Title

Presentation

Blueprint Medicines Corporation misses on earnings expectations. Reported EPS is $-0.79 EPS, expectations were $-0.68.

Operator: Good morning. My name is Nadia, and I’ll be your conference operator today. At this time, I would like to welcome everyone to the Blueprint Medicines 4Q and FY 2024 Earnings Release and Conference Call. [Operator Instructions]. Cassie Saitow, you may begin your conference.

Cassie Saitow: Thank you, Nadia. Good morning, everyone, and welcome to Blueprint Medicines Fourth Quarter 2024 Financial and Operating Results Conference Call. This morning, we issued a press release, which outlines the topics we plan to discuss today. You can access the press release as well as the slides we will be reviewing today by going to the Investors section of our website at www.blueprintmedicines.com. Joining me today are Kate Haviland, Chief Executive Officer; Philina Lee, Chief Commercial Officer; Becker Hewes, Chief Medical Officer; and Mike Landsittel, Chief Financial Officer. Fouad Namouni, President, Research and Development; and Christy Rossi, Chief Operating Officer, are also on the line and available for Q&A.

Before we begin, I’d like to remind you that some of the statements made during the call today are forward-looking statements as outlined on Slide 3 and are subject to a number of risks and uncertainties. These may cause our actual results to differ materially, including those described in our reports filed with the SEC. You are cautioned not to place any undue reliance on these forward-looking statements, and Blueprint disclaims any obligation to update such statements. With that, I’ll hand the call over to Kate.

Kathryn Haviland: Thank you, Cassie, and good morning, everyone. At Blueprint Medicines, we are driving growth and innovation with operational excellence. Our aspiration is to fundamentally shift the way allergic and inflammatory diseases are treated by targeting the mast cell. This begins with AYVAKIT, our breakthrough medicine for patients with systemic mastocytosis. In 2024, we delivered $479 million in product revenue, representing impressive annual growth of 135%. AYVAKIT’s deep and sustained clinical impact in very strong safety profile have transformed the treatment paradigm in ISM. Today, we are pleased to announce our revenue guidance for 2025. We expect AYVAKIT to achieve $680 million to $710 million in revenue this year, placing us firmly on the path to realize $2 billion in revenue by 2030.

With a 45% growth rate at the midpoint, our expected 2025 revenue continues to position AYVAKIT among the most successful rare disease launches to date. And the SM market is bigger than we thought, and is growing faster than we expected, as we talked about at the JPMorgan conference in January. We now project that Blueprint’s SM franchise will reach a peak value of $4 billion with AYVAKIT as our anchor. We’ve gotten a lot of questions on what makes us confident to increase the peak SM franchise opportunity to $4 billion at this point. Our confidence is based on a few key factors. First, only a fraction of currently diagnosed SM patients today are being treated with AYVAKIT. We estimate that we have penetrated less than 10% of the existing pool of diagnosed SM patients.

giving us tremendous headroom for growth. Second, this pool of diagnosed SM patients is growing, and it is growing faster than we expected. We have seen consistent double-digit growth over the last 5 years. And as of today, we can see more than 25,000 diagnosed SM patients in U.S. claims data. Our team has done a tremendous job increasing awareness and the clinical suspicion of SM among providers. as well as establishing the commercial testing infrastructure needed to enable this growing number of providers who are catalyzed to pursue an SM diagnosis. And importantly, we expect this growth in diagnosed SM patients to continue for years to come based on our view that the true prevalence of SM is much larger than we originally thought. This larger estimated prevalence is informed by both new epidemiology data published in 2024 and our own real-world experience.

The new epidemiology data suggests a twofold increase in the number of SM patients relative to prior estimates, bringing the number of potential SM patients in the U.S., up from approximately 30,000 patients to 60,000 patients. In our real-world experience, we have seen SM patients being diagnosed from a broader range of providers than we expected at this point in the launch, most notably from medical dermatologists and gastroenterologists. As both med derm and GI start to actively look for ISM patients, they are finding them in their practice. Many of these health care providers are motivated to manage these SM patients directly and build their expertise in St. And this leads me to the last factor. The critical mass of experienced hematology oncology and allergy immunology providers that we have established.

