Thanks, thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here, and it's my pleasure to introduce the team from Blueprint Medicines. Short one, but that's okay. Cost and travel. To my left is Christy Rossi, Chief Operating Officer, and Fouad Namouni, President of R&D. Just a reminder, format for today is a fireside chat. We'll keep it informal. If anyone has a question in the audience, please feel free to raise your hand, and we'll loop that into the conversation. 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. With that, I'll just turn it over to Christy to give us some introductory comments, and then we can open it into the Q&A. Great. Thanks, Mike, and thanks everyone for joining. Thanks to the Morgan Stanley team for hosting us. For those who may not be familiar with Blueprint Medicines, we are the leading precision medicine company globally. The company is about 11 years old, and since our founding, we have brought two self-discovered homegrown medicines through the clinic to approval to patients globally, AYVAKIT and GAVRETO. And now, where we are in 2023, is really focused on three key drivers going forward as we continue to build the company and create value for patients and for shareholders. So one is driving top-line revenue growth through our ongoing launch of AYVAKIT in systemic mastocytosis. We received approval for AYVAKIT in indolent systemic mastocytosis, which we view as a north of $1.5 billion opportunity in May, and are in the early days of that launch, which is going really well, and I suspect we will talk about that today. The second is advancing our clinical portfolio as well as our discovery portfolio to larger patient populations globally. We're focused both in heme/onc as well as increasingly in Allergy/Immunology, building upon the expertise we've created with AYVAKIT to be able to benefit patients with mast cell disorders more broadly. And we recently announced a development candidate for our wild-type KIT program, which we're very excited about. And then finally, continuing to really operate from a very disciplined financial perspective. We are very smart about capital allocation and moving the company forward, as we continue to reduce cash burn and grow AYVAKIT revenue, where we will be operating from a place of financial self-sustainability. So those three levers, we really see as driving significant value, as we go forward from here. Great. Thanks for that introduction, Christy, and maybe we can focus on the first lever there, which is, AYVAKIT, sort of label expansion. Yep. You're early into the launch. Maybe just remind us the, you know, key points of your strategy and how things are going so far. Sure. So AYVAKIT was approved for advanced systemic mastocytosis about two years ago, and then recently we received the indication for indolent systemic mastocytosis. SM is a rare disease that impacts about 32,000 patients in the United States, and we really see this, as I said, as a blockbuster indication for AYVAKIT. The majority of patients have indolent systemic mastocytosis, and so AYVAKIT is now the only therapy that is really approved to treat patients across the spectrum of SM. We're really excited about what we're seeing in the launch as we progress towards that very large opportunity globally. We reported on Q2, which was obviously, you know, a small portion of that launch, so about a month of commercial experience with the label expansion in the quarter. And we saw really strong growth in patients treated with AYVAKIT that was disproportionately driven by that last month of the quarter, where we really saw inflection. We saw really strong increase in breadth in prescribers, where, you know, 70% of the scripts that we saw come through post the approval were from new prescribers, which I think really stresses it very well in terms of establishing that broad breadth to continue to find and treat patients. We're seeing strong adoption, not only in hematology, but also importantly among allergists, which I think are gonna be a really important audience for this launch as we go forward. We're also seeing nice balance across academic and community settings. We've seen those trends continue into July as we sit in the quarter. So look forward to sharing more about our Q3 experience, obviously, when we get to that point. Finally, access has been a really important focus of ours, and we've been really pleased by what we've seen in terms of strong payer coverage, coverage to label with really no hurdles that are beyond our label, which is very broad. In fact, it was a surprise to the upside in terms of the breadth of the indication that we received. So we're really pleased in terms of patients' ability to get started on drug quickly. I just want to ask a follow-up question, just given the different prescriber base here with the heme/oncs and then the allergists, just initial feedback from both those groups, is there anything unique? Are they looking for specific data points that give them confidence in prescribing AYVAKIT? Yeah, it's interesting. I mean, obviously, hematology, to some extent, is a bit more familiar with AYVAKIT because hematologists are more likely to treat patients with advanced SM. You know, as we've engaged across both, I do see some differences in terms of how they focus on clinical data. Hematologists may be a little bit