of highly prevalent diseases in the allergy and inflammation space, so we're looking forward to having that data in hand and reporting it early next year, and then moving that asset forward into a number of proof-of-concept studies across a number of interesting diseases in the allergy and inflammation space. And then finally, the profile of the company has really evolved substantially on the back of a highly successful commercial launch, a very focused investment plan against our highest priority opportunities, which has enabled us to drive operating cash burn down and really puts us in an incredibly strong position as we enter 2025. Okay, great overview. Let's drill into Ava KIT for ISM a bit more. Speak to what you've seen in terms of the evolution of that market that you think puts you on track to the north of $2 billion peak sales target you have for the product. Sure. So systemic mastocytosis is a disease I think, frankly, a lot of people may not have heard of prior to the approval of Ava KIT. The indolent form of the disease is really a chronic allergic inflammatory condition where patients are living with mast cell proliferation that can cause a number of incredibly troublesome, not only symptoms, but long-term impacts over time. And so we see this as a really compelling commercial opportunity. It can be difficult to fully ascertain the nature of opportunities like this when drugs have not been approved before. And so what we had seen prior to the availability of Ava KIT is a large patient population, many of whom historically had not been diagnosed, but we've seen diagnosis rates continuing to grow and have been very confident about this being a blockbuster opportunity when we first launched Ava KIT. What we have seen over the last 18 months since launch is evidence that really just increases our conviction in the size of the opportunity. So first, what we're seeing is that the true prevalence of this disease has likely been undercalled historically. So we've talked about a prevalence of about 1 in 10,000 or about 32,000 patients in the United States. More recent data, just over the last 12 months that's been published, suggests that the prevalence may be twice that. And so we're seeing many more of these patients. We're seeing diagnosis rates continuing to grow at a very significant clip, double-digit year-on-year growth rates. So last year, we talked about 21,000 diagnosed patients in the U.S. That number climbs in real time. We'll likely put out an updated view of that early next year, but we're continuing to see diagnosis rates growing. So more of these patients are being identified and diagnosed. That's not a surprise. You typically see that in rare disease launches where before therapies are available, the incentive to really diagnose a patient may not be there in the same way. And so we're really quite excited to see that growing under the trajectory of the launch. And then we're also seeing continued growth in prescriber breadth, a growing number of prescribers who are comfortable and confident managing SM patients and treating them with Avakit, increasing depth, and a widening lens on patient type. So the dynamic of a provider treating their first patient, growing comfortable with using Avakit and really seeing the benefits that Avakit can drive in a real-world setting, and that widens the aperture on who an appropriate patient may be. So all of that really together indicates just a significant opportunity to continue to drive growth over the long term in this disease. Great. You mentioned, of course, it's a new market, but you were brave enough to guide for investors what 2024, the first year of full year ISM would look like. Talk to me about what the learnings of that have been, because that number has updated as we've gone through quarters and we're all thinking about how you are thinking about offering a 2025 guidance when you get to your Q4 call. Yeah, so we guided this year for the full year. We were two quarters into the ISM launch when we issued guidance this year. And to the point, it's always challenging, I think, to guide in any new launch, but in particular when you're really the first approved therapy and an indication where you're building a market, being able to guide with a lot of certainty is frankly a challenge. We had a good idea of what the key levers were, and we were really trying to kind of manage around those levers to provide a view on what we thought was realistic. As it turns out, our performance this year has been very strong and exceeded our initial expectations. So we started with a guide of $360-$390 million, and we're $100 million plus above that, right? So it's been really gratifying to see that performance. Our philosophy on guidance has always been that we are really trying to give as realistic a view of what we think will happen as we can to really inform how people are thinking about the opportunity and modeling it. Obviously, our recent update on our Q3 call really tightened the range on the year, $5 million range, and that's our best view of where we think the year is likely to land. We'll take that philosophy forward as we think about next year too. So our goal will be to provide guidance that's useful when it ceases to be useful. Obviously, we update it. I think we've shown that, but we'll really try. I think we're in a better spot coming into next year where we now have more than a year. We've seen every calendar quarter in this launch and so have a better sense of what some of those sort of quarterly dynamics may look like, and our practice is to guide when we report Q4 revenue, which will also give us a little bit of insight into some of the variables that will unfold early next year with dynamics like, for example, free drug. Okay. Now maybe to dive a little deep into two of the variables that I'm thinking of. First is the majority of the sales are still U.S.