This foundation of AYVAKIT experience providers will be an engine for growth this year, and we have a significant opportunity to continue to increase the depth of prescribing amongst this group while we also grow the breadth of new prescribers. In 2025, we are increasing our investments in education and market building initiatives as well as in the expansion of our commercial and medical field infrastructure. In order to drive multidimensional growth as we make progress towards our goal of $2 billion in AYVAKIT revenue by 2030. Philina is going to spend more time and go into more depth on our planned investments. and the factors that inform our 2025 guidance later on the call. Beyond driving AYVAKIT revenue growth, we have clear areas of focus to create value this year.

This includes building a durable SM franchise with elenestinib that will enable us to drive growth throughout the next decade. Elenestinib is our next-generation KIT D816V inhibitor. With our Phase III trial of elenestinib now underway, we are driving innovation in the treatment of SM by moving beyond symptom control to disease modification. We are prospectively measuring the impact of elenestinib on significant ISM disease morbidities in the HARBOR registration study. And we are confident we will be able to clinically differentiate elenestinib and deliver improved outcomes for ISM patients, putting Blueprint in the driver seat of innovation in SM for years to come. This year, we are also initiating a range of proof-of-concept studies to further define the broad potential of BLU-808, our next blockbuster opportunity.

The healthy volunteer data we presented last month showed that BLU-808 has a wide therapeutic index and impressive pharmacodynamic impact. BLU-808’s clinical profile positions it as the best-in-class and likely the first-in-class oral KIT inhibitor across a range of mass cell-mediated allergic inflammatory diseases that impact many thousands of patients. Later on the call, Becker will talk more about our next steps as we stand up our proof-of-concept studies, which we expect to begin generating data later this year. And last but not least, we are advancing our portfolio of earlier-stage programs that will be the core value drivers of tomorrow for Blueprint. Our 2025 capital allocation strategy is aligned with our plan for value creation. We are prioritizing investments that will enable us to drive significant near-term growth while solidifying us as leaders in developing novel mast cell therapies.

Importantly, we are leveraging our clinical development and commercial infrastructure, as well as our deep scientific expertise to drive growth and innovation, while at the same time, maintaining a financial discipline that only allows our best programs to advance. You can see the impact of our approach as evidenced by the significant reduction in cash burn we achieved in 2024. Mike will talk more about our investment plans and the strength of our financial profile at the end of the call. Altogether, we have an industry-leading expertise in targeting mass cell biology. We have a unique portfolio of novel mast cell targeting commercial and investigational programs. And we have a track record of operational excellence, which placed us in the strongest position we have ever been in as a company as we’ve set up 2025 to be another great year.

With that, I’ll turn it over to Philina to dive deeper into AYVAKIT performance. Philina?

Philina Lee: Thanks, Kate. Last year, I highlighted the importance of the first quarters of launch in setting the growth trajectory for a new product. Reflecting on 2024, I’m proud to say that our team has truly hit it out of the park, establishing a rock-solid foundation for AYVAKIT in Blueprint. Let’s look at our results. In 2024, we achieved $479 million in AYVAKIT net product revenues. Fourth quarter revenue was $144 million, with $124 million in the U.S. and $20 million ex U.S. Growth in the fourth quarter was driven by continued strength in the business fundamentals we’ve been reviewing throughout the year across our key stakeholders, patients, payers and providers. Starting with patients. We continued to see strong and steady new patient starts and low discontinuation rates.

Compliance remained high, and we saw a trend towards multiyear durations of therapy underscoring AYVAKIT’s sustained benefit and tolerability, which many patients have described as life-changing. In recent market research, 95% of patients strongly agreed they’re satisfied with AYVAKIT and more than 80% said they would recommend it to another patient. Now turning to payers and Access. Access remains strong in Q4 with robust payer coverage and fast times to fill. Our mix of free and commercial goods remained stable and similar to what we saw in Q3 as we expected. In Europe, our international team recently obtained ISM pricing for AYVAKIT in Germany. The price reflects AYVAKIT’s proven benefit risk profile and sets a benchmark as we move through additional price negotiations and launched ISM in more countries this year.