more prone to really get into a lot of the details on our clinical data set, which, you know, is really compelling in terms of the benefits that we saw across not only objective measures, but importantly, symptom benefit across really every symptom domain, as well as quality of life. Allergists, I think, are much more focused on, you know, I wanna be convinced that the therapy works, which again, having this very strong, robust data set across all these endpoints, really helps to tell that story. And then they immediately move towards, you know, what does it take to get a patient started? And so I would say with allergists, you know, we're getting them familiar with the therapy and really walking them through, you know, our strong support, patient support offerings that we have, the ease of prescribing, and really making sure that it's seamless for them as well as their patients. Can you just talk about those two prescriber groups in terms of the percentage, you know, that would be prescribing as a majority allergists and immunologists, and how large is that relative to? Yeah. So over time, I think allergists will become a more important part of the launch. We've said that, you know, initially, our expectation is that hematology will be the predominant prescribing base. And so what we saw in Q2 was that we added, as I said, 70% of our scripts were coming from new prescribers. Actually, most of them were hematologists, which is interesting, right? So we're bringing new hematologists on board with this launch, but we also saw uptake in allergy right out of the gate. In fact, our first prescription came from a community allergist. We've continued to see allergy uptake over time, and so, you know, we'll share more about that, but expect this to be one of the, you know, where we see hematologists perhaps more dominant initially, and then over time, allergy becoming really more of the predominant prescriber base. How do you drive that sort of increase in the allergists? Is it just they need experience, and that's kind of the trigger, or are there other hurdles there? Yeah, it's really about, you know, allergists finding their first patients, which is what we're seeing happen right now. So, you know, allergists don't have as much innate experience with AYVAKIT, obviously, given that the previous indication was advanced SM, which they are less likely to be the kind of managing treater. And so as we now have the ISM approval, we've been out, you know, educating on the clinical data. What we're seeing is that allergists will find their first patient or two that they think is a really good candidate to try prescribe, and then based on that, they often have additional patients that they're talking about that they can see also utilizing AYVAKIT. This is why, you know, prescriber breadth, in my experience, is so important, something that we're focused on as you build that base of experience, and then, you know, prescribers can deepen within their practice as they find additional patients. You maybe also just talk about what you're seeing in terms of the split between academic prescribers and community prescribers, and how do you drive more use among the sort of latter category? Yeah. So again, I was pleasantly surprised, I would say, to see the uptake in the community right out of the gate. So, it's been very balanced about 50/50 in terms of academic versus community. Obviously academic centers, by and large, have experience with AYVAKIT, certainly the large centers that treat advanced SM as well. We were already, you know, pretty well established there. So expect to continue to see them finding patients and treating patients, but very encouraged to see that adoption in the community out of the gate. And I think that speaks to the comfort level of, you know, AYVAKIT's profile, frankly, in ISM. Certainly it's part of our strategy, is that we believe that these ISM patients can be effectively managed and treated in the community by allergists or hematologists, but you know, that there is that comfort in prescribing and being able to manage the patient. Can you maybe talk about the type of patients that are getting treated in ISM? Is it majority severe? Are you seeing moderates, moderate patients, or have you even seen mild patients yet, or how do you get there? Yeah. So, you know, maybe taking a step back again, for those who have been kind of following the story for a while, the PIONEER study was conducted in what we would call moderate to severe patients. That's not a clinical definition that really exists. It's more of a way of thinking about patients who have symptoms. In our study, they had to meet a certain threshold of symptoms, despite having been treated with some supportive care medications and stabilized on those medications. So that's how we think about moderate to severe patients. When we got the approval for AYVAKIT, as I mentioned earlier, we were really pleasantly surprised to have a label that's for all ISM. Typically, you get a label indication that is aligned to the patient population you studied, so that was certainly, you know, a surprise to the upside. What we see in terms of initial patient selection is in line with what we expected, which is that it is those sort of symptomatic patients that are being started initially that would fall kind of more into that moderate