-based for ISM. How should we all think about E.U. and other ex-U.S. markets as a contributing factor for 2025? Yes. Our international team has done a tremendous job this year, and we've seen really nice growth coming out of our international business. I think that's going to be a continued driver of certainly top-line revenue growth, even as it's a smaller percentage of the overall pie, certainly an important catalyst. We also said we're poised to break even in our international business this year, which is really, I think, a pretty great milestone to reach for an emerging biotech company. So not only are we driving top-line growth, we're doing it in a way that's resource efficient. I would expect to see continued growth coming from international. This year, a lot of the ISM opportunity was driven by Germany, which is usually the first market out of the gate. We should see some other markets coming online from a pricing and reimbursement perspective next year. So this year we talked about international being in kind of that 10%-15% range in terms of the overall revenue. I would expect probably a similar range will probably provide a bit more color on that as we think about guidance for next year. But over time, I would expect international to continue to tick up as a percentage of the overall opportunity. Okay. And then in the U.S., in terms of demand and volume, this past year you've given us a lot of data that have spoken to your ability to really activate a lot of prescribers for the first time. As I think about, and you think about 2025, is that the pace that you want to stay on? Is that the main driver of volume, or is this going to be a lot of now going down into the depth within those individual practices and getting additional patients on drug at those practices? I think both dynamics will be important as we think about next year. Obviously, prescriber breadth is not, I think of it as a qualitative KPI that helps you understand sort of the overall what's happening in a market, gives you insight into some of those dynamics. Ultimately, patients on therapy are what's driving kind of the continued growth in the launch. I think we still have room to drive increasing breadth. We are seeing interest continue to come from not only new prescribers, but even new specialties. We talked about dermatology as a specialty that we really haven't targeted with a lot of focus, but we're starting to see organic interest coming from medical dermatologists who may have SM patients. So it'll be interesting to see that continue to evolve, but lots of room to drive growth. Deepening is certainly a dynamic we continue to see. We've shared sort of a snapshot of a smaller number of accounts where you can kind of see that cadence over time of somebody identifying a patient and then starting to identify more. You see deepening once prescribers have that first experience. An important part of this is that the market is being shaped, frankly, by our activity, again, underneath this launch, and so as with a lot of rare diseases, now that prescribers are getting experience, patients may start finding their way to a prescriber that has more experience treating SM, may have experience utilizing Ayvakit, and so the opportunity to go deeper actually evolves as some of that patient sort of funneling happens over time. Yeah. Maybe to continue on that, last question on the commercial side is you're talking a lot about the increase in diagnosis is helping to build this market even above and beyond what you originally expected. But those diagnoses that are taking place, what is the spectrum of severity of those patients? Are those all patients that could be eligible for Ayvakit as well? Almost any patient is eligible for Ayvakit per our label, right? So we have quite a broad label. A lot of the utilization is based on a prescriber and a patient sort of talking about the clinical characteristics of that patient and how well they're doing. The lens of what does it mean to be sort of controlled or uncontrolled is ultimately a judgment call, and it's one that's informed by really sort of the alternatives available to that patient. And so again, as prescribers are understanding how Ayvakit performs in the real world and the kind of results that they can get, the safety and tolerability profile, it's natural that they will then start to widen their lens of who they want to treat. You see the same thing with patients where patients will talk to other patients about their experiences, and I think that can catalyze a patient rethinking how they're doing and maybe thinking about adding Ayvakit into their treatment. We see a lot of opportunity to continue to grow. In terms of, I think what's underlying that question is, as more patients are being diagnosed, do they look different than perhaps