Last, let’s look at health care providers. In Q4, new and repeat AYVAKIT prescribers grew significantly in both academic and community sites of care. Let’s take a closer look at how we’re growing breadth and depth in this next slide. In prior quarters, we’ve talked a lot about breadth and depth of AYVAKIT prescribing in the top 400 providers by patient volume to show how first positive experiences with AYVAKIT lead to increased use over time. Over the course of this launch, our field teams have been engaging several thousand providers, establishing a large and growing base of prescribers who have experience and are motivated to diagnose and care for additional SM patients in their practice. These new charts now capture the full experience from all the providers who have prescribed AYVAKIT for SM since ISM approval.

There are a couple of important points to highlight here. First, you can see in the chart on the left that the total number of AYVAKIT prescribers has grown significantly. While we’ve seen growth in prescribing across the thousands of hem/onc and allergy specialists we’ve been targeting, the number of allergists with AYVAKIT experience has grown tenfold since ISM approval. This is crucial because many of the providers with the highest volume of ISM patients in their care are allergists,; both in academic and community sites of care. Second, positive first experiences with AYVAKIT are driving repeat prescribing and broadening the lens on who is an AYVAKIT patient. In the right-hand chart, you can see we’re growing the number of prescribers with multiple patients on therapy.

This is predominantly by allergists who are moving quickly to treat more of their patients. They’re finding AYVAKIT’s profile easy to manage with nothing beyond their typical check-ins, 2 or 3 times a year. The large and growing base of AYVAKIT prescribers across all specialties and settings, is an important lead indicator. When we activate a new prescriber, we’re planting a seed for future growth as we know that prescribers deepen use of AYVAKIT over time. Taken together, these results exemplify how we’ve built the engine for continued growth. As we enter the next phase of launch, we are making strategic high-return investments to drive growth over the course of this year and beyond. As Kate said, we’re scaling our infrastructure and expanding capabilities to reach more providers and patients, in line with the larger SM opportunity we see in front of us.

These investments are focused on 4 key priorities: first, driving urgency to treat with patients and providers through tailored peer-to-peer offerings and direct-to-patient initiatives. Second, generating and disseminating data on real-world AYVAKIT experience and ISM disease burden. Third, enabling ISM launches in additional geographies. And finally, expanding our commercial and medical field teams in the U.S. to broaden our reach to additional providers and specialties. The field team expansion is a key investment that will enable us to increase our interactions with heme/oncs and allergists and also broaden our reach to medical dermatologists and gastroenterologists who are managing SM. This will enable us to engage several thousand more providers, increasing the pool of diagnosed patients we can directly impact by 40%.

We plan to have our expanded team hired and in the field by the second half of 2025. We are confident these investments will continue to build this market drive growth and sustain AYVAKIT as the durable market leader across the spectrum of SM. Turning now to our guidance. The strong foundation and trajectory of growth we established in 2024 informs our revenue expectations for this year. As Kate mentioned, we expect to achieve $680 million to $710 million in AYVAKIT revenue in 2025, representing a 45% increase at the midpoint and robust year-over-year growth. At this point in the launch, we have good insight into the factors that drive our business overall and impact quarterly revenue. This includes more fundamental drivers of growth over the long term, such as new patient starts and discontinuation rates and the growth of our international business as we achieved pricing and reimbursement outcomes in additional markets through the year.

It also incorporates factors which can impact shorter-term revenue performance, such as compliance and free goods rate. Our guidance range is narrow and accounts for the variability we’ve come to anticipate across these key factors. With this guidance range, we expect to see strong and steady growth in patients on therapy through the year as more patients are prescribed AYVAKIT and stay on therapy, putting us further down the path towards realizing $2 billion in AYVAKIT revenue by 2030. Overall, we couldn’t be happier with where we sit today with another year of tremendous achievement under our belts and a proven track record of commercial and medical execution. With the vast majority of SM patients still untreated today, we have important work to do and incredible growth opportunities ahead.

With that, I’ll turn it over to Becker.