to severe bucket. Exactly where you draw that line is, you know, a little bit in the eye of the prescriber and the patient. But in general, patients who are diagnosed, who are not well controlled despite symptomatic therapy, that is where most prescribers are going first. But certainly have had, y ou know, there are prescribers who are offering it to any patient. I think, you know, one interesting, sort of, scientific insight that I think we're starting to generate in conjunction with the community is that, ISM is a progressive disease. I think historically, it's been viewed maybe as, as not being that. There's been historic data that has said that progression rates from ISM to advanced disease are maybe in the single digits, and increasingly data is coming out to suggest that that may be more like 20%, and particularly for our KOLs to understand that, I think the urgency to intervene with a disease-modifying therapy early on is higher, and that's a place that we're continuing to explore in conjunction with the community, and I think we'll see more data generation around that as we go forward. Makes sense. Can you just talk about the launch trajectory going forward? I know it's still early, but, you know, how should we think about that? Should we be thinking slow and steady? Is there opportunities to sort of accelerate that over time, or any of your thoughts there? I think steady. I wouldn't use the term slow. We've definitely seen, as I said, a really exciting inflection, you know, even in that last month of the quarter. Part of the reason we're sharing patients on therapy is to sort of help people triangulate what's reasonable to expect going forward. So I think even just looking at our experience in Q2 can be helpful as you're thinking about the next couple quarters, where, you know, we added an incremental 35 patients really in that last month above the baseline of about 10 patients a month that we had been adding, right? So that, that can be a way of thinking about it. We are early in this launch. We have said we're not gonna guide until we have a little bit more experience under our belt, and so, you know, we'll provide more guidance, likely next year in conjunction with our Q4 call, as has become our approach. But I think that steady growth in patients on therapy is reasonable to expect. We said, you know, we don't expect a bolus. We have no indication that what we're seeing is a bolus. That's good, right? That sort of bodes well for our ability to continue to grow patients treated. And this is a chronic indication, and so, you know, the idea of growing patient, having consistent, strong patient starts really sets you up very well to see revenue inflect as we go forward. Will you continue to give us those patient metrics through the remainder of this year, or will you stop at some point? No, I mean, that's our intent. Part of the reason we started doing it, you know, Q4 of last year was really, again, in anticipation of this and knowing that in, particularly in a launch where you're kind of adding patients, patients are a leading indicator of revenue, that giving some color on quarter exit patients should be a helpful way for people to understand sort of what that trajectory is looking like. Can you maybe talk about just expectations around duration of a patient on therapy? So we expect that to be, you know, extended. It's a chronic disease, so there's really nothing, I mean, if we think about advanced systemic, we see average duration or median duration of around 18 months. And when we see patients discontinue for advanced systemic, often it's clinical issues that are driving that, right? It could be progression of an AHN, it can be bridging to bone marrow transplant. Those dynamics don't exist in non-advanced disease. Obviously, there's no drug that patients stay on forever, right? So in chronic markets, certainly you could see durations of several years, if not more. So we'll continue to keep an eye on what we're seeing, but all early indications are positive. Importantly, I think our clinical experience from PIONEER is also really positive, where we saw, you know, very few discontinuations, really strong profile in terms of tolerability, strong rollover of patients into Part 3. Got it. Maybe just last question on AYVAKIT before we move on to some of the pipeline. Just can you comment on pending competition here and how you view your positioning coming up? Yeah, I mean, AYVAKIT is the standard of care for, for the treatment of ISM, and sets a really high bar for any therapy coming forward, including any therapy that we would develop coming forward. We're, we're well aware of the very, very high bar that's set by PIONEER, and also the fact that, you know, we have a significant head start in terms of, you know, patient and prescriber comfort, data generation, et cetera. So I think the bar for a new therapy coming in is to be able to demonstrate symptom benefit in a clinically meaningful way across all symptom domains in ISM, in a way that's differentiated from AYVAKIT. And that, I think, is a very, very high bar. It's not enough to show, you know, objective measure data, which we know does not correlate. It's really being able to show how that translates through to symptom benefit. Got it. You brought up the 263 or elenestinib. Obviously, we have some data there, second