the patients that were diagnosed a few years ago? So far, the answer to that has been no, right? We look at patients and claims data. We can look at healthcare utilization, histories of these patients, and the mix of patients has looked fairly consistent as diagnosis has continued to grow. We'll see what that looks like over time. Again, we're now getting new data that suggests that the ultimate prevalence here may be a lot higher than what we had initially estimated, so it's something for us to continue to watch over time. Okay. And maybe to Becker, to wrap in now, elenestinib, which you've mentioned is the lifecycle product for the strategy of Ayvakit and ISM. Maybe just introduce the drug, Becker, and then talk about what the differences are of the phase three trial that you just announced versus the legacy Ayvakit trial. Sure. So elenestinib is our selected D816V inhibitor, but it's not brain penetrant. The potency of all these D816V inhibitors is the same, but it is a different drug with different properties. But we're developing it to impact the disease in a much more broad way than what we've illustrated with Pioneer. It's important to remember that the Pioneer study was focused on the symptoms and the TSS score, and that was our primary endpoint. We're going to continue to use that as our primary endpoint, but what we're starting to learn a lot more about this disease is that it's not just about the symptoms. When you think about the disease evolving over time, you have indolent disease, and then what defines smoldering is the organs start to get larger, and then advanced, you start to have organ shutdown. But this doesn't happen overnight. What we're learning is that in the indolent population, there are things that are happening in the body that may not be evident or well measured on a symptom score, such as increased bone turnover and decreased building of bone, where we need to be more specific in the way that we measure this. We're working with the agencies to better understand what's necessary to show this in a labeling fashion that we can impact bone turnover and improve bone health over time. The other thing that when I first was interacting with investigators on the Pioneer trial, what I heard frequently was, "I have patients who have episodic events. They have either grade two or grade three anaphylaxis events." This does a couple of things. On the days that they have them, it shuts down their day, and they often have to wait for these events to pass. They'll have lower blood pressure, high heart rates, they can get flushing, they can get diarrhea. And this really impairs their quality of life. But in a number of these patients, it happens pretty frequently, and it's not measured in the ISM SAF effectively. And so what we are going to try and demonstrate convincingly is that in the Harbor Part II, we can show a reduction in these events. And so similarly, we've been working with the agency to better understand what they want to see to show that these events are reducing. We can look at EpiPen use, but that's really the tip of the iceberg. And so showing that we can impact a broader patient population and that treating early matters, that just waiting until someone has symptoms that they have decided are too much to handle is not the way to treat a chronic disease like this where you impact organs over time. Okay. I think the question I get a lot is, okay, if you have a label that has a broader view of the benefit of the drug for the patient population, how do you still realistically commercialize that in 2030? And what does that look like? Is it patients switching from Ayvakit? Is it new patients will start to just go on to elenestinib instead, and that's how you build that business? How do you think about that today? Yeah. So again, what we're kind of driving towards here is a longer-term view of a Blueprint SM franchise that we think could be very valuable both for us and for patients sort of late in the 2030s and beyond. When we think about a launch, I mean, obviously, we'll have to get the data in hand from Harbor and really understand what the profile looks like. But we expect that, first of all, Ayvakit will be continuing to grow over this period of time. And against this opportunity that we think is going to be continuing to grow from an SM perspective over time, there will still be a meaningful number of patients who will be starting therapy for the first time, right, in that timeframe. And so if we can develop a therapy with a differentiated clinical profile, really show the breadth of clinical benefit even beyond what we've been able to demonstrate with Ayvakit and Pioneer, we think that could be an option for patients who may be starting on their first SM therapy over time. And again, you can start to build, as you say, a patient base there. There could be patients who choose to switch, but you don't need to rely necessarily on switching. You can really, again, launch a therapy and have some overlap there and I think drive benefit for the franchise over the long term. Okay. Great. Maybe back to Becker. We'll move on to BLU-808. Could you introduce the wild-type KIT inhibitor and talk about its current progress in the phase one development? Sure. So being in systemic Mastocytosis, we've learned a lot about mast cells and what causes them to degranulate