Becker Hewes: Thanks, Philina. In ISM, we know that providers and patients find long-term safety and efficacy data meaningful and motivating in the setting of a chronic lifelong disease. Later this month, we will share 14 presentations at the American Academy of Allergy, Asthma and Immunology Annual Meeting. A key update will be 3-year follow-up data from the PIONEER study of AYVAKIT in ISM. We now have a very large body of AYVAKIT data, including PIONEER results beyond 3 years that we can now combine with real-world evidence beyond 18 months. Together, these data confirm that 25 milligrams strikes the right balance of benefit and tolerability for the vast majority of ISM patients, enabling patients to stay on therapy chronically and continue to benefit over time.

At AAAAI, we will also present new data for the minority of patients with high disease burden, who escalated to 50 milligrams in the PIONEER study, with a median follow-up of 10 months post escalation. In these patients, 50 milligrams had a similar safety profile as 25 milligrams did in the 6-month registrational portion of the PIONEER trial and no patients discontinued treatment due to side effects. In addition, we will share data on the positive impact of AYVAKIT on bone health from a subset of patients in PIONEER who had bone scan data available. As Philina discussed, these types of data highlight the importance of early treatment to prevent significant morbidities driven by the chronic effects of the disease and provide additional reasons for both providers and patients to start treatment with AYVAKIT.

These data also underscore our decision to prospectively include rigorous assessments of bone density in the HARBOR study of elenestinib, which we designed in collaboration with the FDA. Now moving to BLU-808. At the JPMorgan conference last month, we were incredibly pleased to share positive healthy volunteer data showing BLU-808 was well tolerated with dose-dependent pharmacokinetics and rapid, robust trip days response. These data were exactly what we were hoping to see from BLU-808 in the clinic, and positively differentiate BLU-8028 from other programs targeting wild-type kit. BLU-808’s unique clinical profile and wide therapeutic index support our differentiated approach to development. exploring innovative dosing regimens to achieve the right balance of efficacy and tolerability.

Our goal is to provide meaningful clinical benefit to patients across multiple allergic and inflammatory diseases, with an oral medication that is well tolerated and can be taken chronically. Today, we’re working to initiate proof-of-concept studies in chronic urticaria and allergic rhinitis and conjunctivitis in the first half of 2025 and with additional studies in allergic asthma and mast cell activation syndrome or MCAS, in the second half. Our proof-of-concept studies are designed to inform the most efficient next steps in developing in development by exploring various doses and dosing regimens. In chronic urticaria, where wild-type targeting has been derisked by others, our studies will include several arms to measure the impact of various dosing approaches.

In allergic rhinitis and conjunctivitis we will also be looking to derisk mast cell biology and respiratory disease to inform additional development. Importantly, across all of our proof-of-concept studies, there are opportunities to rapidly generate informative data, and we expect to report initial data later this year. In MCAS, we see an exciting opportunity to tie together much of what we know about mast cells across our portfolio. Here, we’re working to utilize advanced diagnostic testing to help us better characterize patients with symptoms of mast cell activation who may benefit from our efforts in both AYVAKIT and BLU-808 programs. In the next installment of our scientific seminar series planned for the first half of this year, we will dive deeper into the biology of MCAS and the potential impact to the large number of patients suffering from this underserved disease.

We believe BLU-808’s unique profile and our differentiated approach can unlock true pipeline and a product potential, with the benefit of strong early data, our investigators and all of us at Blueprint are really excited to embark on this next phase of development as we pursue a new treatment approach that could have tremendous patient impact. Now over to Mike for more on our financial profile.

Michael Landsittel: Thanks, Becker. Earlier this morning, we reported detailed financial results in our press release. For today’s call, I’ll touch on a few highlights. 2024 was a remarkable year of progress with significant revenue growth and continued OpEx discipline, leading to further strengthening of our financial profile. As previously mentioned, we achieved total revenues of $479 million from net product sales of AYVAKIT, representing robust year-over-year growth. In addition, we reduced our operating expenses in 2024 compared to 2023 as we focused investment on our mast cell franchise programs and efficiently operated the business. As Philina noted, our 2025 revenue guidance and the relative narrowness of our guidance range reflects our confidence in our understanding of the fundamental drivers of our business.