half. Maybe just share your current thinking on the strategy there, and what do you need to see to move this forward, and how would you move it forward if you decide to do that? So maybe I'll start high level, and then Fouad, I'm sure, will wanna chime in on this one as well. So, you know, our strategy around elenestinib or BLU-263 is really life cycle management of our franchise, and that's been something that's evolved. You know, initially, BLU-263 was developed as a backup for AYVAKIT, something we do across our portfolio, before we really had data to understand what the profile of AYVAKIT would be in the clinic. Now we understand that, and so we are very confident that SM is a significant opportunity, that AYVAKIT will penetrate it and therefore be a significant asset in our portfolio. And so having a life cycle management strategy that, you know, comes into play, particularly as we think about, like, the mid- to late 2030s and beyond, can be very valuable. There's also considerations around things like the IRA, that make having a next-generation asset, you know, potentially valuable. In order to capture that value down the road, we know we need to differentiate. And we are in a strong position to do that because we now understand how to develop therapies in SM, how to think about things like novel endpoints, different patient populations, and sort of skate to where the puck is going. So you know, we'll be strategic in what data around 263 we share, knowing that we are in a competitive environment, and we've seen people take lift, lift and shift a lot of what we've, we've done from a competitive perspective. So we'll be thoughtful about that, but you can talk more about, about that. No, very well said. I mean, the only thing I would add, Michael, is, when we think at Blueprint, about elenestinib or 263, we really think about what the treatment and the management of SM will become, in five to six years from now, not repeating the AYVAKIT PIONEER study, the work we started back in 2016. So it's really and we are actually with the academic community in the driver's seat, in shaping how the management of ISM, well, is going to become. We're very happy with the feedback we are receiving on avapritinib, the reception of avapritinib and ISM by key opinion leader experts, investigators. And I think we have a strong advantage as a company to think about what's going to happen a few years from now, instead of just copying a PIONEER study. Gotcha. Maybe we can shift to BLU-222, your, your, CDK2 inhibitor. You shared some data earlier this year. Maybe just remind us what you saw there and, and what kind of drove your excitement. So, BLU-222, or our CDK2 inhibitor, is something that I really believe eventually will have impact on patients and have that potential, at least at first, because the target is an important one. The people will remember ASCO 2023 as the time where two companies separately, it was a Pfizer team and Blueprint team, showing data in a new target, not only preclinical data, but clinical data, that they're validating basically the target and trying to really transform the resistance to CDK4/6 treatments or CDK4 in hormone-positive, HER2-negative breast cancer. I think the data we reported at ASCO is very compelling and very promising. We showed some clinical activity, which is not expected with these agents to see clinical activity. Those are also really a big, another good surprise, back to the earlier point on the label of avapritinib. The safety profile, we believe, is going to continue to be differentiated with really not that much of hematological toxicities, and we have the potential to be best in class. Where we are now with our CDK2, we are in the phase where for monotherapy, we are determining the RP2D. And on the combination side, we are moving pretty fastly or quickly, the combination with ribociclib and hormone therapy, namely fulvestrant, in a patient with hormone-positive, HER2-negative breast cancer. So that's really something that we are very excited about in our pipeline. When can we get the next sort of update, and will it include the monotherapy and the combo as well, or will those be? In 2024, we will report data from the dose escalation and safety at the beginning, for the combination of ribociclib and hormone therapy in hormone-positive breast cancer and also monotherapy data. As we get closer to it, we'll, we'll be able to guide more precisely on the timing, but it's next year. Yep. Gotcha. And you mentioned for the Pfizer product, and as we think how this could evolve going forward, is it should we think you have to differentiate and compete directly, or are there opportunities to maybe do something different, or is it large enough that you don't need to be differentiated? I think if you think about our corporate strategy overall, today, we have really two sides that are both comparing to Blueprint Medicines. The oncology side will be precision at scale, because we're already going to larger opportunities than back in the day, when we are interested in, you know, 1% and 2% of cancer. And on the other side, obviously, we talk about probably later, the AI side of Blueprint and mast cell and so on. So clearly, I mean, the opportunity for CDK2, to your question, is are patients with hormone-positive, HER2-negative breast cancer. That's actually a