Hello, everyone, and thanks for joining our Stifel Immunology and Inflammation Virtual Conference. This is predominantly being hosted by my colleague, Alex Thompson, but my name is Brad Canino, and it's my pleasure to host Blueprint Medicines, and for our next fireside, we have a great tag team to cover end-to-end the state of the business with Christy Rossi, Chief Operating Officer, and Percy Carter, Chief Scientific Officer, so thank you so much for joining us. Thank you, Brad. Thanks, Brad. Now, before this call, I was actually reflecting because about a year and a half ago, we hosted Percy and Fouad, your President of R&D, at our Stifel Oncology Summit, where we actually made the decision not to discuss ISM, because at the time, so much of other firesides were focused on that. But now here we are. Christy, you're a year into establishing Blueprint as a successful commercial company in a subsegment of mast cell-mediated diseases. So what is the strategy to leverage that towards growth in the broader allergy and inflammation space? Yeah, thanks. Thanks for the question, and again, thanks for having us. We're thrilled to be able to participate in this summit. You know, allergy and inflammation is a space that Blueprint has been moving towards actually for some time now. In fact, we were just having a discussion earlier today reflecting on when I joined the company in 2018, and at that moment, ISM was really emerging as an incredibly compelling commercial opportunity, albeit one that we did not necessarily have, you know, a clinical data set in yet, and what has evolved over the last several years is, you know, our increasing knowledge of the systemic mastocytosis space, working very collaboratively with KOLs and patients in this area, and also understanding the transformational benefit that Ayvakit can provide to patients with SM. We're really seeing, you know, that come to fruition now in the commercial launch of Ayvakit, which, as you say, we know we're now more than a year in, has been going incredibly well. You know, we're driving a significant amount not only of commercial revenue and revenue growth against an opportunity that we see as being well north of $2 billion, but a tremendous amount of patient benefit. You know, part of what that has enabled us to do is, you know, as we've engaged, particularly with allergists and in this space, really start to understand some of the other opportunities that are there from a medical need perspective. We have, obviously, elinestinib coming behind Ayvakit, from a lifecycle management perspective, that we think will enable us to continue to address where the systemic mastocytosis space is moving and the needs of patients as they continue to evolve into the next decade and beyond. And then importantly, BLU-808, which, you know, is a program that, while we just brought into the clinic very recently, and Percy can speak to this, you know, we've been working on against this target for quite some time at Blueprint. Being able to achieve the kind of potent and selective wild-type KIT inhibitor target that we're looking to achieve with BLU-808 was not an easy task from a chemistry perspective, but very excited about the potential for that program to, again, you know, address patient needs in very significant spaces beyond SM. You know, we have a lot of knowledge and sort of operational leverage now in the allergy and inflammation space, and a significant amount of, you know, scientific expertise that we can bring to bear as we bring forward additional programs into the clinic. Right. And now, Percy, I'm looking forward to diving into BLU-808 specifically, but maybe at a high level, as we step back, in your labs, as you think about design principles for compounds intended for the oncology markets and then the allergy inflammation markets, what are the commonalities, but what are the differences now that Blueprint is also implementing? Yeah. Thanks for the question, Brad, and thanks for hosting us today. So actually, there are really more commonalities than differences in today's world, right? So very strong emphasis, obviously, on the mechanism of action and making sure that's gonna have the intended, you know, therapeutic effect on the patient population. Still at Blueprint, we do have a strong desire to match mechanism to a patient population, right? To ensure that we're bringing the right drug to those patients. And then across, really across all of our work, whether it's a small molecule program or a targeted protein degrader, whether it's for oncology or for inflammation, we have a very heavy emphasis on selectivity. I think the company has done historically a great job with that, and we continue to emphasize that today. I do think in the context of, you know, an otherwise lethal oncology indication, there are some considerations around therapeutic index that might permit a slightly smaller therapeutic index, but we don't really incorporate that from a design perspective, Brad. We actually look to come in and bring in highly selective, highly potent molecules with the right pharmacokinetics. Very helpful. And then, Christy, you know, for the disease Blueprint will target in the future, 'cause you, you're mentioning a lot of this inbound knowledge is actually coming from the allergists where you're installed today, but how important is the achievement of a drug profile that can