We’ve also incorporated our view of the quarterly revenue dynamics inherent in our business into this range. For example, we expect Q1 to be more challenging due to a number of financial factors including the typical insurance reverification process challenges common across our industry that are now impacting a much larger base of patients on AYVAKIT as well as potential FX headwinds given the larger contribution from our international business. Looking at operating expenses. We anticipate a modest increase in both R&D and SG&A expenses in 2025 as we increased investment in commercial infrastructure and progressed development of elenestinib and BLU-808. Importantly, the inflection in AYVAKIT revenue, combined with a focused, disciplined approach to investment, led us to further reduce our operating cash burn by more than half last year.

And in 2025, we expect our operating cash burn to continue to decline significantly. We entered 2025 with a cash position of $864 million, and we expect our cash balance to be further strengthened by the approximately $80 million payable to us upon the closing of GSK’s acquisition of IDRx as a result of our equity stake. Together, this puts us in a position to be able to sustainably invest in compelling growth opportunities and drive multiple value-inflecting catalysts across our portfolio. With that, I’ll now turn the call back over to the operator for questions. Operator?

Operator: [Operator Instructions]. The first question goes to Brad Canino of Stifel.

Bradley Canino: The simple math on the guide calls for adding $215 million in AYVAKIT’s sales this year. But then to straight line from the end of this year to the $2 billion number in 2030, you’ll need to step that up to around $260 million in absolute sales addition each year from ’26 to ’30. One, am I thinking about that right? Two, what is the most important lever you have to pull to increase the absolute sales dollar addition in year 4, the ISM launch and beyond?

Kathryn Haviland: Thanks, Brad, for your question. We are incredibly pleased to be able to project the midpoint of our ’25 range to 45% growth rate, which is — really puts us again, in pretty rarefied air relative to other rare disease launches. And to see this type of growth is really incredibly exciting. Chris, do you want to talk a little bit more about Brad’s questions relative to ramp?

Christina Rossi: Yes, sure. So as Kate said, we are really pleased with the growth that we see coming for AYVAKIT in 2025. And — this growth rate puts us very much in line and actually at the upper end in terms of analog rare disease launches that we see. . I’ll also note that if you just look at external views on consensus now and in 2030, I think this is very much in line with that ramp. So a very reasonable ramp. What we are seeing in terms of steady growth in patients on therapy is really being driven by the growing base of experience that we have with AYVAKIT. We’ve spent the last building a really strong commercial foundation and really an engine that will drive continued growth. We now have more prescribers that are experienced.

We know that once a prescriber has that positive first experience they go deeper. So we’ve planted a lot of the fees that are going to drive that growth over the next several years. I also think some of the investments that Philina mentioned in terms of expanding our commercial field infrastructure are really putting that foundation in place to drive growth into ’26, ’27 and beyond, right? So it’s really about building that foundation that will enable us to reach more of the patients who are diagnosed with ISM and get them on therapy. So we’re very much at the early stages of this. There’s a ton of headroom for growth. And we really see a strong steady growth to get to 2030 and the $2 billion goal that we set.

Operator: The next question goes to Salveen Richter of Goldman Sachs.

Salveen Richter: Post reporting 808 data in healthy volunteers, could you just speak to us about how derisked do you believe the safety profile is and how you’re thinking about potential dosing strategies and the different indications. And as we look at these indications of CU, asthma and others, you read through as well as when we might see these data sets.

Kathryn Haviland: Yes. Thank you, Salveen, for that question. As we said at JPMorgan and Becker just mentioned, we’re just incredibly pleased with the profile of 808 is exactly what we’re hoping to see healthy volunteer study. And now we’re embarking on moving into patients. So Becker, do you want to talk a little bit more about how you want to think about the derisking of the healthy volunteer data and then also just what we hope to see this year?