large number of patients that we can help. I really think it's in, w hen you have great targets and when you have broad population of patients, I think it's a good thing to have two or three leading companies, you know, driving the field. Mm-hmm. And creating the opportunities. We, and I have been a part of stories like that in different areas in oncology in the past. When the targets are compelling, the opportunity is also compelling. I think it's a good thing to be a couple of people helping the disease. Makes sense. Maybe we can shift to the EGFR program. You got two assets in development there. Maybe remind us of the strategy and what you've seen so far. So let me start with BLU-945, that is targeting the most frequent sensitizing mutations in EGFR-mutated non-small cell lung cancer. That asset was developed initially to target a smaller group of patients with triple-mutated EGFR non-small cell lung cancer. We have seen early preclinical data that really made us think that beyond that very small portion of patients, we can go to the earlier setting of the L858R mutation in combination with osimertinib and really be able to improve on what osimertinib does in that population of patients, compared to an exon 19 deletion data with osimertinib. Actually, we have today recruited the patients in the dose escalation study, and we are really gathering the data, and we're going to have. You know, we put the bar very high, well, for reasons to go to the frontline in first line. So we'll obviously looking at what we have in terms of data, trying, we'll make that choice in the next months. And also, we are looking also at the environment. What is, you know, is the standard of care changing environment, and what is there a new bar to hit? So all these elements between our own data that is coming to us and the environment, I think we'll be able to really make the choice whether or not we will move to frontline BLU-945. But that's too early to tell now. BLU-451, we, when we acquired Lengo Therapeutics, we said that in order to be the best in class, it's obviously about safety over, you know, selectivity over wild-type EGFR and covering all the exon 20 insertions and being an oral agent. But most importantly, is being able to deal with the CNS metastasis, the brain mets disease in exon 20 patients. That's actually the challenge. Nobody is able to do really a very good job at this today. So we said, for us, in order for this to become a leading agent in the class of exon 20 molecules, we would like to see robust activity in the CNS. We are continuing those escalation. We are having, you know, more patients in the study. We're still not at the MTD, RP2D level. We are seeing some CNS activity, but it is early days. I think sometime next year, we will be able to look at the totality of the data when we have it, and we have the dose and see if the activity we are seeing in the CNS is something that will make BLU-451 a best-in-class. But so far, we are really tracking pretty well on BLU-451. Gotcha. Maybe just quickly back to 945, can you remind us when we might see the next update there, or how you're thinking about that? We have not guided to the next update. I think we are in the midst of gathering the data from the phase I. We have a good number of patients. As soon as we are able, we see the data and we are able to disclose the data, we will guide you on that. Yep. Makes sense. And maybe just in the last two minutes, if you can touch on BLU-808. You recently sort of announced that one. Why is that attractive, and, and what are you seeing so far pre-clinically? Yeah, I think, I mean, having been urged by the allergy community to really look at wild- type KIT as a target for allergy in general, in particular chronic spontaneous urticaria, and these are the same, you know, treaters and investigators that we have been working with in the ISM world, as you know. We spent the last two years developing an agent that we believe has the potential today to be the first and best-in-class tyrosine kinase inhibitor wild type targeting for CSU and maybe other diseases. As we mentioned earlier, the preclinical data we have seen have been very compelling. We declared the candidate a couple of months ago. It is in IND enabling work now, and we expect to start the clinical work sometime mid-next year. Our first target for in terms of disease is chronic spontaneous urticaria, where we believe there is a large unmet need. As we know today, after H1 and H2 drugs and, and so there, there are really no solution for patients. Large number of patients, and the majority receiving cyclosporine, which we know patients don't like, and their physicians don't like it either. So I think there are opportunities to go there. I think, our aspirations, in terms of helping patients in mast cell disorder go beyond, treating, chronic spontaneous urticaria. We can think of mast cell disorders being in the respiratory system or even in some, you know, bowel diseases. So that will be really a next chapter. back showing how we're developing, as we continue to push the likes of CDK2 in oncology, we are also developing really a very solid expertise in the world of ISM. Great. Sounds like a lot of exciting things going on. Why don't we just stop there? Thanks, Christy and Fouad. Appreciate your time today. Thank you. Thank you, Michael.