be used broadly across physician specialties that treat allergic diseases, even beyond those allergists today? That's certainly, certainly the goal, and I think, you know, a very, a very attainable goal. And actually, what I would say is, you know, even if, again, if we look at the profile of Ayvakit, one of the incredible strengths of Ayvakit, you know, 25 milligrams in ISM is that you know, it's one pill once a day with an incredibly compelling clinical profile and a very well-tolerated safety profile that supports long-term dosing. And so what we're hearing and seeing is a lot of comfort in the community utilizing Ayvakit. You know, physicians are able to keep patients in their practice and really be empowered to treat them versus feeling that they, you know, potentially would have to refer them. Of course, systemic mastocytosis tends to be treated primarily by allergists or hematologists, so that's where we're seeing a lot of the use. Although we've seen, you know, dermatologists and other, you know, specialties, advanced practice clinicians being comfortable prescribing Ayvakit as well. When we think about these larger indications that we would be targeting with BLU-808, of course, it's a much, you know, even broader physician population that we will be potentially educating and interacting with. And again, you know, if I think about one of the advantages of BLU-808 from a profile perspective as we bring it forward, again, you've got a small molecule. You know, the goal certainly is that we hope to see a very, you know, favorable benefit-risk profile, one where we can really tune dosing and therapeutic window to, you know, to the needs of the patient in front of us. And if you compare it certainly to other strategies like, for example, biologics, I think there's a lot, you know, a lot to be said for the benefits of an oral approach that fits really nicely into, you know, a very broad range of practice settings as well as for patients. Yeah. Now, Percy, the company has described BLU-808 as having gone through multiple years of very deliberate preclinical development. What would you highlight as the key aspects of focus that went into that effort to obtain the ideal profile? Yeah. So, Brad, we started the program in the middle of the year 2021, actually shortly after I arrived at Blueprint. And the team made, you know, really rapid progress in terms of potency, selectivity. And ultimately, what we really spent our time focusing on is ensuring selectivity against the broadest range of off-targets possible, right? So again, emphasis on safety. And actually optimizing the pharmacokinetic profile, which actually plays into the comments that Christy was just making. We really wanted to ensure not only oral bioavailability, but you know, low dose and once daily PK profile. Mm-hmm. So the team did a great job. Did a great job with that. Yeah. Now, there was a previous oral wild-type KIT inhibitor from Third Harmonic that ran into liver toxicity early in human testing. How possible is it to better predict and limit the risk of such a safety event before moving into the clinic? Yeah. Yeah, the historical, I think it was THB-001, I think was the compound number. Yeah. So yes, at a general level, liver toxicity is a focus of all preclinical safety assessments. And you know, today, if I look today relative to when I started my career, the field in general has brought forward a number of new tools, some of which are in vitro, some of which are in silico, and then, of course, the traditional armamentarium of in vivo assessments. Moreover, our colleagues at Third Harmonic have indicated that their concerns relate to reactive metabolite. In fact, of course, the tools now for studying metabolism have also increased. So I think as a field, we're well positioned to study those issues now preclinically. Okay. And then maybe looking forward into the future in the clinic, 'cause a lot of these patients might be on other concomitant medications that they take chronically. How do you think BLU-808 could perform when dosed with those other medications that they're using for allergic diseases? Yeah. So this is an important question, and definitely something when I mentioned before about, you know, optimizing the pharmacokinetic profile. Part of it, of course, is optimizing for the PK profile of the molecule that you intend to administer. But part of it is also making sure that that molecule doesn't have any drug-drug interactions with other concomitant medicines that might be taken. And so in the case of BLU-808, that was definitely part of our design criteria, and we're very, very pleased with where the team netted out on that and encouraged that the combination is something that should be possible. Again, when we think about small molecule pharmacokinetics and the ability to come in once daily with a well-behaved molecule, what we can do is we can control that peak to trough ratio. So we can... We think about the desire to combine. In some patient populations, we may want to have sort of dialed up the level of KIT inhibition, perhaps to an antibody-like level. In other patient populations, we may wanna be, you know, running at a slightly lower level of inhibition, you know, an IC50 or an IC70. And by having that well-controlled PK, that allows us to do that, just sort of once a day, kinda keep it in, sort of, have that drug concentration