Becker Hewes: Yes. Sure. So Salveen, the healthy volunteer data gave us a very wide therapeutic index. We have multiple doses that we can work with, and we have multiple different strategies that we’ve talked a little bit about before to dose the molecule. This includes a single dose does chronically. It includes dosing strategies where we start with a brief high dose and then go to a lower dose to maintain a response or one where we titrate to an effect either in a patient or a patient population. So what we’re doing in the first half of the year, particularly in the chronic urticaria space and the inducible urticaria space is we’re using a purely kit-driven disease to better understand some of these dosing strategies that we can then apply differently to different disease indications.

And so in the second half of the year, we will get into asthma and to MCAS and better understand both in those diseases, how to use the various dosing strategies that we’re elucidating in the first half of the year. And as I mentioned in the prepared remarks, our expectation is to be able to share some of the early data from the first 2 — or at least 1 of the first 2 programs in the latter half of this year.

Operator: The next question goes to Michael Schmidt of Guggenheim.

Michael Schmidt: I just had a follow-up regarding 2025 guidance. And so — how much of the expected growth in 2025 is driven by your expectation of continued use of AYVAKIT in existing patients versus adding new patients? And when I look at the chart on the slide 7, it looks like a lot of the prescribers have only 1 patient on therapy. How much opportunity is there to prescribe the drug to additional patients at those existing prescribers versus adding new prescribers to drive some of the growth?

Kathryn Haviland: Yes. Thank you, Michael. I think what we’re really pleased about is that we’re off to an incredibly strong start. And as we said, we believe that less than 10% of the currently diagnosed SM population is currently on AYVAKIT. And to your point, we have a tremendous number of prescribers that have an opportunity to both deepen their experience as well as adding new prescribers. Philina, do you want to talk a little bit more about that?

Philina Lee: Yes. As Kate mentioned, we see tremendous potential to continue to drive growth, both from breadth and depth. Importantly, when we look at that chart of providers, I think the most exciting piece that jumps out to me is how it shows that AYVAKIT’s experience appeals to a broad base of customers across all specialties and settings. We see adoption across both hem/onc as well as growth in the allergy-immunology setting and as we expand our field force, we’ll also be broadening the range of providers that we’ll be able to engage. So we would expect to see breadth to continue to grow. We also expect to see deepening because with every provider who starts a patient on AYVAKIT, we know that, that first positive experience will lead them to identify additional patients over time. It’s really like planting a seed for further growth. And so in short, I would say we would expect to see growth across all of these dimensions.

Kathryn Haviland: And one thing just to note for you guys. I mean I know we have shown this type of visual representation of breadth and depth previously. This is a little bit of a different view. And Philina mentioned this in her prepared remarks, we had typically looked at the top 400 providers by what we look at SM volume. We’re now showing you everyone since ISM approval, who has been prescribing AYVAKIT. And I think what you see here and what we’ve always said is we’re calling on multiple thousands of these providers, and we’re seeing uptake not only in those concentration providers, but also throughout the middle and tail of this to Philina’s point. So AYVAKIT’s profile is very conducive to a range of specialties in community settings as well as academic centers. and we are excited to see that continued growth on both of those parameters this year.

Operator: The next question is Brian Chen of JPMorgan.

Lut Ming Cheng: Just on 808, as you think through your first set of POC indications, what’s your latest thoughts on the death and also duration of tryptase reduction that will ultimately deliver response and also have the minimal safety package?

Kathryn Haviland: Yes. Yes. Thanks, Brian. We at Blueprint have been good students of tryptase over the last decade and have probably gone deeper than most on this. I’m going to hand that over to Becker on that.

Becker Hewes: So it’s important to remember that tryptase is not a mediator. It is an indication of target engagement, as we’ve seen in systemic mastocytosis and expect to see throughout multiple diseases, particularly the more complex diseases like asthma that there will probably not be a one-to-one correlation between symptom reduction or disease reduction and tryptase. So what we’ve used the tryptase for us is define a therapeutic range. And we also know from ISM that once you get a mast cell under control, you can maintain that control, oftentimes without killing it. So I think — what I would say to that is stay tuned for our results for the first few proof-of-concept studies and we’ll be able to explain more with respect to the level of drug needed over time. But I don’t think it’s going to be a tryptase story throughout the program.

Operator: The next question goes to Ami Fadia of Needham & Company.