and how they survive. And we were encouraged by the people that treat SM that also treat a lot of other allergic and inflammatory disorders to develop a wild-type kit inhibitor. And in order to do that, we needed to make sure that it was highly potent and selective. And so we spent a bit of extra time to make sure that we had the most potent and selective wild-type kit inhibitor out there. Our intent is to take it into a number of diseases that have a major component of mast cell biology, and there are some like chronic urticaria where the mast cells are the primary driver of disease, and then more complex disease like atopic dermatitis or asthma where the mast cells play a key role, particularly in initiating and propagating the disease, and so we're developing BLU-808 as a very tunable tool to use or drug to use to modulate or eliminate mast cells. So in our healthy volunteer study, what we're doing is, in addition to looking for a very tight PK profile and predictable pharmacodynamics, we're looking at a number of different pharmacodynamic markers to define the range in which we can start to dose this drug, to understand when the tryptase starts to go down, to understand when we might see some of the typical side effects for any KIT inhibitor, like impacting the bone marrow, the neutrophil count. You can take any KIT inhibitor and drive it to that point, but what we're defining with BLU-808 is a therapeutic range that we expect to be quite wide that will allow us to examine a number of different doses and dosing strategies to address different indications or different patients in a way that's very tunable. Okay. Now, you're actually the only company developing a KIT inhibitor that's got a commercial presence in the mast cell space. So I guess how has that influenced what you are aiming at for a target product profile of the drug? And I guess this could be to either of you. Go ahead. I'll start, but you should absolutely chime in. If I think back to what drove this program, the foundation of this program, it was really discussions that we were having in the allergy space where we were hearing a lot of feedback, not just about urticaria, but other indications where there was a lot of interest in this pathway and how it could impact patients. And so I think our ability to be out there and having those conversations in real time, understanding sort of the landscape as it's emerging, understanding feedback on other sort of mechanisms and data that is sort of being generated in real time has been a huge, huge advantage. Yeah. And I think one of the learnings for me over time has been that allergists want to be able to titrate their therapy to the patient's needs. And they are treating these patients often lifelong, and to be able to start at a relatively low dose and work the way to the dose that they are looking for and get the efficacy and the tolerability that they want for each patient or each patient population is the way that allergists think. It's quite different from the way that oncologists think, which is hit it hard upfront to get in front of a deadly disease. And so really having these tunable and well-combined or easily to combine drugs is what allergists are looking for over the chronic therapy landscape. Okay. Now, can we drill a little bit deeper into tryptase as a PD marker, and is that really the best marker to rely on as you think about the dose range that you're trying to achieve? Yeah. We've gotten a lot of questions about tryptase both in SM and in other diseases that don't have mutated mast cells. But speaking specifically to the patients with chronic urticaria and asthma where the tryptase levels are normal, I think of tryptase as necessary. In other words, you need to see the tryptase going down, and it can start to identify the leading edge of where you would expect to see efficacy. So somewhere between, say, 40 and 70% reduction in tryptase seems to correlate when you look at the antibodies. Even the early data from Third Harmonic, you start to see the efficacy in chronic urticaria there. But when you get beyond that, you're talking about very low levels of tryptase that are normal to begin with. Being able to understand a correlation between that and the ultimate response rate, I don't think there's a correlation there. Mast cells come in a lot of different shapes and sizes and phenotypes, and really trying to understand how hard you need to hit each one or in a specific disease, how much you need to hit it to get a certain response rate is something you have to figure out in the clinic. Okay, and now you've been early to introduce a topic of a potential dosing paradigm of this induce and maintain, which you think is only going to be achievable with the oral wild-type KIT inhibitors. I guess where do you actually see that potentially playing a role? Yeah, so our reason to introduce the induce and maintain strategy is really to illustrate that we have a number of ways of utilizing an oral small molecule that antibodies can't replicate. The antibodies often give much more than is necessary to either kill or to decrease the activity of a mast cell. And once the antibody is in, for the most part, with barzolvolimab, you have a number of weeks or sometimes months before it comes out of the system. So there's no ability to adjust over time. What we've learned from a