sitting at that level. Okay. And you've actually published some work with 808 in an animal model. Yes. So I guess as we think about all those preclinical design elements, what was the key profile demonstration in that model relative to the competitive antibody approach that we think about? Yeah, so both in vitro and in vivo, what we wanted to demonstrate was that, the molecule would have an element of tunability to it as it relates to PK, so again, our ability to come in at different levels and achieve and maintain those levels on a daily basis, and that in vitro and in vivo, we could demonstrate that pharmacologically, the molecule was well-behaved, right, so if you think back to your basic biochemistry classes, you know, you're looking for sort of sigmoidal dose-response curves, right, so well-behaved response in vivo, you know, correlating to a certain coverage ratio. That's exactly what we see with the molecule, and we've shown that actually in the Quad AI poster in a number of settings and number of different assessment points, including, as you mentioned, Brad, an in vivo efficacy model, where you can see that again, it's possible to be at sub-maximum levels, but still achieve, you know, meaningful inhibition of that. ... Yeah. And now, Christy, Percy touched on this a little bit around the aspect of the dose range. As you think about it from a commercial perspective, selling to multiple different physicians and specialties, how critical of a component is that for a profile of the drug, in your view? Yeah, I think, you know, in general, one-size-fits-all approaches, you know, may not work for a diverse set of patients and indications. And we know that, and certainly we know that from our experience with Ayvakit in systemic mastocytosis. Again, where we, I think that proves a bit of the sort of theory here of, you know, it is possible at very low doses to inhibit mast cell activation, and at very high doses, we, you know, can rapidly deplete mast cells and impact mast cell burden in a quick way, which is indicated in more severe patients with advanced SM. Having a range of dose strengths across that spectrum has been really one of the more compelling parts of the Ayvakit profile and the fact that, you know, physicians are able to adapt and customize dosing based on the needs of the patient in front of them. Obviously, we're gonna have to get into, you know, studying BLU-808 in patients to really understand what is needed, you know, across these different indications. But, you know, we sort of... We understand how to develop therapies in spaces where you may need to adapt dose and be able to tune the therapeutic window based on, you know, the patient in front. And that's something that we'll be looking at as we bring it forward across, you know, a range of potential therapeutic indications. Okay. And then, Percy, one of the debates now among investors and even companies is the anaphylaxis potential risks from antibodies. We have seen some reports for some of the companies. Do you expect an oral wild-type KIT inhibitor to have that potential anaphylaxis risk? No, but I, that's not something we expect with BLU-808. I mean, I think as you're aware, certainly antibodies in general, anaphylaxis is a risk that everyone runs into with antibodies. In the context of 808, being a small molecule, we would not expect that risk, and none of our data preclinically point to that. Okay. Maybe moving, Christy, to some commercial questions for Ayvakit. You know, oftentimes you've described the guidance as the best estimate of a number of variables that are incorporated. I think most important for me, and likely for you, is the element of new patient additions. I'd just like to ask at the top, how has the rate of new ISM patient additions in the past months been relative to what you've experienced in first half? We have seen very steady new patient starts and very favorable trends on duration of therapy really since launch. You know, this is a rare disease launch, so of course, as we've said, there's always gonna be variability kind of week to week, but we have been really pleased to see, you know, continued robust new patient initiations and again, importantly, you know, very strong trends in terms of keeping patients on therapy, which, as we continue to, you know, progress through this launch and have a growing base of patients on therapy, becomes more and more important. Obviously, I'm not gonna comment on Q3 that we're in the middle of. We will be sharing our results when we report Q3 earnings. But if we kind of take a step back, you know, when we talked about the guide, again, you know, did talk about some of the different variables that impact that, including some of the factors that impacted the first half of the year, like free drug, et cetera. We've talked about our international performance and some of the other variables that impact, you know, sort of revenue on a quarter-to-quarter basis. The big picture is we are at the very beginning stages of, you know, a blockbuster launch and, you know, we've raised guidance now twice. You know, we are gonna be approaching a $500 million drug, you know, this year. And, yeah, you know, are very not only excited, but really pleased about, you know, what we're seeing in terms of how performance now portends what the peak of this could look like. I think it's, you know, one of the most exciting launches that is underway and, you know, really a lot of headroom to continue to grow and impact patients in what is, you know, really a prevalent rare disease. Yeah. Well, you provide a very handy chart in your quarterly earnings deck on this prescriber breadth and depth chart, which is wonderful, but also, as an analyst, very frustrating because it doesn't include a y-axis on the label for numbers. Right. So it's going up and to the right. Yes. But how much headroom is left in terms of new practice activation for growth in the U.S.? Yeah, quite a bit. There's quite a bit of headroom to continue to activate practices as well as, as I said, to continue to, you know, penetrate patients on therapy. Because what we're seeing is that this market is growing and evolving underneath the launch, which is exactly what we had hoped to see. The chart you're referring to, I'm sure many people who follow Blueprint closely will know that chart. It's a chart we've shown in earnings calls, a few quarters in a row. And, you know, it's meant to be illustrative of kinetics rather than sort of an absolute, you know, representation of breadth and depth. That chart is focused on our penetration into, you know, a small number of top accounts that have the highest volume, patient potential. Our true breadth is well, well beyond that, right? So we see utilization of Ayvakit in a broad set of prescribing settings. But I really like that chart because, you know, it sort of shows the kinetics that we've continued to really steadily add new prescribers. And then once we get that new prescriber on board, we see prescribers finding more patients both because they're widening the aperture of, you know, who they think an appropriate patient is. They're more motivated to find these patients. And patients' behavior is also changing as we continue to, you know, evolve through the launch, where patients are seeking care. They're finding providers who have experience treating systemic mastocytosis because they want to be given, you know, the possibility of having a therapy like Ayvakit that can really impact their lives. You know, again, we're in the early innings. There's a lot of headroom, but I think those trends, you know, again, are a nice proof point around the fact that we are really kind of seeing that very strong, steady growth. Yeah. Now, in the U.S., you, you're talking about a prevalent pool of uncontrolled patients of 9,500. Now, that's a dynamic number. Yeah. We'll speak next year. That might be different, but let's keep it static for now. Yeah. I think generally the question is, you know, what proportion would be realistically prescribed for Ayvakit? I actually want to flip the question and ask, what would prevent you from capturing the majority of those patients? I think it's a great question. You know, there is really nothing, to your point, that, you know, would make a patient not a candidate for Ayvakit, barring some specific medical issue that, you know, would be sort of a contraindication to therapy for some reason. So, you know, we have a profile that, again, is really, I think, compatible with broad use. And, you know, what we're seeing in the launch is, again, you know, prescribers getting comfortable. We're really changing the paradigm of treatment away from symptomatic therapy and towards one that addresses the underlying driver of the disease. We're seeing providers understand that the benefits of treating, you know, can extend beyond just how a patient feels day-to-day, given that they are living with really what is a chronic malignancy in some ways, right? I mean, you have cell proliferation going on here that these patients are living with for years and years. And we're also seeing patients really you know understand more about their disease and become activated and you know want to seek treatment. And so those are all the dynamics that you often see in a launch, right? I mean, you have to kind of you know move through the dynamics of getting people educated, comfortable, getting patients activated, and we're seeing- Mm-hmm ... that sort of happen underneath us, and I think that will continue to happen. I mean, I've never seen a market where every single patient is on a therapy. But again, if you think about a prevalent pool of 9,500 patients, that's a multibillion-dollar opportunity in the U.S. alone. Yeah. If I could just double-click on the free goods reduction that you've talked about. This, you described that as a tailwind for the first half, as the mix shift has moved towards a higher proportion of ISM patients that are on commercial, and you're capturing revenue from them. You know, I guess the question everyone has is: how does that potentially impact sales performance in the second half, and how does that variable drive in to your guidance as a dynamic element? It's a great question. And just, you know, to kind of orient everyone who's listening, there have been a couple of, you know, sort of drivers of that tailwind, where we've essentially seen a greater proportion of our patients on therapy be able to access paid therapy in the U.S., which is great, and I think from a overall kind of, you know, perspective of this opportunity over time is a very attractive component of it. We know that ISM is a more commercially skewing indication, like many other chronic immunology diseases, where, you know, you see a patient