lot of mast cell experts in the past few years is that you can deprive a mast cell of kit signaling, a normal mast cell of kit signaling for probably a week or two, and then you start to see pretty significant apoptosis or reduction in mast cell numbers. By inhibiting for a short period of time, you can eliminate mast cells. And then I think in order to navigate the toxicity that may come with certain doses, to be able to go down to a lower dose and maintain the response that you've started is a strategy that we'll look at. But it was really just illustrative of the fact that we have a lot of variables that we can play with a small molecule that you can't do with an antibody. We can look at what we've done in SM, which is a rising dose, a rise to effect, for example. So when we get into the phase two portion and some of these shorter proof of concept studies that we have lined up, we'll be able to better define for each indication what the right strategy for dosing is. Okay. And now for the phase one in healthy volunteers, what should we expect for safety? And are you using safety parameters as well to help understand dosing decisions? Yeah. So as I said, the tryptase reduction starts to define the leading edge of efficacy. And then in this relatively short dosing period of a healthy volunteer study, what we'll be looking at is early indications of emerging toxicity. Some toxicities you can see very quickly, like some of the blood counts will change. But there are others that take time to develop. We've seen in the barzolvolimab study that the real hypopigmentation and the hair whitening often doesn't show itself as robustly as it eventually will until later in their studies. So the year-long studies showed that there's an emergence even beyond what they saw in the short term. But what we'll be looking to do is define that range within which we should be working. Using some of the other pharmacodynamic markers, we'll be able to understand when we're just calming mast cells down and when we're actually eliminating those. Okay. And now if you reach the target product profile in healthy, how should we think about what Blueprint is prepared to do for phase two development or phase one B, whatever we want to term it? We've got proof of concept for this mechanism in urticaria. Where else do you see potentially an ideal indication where you can generate quickly additional proof of concept to show the breadth of potential utility of wild-type kit inhibitors? Right, so I like to think of the diseases as either primarily mast cell driven, like chronic urticaria, or a more complex situation that often has broader impact, like asthma or atopic dermatitis, and so in order to maintain the spend along the way, we have planned serial de-risking events where we're starting with diseases like chronic urticaria or allergic rhinitis and conjunctivitis, where it's clearly inhibition of mast cells that's going to make a difference, and we'll be able to tell pretty quickly based on the symptomatology and objective measures in patients. You can see the skin change in chronic urticaria. You can see people's rhinitis and conjunctivitis, so we'll be able to understand better the dose range and those indications. And then as we shared on our online seminar last week, asthma is a pretty unique situation where these challenge tests give you an opportunity to understand the impact on both the early and the late phase of the asthmatic response. And then that sets the stage for subsequent development in more complex diseases and with larger trials. And we'll look at both the likelihood of success, the biology, the combination partners, and the commercial potential for these larger indications and make decisions along the way about what we invest in when. Okay. Last question to Christy. How would you articulate why Blueprint is positioned to capitalize on a development strategy that will require such parallel and some risk, some less risk development? We've developed a significant amount of understanding around mast cell biology over the last several years. I think SM is a really interesting blueprint in many ways for what we're trying to do with 808 in terms of really tuning dose and response based on sort of the clinical needs of different patient populations. We have a significant amount of engagement across the allergy community, and that's really informing how we're thinking about taking this forward, and to Becker's point, I think we have a really nice plan around how to first de-risk the profile of the asset, and we'll start to see data there early next year, and then really understanding the biology around a range of indications. Of course, as with everything in our portfolio, we are always having conversations strategically around our pipeline, our assets. We've used business development strategically inbound as well as outbound. That won't change, right? I mean, we're always going to engage there and think about kind of where we can use our capabilities most effectively and where we may want partnerships or other approaches to help do that as well. But we feel like we're in a really good position with ramping revenue, focus, discipline, spend to drive this program forward, and it's certainly a priority for us from an investment perspective as we get into next year. Okay. Great. We'll have to leave it there.