population that's a little bit younger, a little less Medicare. You know, that is a long-term, you know, favorable dynamic for us. We've also seen some of the impact of both IRA restructuring of the Part D benefit and, you know, patients being able to access external sources of support, enable more patients to access commercial therapy. As we look forward from here, I think there's two things to take into account. One is that those factors, because they happened, you know, pretty rapidly over a few quarters, certainly contributed to revenue growth quarter on quarter. So I think people just need to factor that in as they're thinking about growth. Mm-hmm ... in the second half of the year. And then, you know, in terms of where the free goods may actually end up, we think we're about in the, you know, in a ballpark where it's gonna be difficult to further improve. I don't think it will erode significantly from where we are, but we could see things sort of tick up or down by percentage points here or there. And a lot of this depends on, as new patients are coming in, are some of those factors that were in play in the first half still there, right? So external sources of funding for patients can come and go day to day. We have no involvement or control over that. So there's some of those dynamics that, you know, are a little bit more difficult for us to predict, and we just need to make sure that as we think about setting guidance, for example, we're accounting for the range of outcomes on some of those variables. Very helpful. Now, as we watch the commercial performance for the back half of this year, we're also going to see you move the second mutant KIT inhibitor into pivotal trials, elinestinib. So maybe a question to both Percy and Christy. One to Percy: did you design elinestinib to be a better version of Ayvakit for ISM patients? And Christy: how do you plan to create sufficient differentiation to extend your ISM franchise beyond the Ayvakit LOE? Yeah. So Elinestinib was designed to be a peripherally restricted molecule to sort of stay out of the CNS, and ... Yeah. Right. So as Percy said, you know, we had, it was really a follow-on to Ayvakit, which is something those of us, those of you who follow Blueprint know that we do, across targets that we think are going to be really important to the company. Certainly, KIT D816V is one of those targets. You know, the differentiation for elinestinib as we bring it forward, is really going to be, about starting with really good raw material, and then we have a, you know, very potent, selective, KIT inhibitor. And, an understanding now of what is, you know, what do we think is relevant in the disease process around SM? And what are the medical needs of patients now that we already have a really good therapy available in Ayvakit, right? How do we think about what else we can do to really impact the prognosis of these patients over time? And so, you know, as we think about designing a study, now we have the wherewithal to be able to think about developing a differentiated set of clinical evidence that, you know, frankly, we just were not in a position to do back when we started Pioneer. We know so much more about the disease, the long-term outcomes of these patients, having followed them over time, having, you know, data on patients on Ayvakit for many, many years now. And so, again, as we think about bringing elinestinib forward, we're gonna share more about exactly what is the design of the next phase of Harbor look like. You know, what we're not going to do is simply redo the PIONEER study with elinestinib. You know, we don't think that's really adding to, you know, the sort of, the treatment paradigm for ISM in a meaningful way, and that is absolutely our goal. Okay. And if I could steal one more minute while we've got Percy here, because I'd love to ask about the protein degradation platform that you mentioned earlier. One, just generally, is the therapeutic area of focus for that exclusively allergy, inflammation or predominantly allergy and inflammation? And then second is, how does Blueprint uniquely leverage that platform relative to, say, some of the other public companies that are focused specifically on protein degradation? Yes, great question, Brad. So as you know, the protein degradation space is fast-moving, just very exciting area of science to be involved with. Our initial focus has been actually in oncology, is where we started the effort. And then over time, we have brought in immunology, the allergy inflammation space. And so now we're sort of moving to a place where we're really operating across our portfolio. As we look at every target, actually, we consider whether the optimal profile is going to be achieved through a inhibition approach or through a degradation approach. As it relates to the approaches relative to others, I won't say anything at this early stage of our platforms. As we, you know, describe our first development candidates in this coming, you know, time period. We can kind of talk more about that, about why we're excited about it, but what I would say is it's, it is a great area of science, and we're certainly, certainly impressed by what one can do with degradation. Okay. Unfortunately, we are out of time. But Percy, Christy, thank you so much for joining our Allergy and Inflammation Summit. Thank you. Thank you. you. Thanks for having us.