Unknown Analyst: This is [indiscernible] for Ami. What assumptions have been built into the $2 billion guidance, example, like the sequential patient growth, market expansion, mix of OUS sales and growth in other indications other than ISM? Also in your $2 billion guidance, have you made any assumptions for any competitor entry? And lastly, do you expect to expand your current commercial footprint to achieve the $2 billion in sales.

Kathryn Haviland: For that question. Christy, maybe if you’ll talk about how we’re thinking about the ramp to the $2 billion in the competitive dynamic? And then Philina, do you want to take the field expansion and what you’re hoping to see that? .

Christina Rossi: So our view is that we have a lot of headroom to continue to grow AYVAKIT penetration. And if we think about a $2 billion opportunity in 2030, in many ways, I think that’s a conservative view of what can be achieved, right? We see more than 25,000 diagnosed patients in the United States as of today. We know that, that diagnosed patient population has been growing at double-digit rates. And we believe it’s going to continue to grow robustly given an updated view of what we think the true prevalence of this disease is with more than 60,000 patients in the United States. So if you just make some kind of reasonable assumptions about patients on therapy at a $2 billion run rate, you’re talking about a minority of patients still even in 2030, being treated with AYVAKIT in the United States.

Our view is that for the foreseeable future, the most significant competition for AYVAKIT is symptom-directed therapy. And we are really catalyzing a new market where prescribers and patients are understanding the benefits of treating the disease — with a therapy that affects the underlying driver of the disease. So we’re very confident in our ability to continue to get to that number with very much strong, steady growth in patients being treated. And given the dynamics of AYVAKIT, where we see that when patients start on therapy, they are staying on for long durations of treatment.

Kathryn Haviland: Philina, do you want to a little bit about what you’re hoping to achieve with the field expansion?

Philina Lee: Absolutely. And so the things that we’re focused on in the near term are really twofold. So one is increasing the urgency to treat and also broadening our ability to both increased the number of interactions with our core hematologists and actin allergists as well as to broaden the breadth of providers though. — aging with. And so there’s both — there’s investments, I put them sort of in 2 buckets where we would expect both nearer term as well as longer-term impacts. The field force expansion, we really don’t expect to see impact in 2025. That’s not baked into our current guidance. We expect that to drive growth really in 2026 and beyond. In the meantime, we’re also increasing our investments in really driving that urgency to treat by engaging with providers, tailoring our peer-to-peer engagements, as well as increasing our direct-to-patient programming, and we expect those investments to continue to drive growth in 2025 and beyond.

Altogether with these investments, we feel confident in our ability to drive that patient ramp that Christy spoke to, both in — starting in 2025 and through to 2030.

Kathryn Haviland: Yes. So I think what you’ve heard is we’re investing in more surround sound, building on our critical mass. And then as we increase the number of our field team members and we can reach more prescribers we expect we will increase treatment rates, and we will see that really take effect predominantly next year, as that team gets into place and really starts to get embedded in their territories. As we said, this is — as Christy just mentioned, it’s a growing compelling large rare disease market. And this is our plan to invest in capturing and be able to leverage all of those dynamics.

Operator: The next question goes to Derek Archila of Wells Fargo.

Derek Archila: Maybe just some follow-ups on the field team expansion. I guess how big is this expansion going to be, I guess, in terms of a percent or absolute basis? And then I guess, what percent of the patients are actually being seen by the GI and the medical derms that you can also target with the expanded sales force?

Kathryn Haviland: Yes. Philina, do you want to talk about just the relative magnitude of expansion here and then also what that benefit is going to get us, we’re actually going to be able to get to a significant number of more patients directly with the expansion?

Philina Lee: Yes. So Derek, this is really an incremental field force expansion that will enable us to not only have more frequent engagements on our existing provider base, which we know is important to remain salient for SM, but really also expand our ability to engage with med derms and GIs, which together, we can see a couple thousand med derms and GIs who are managing 2 or more SM patients today. That piece is really important because hem/oncs and allergists, while they manage — there’s 2 specialties that manage sort of the sort of larger tranche of SM patients like by expanding the field team, we will actually be able to address providers who are treating the majority of diagnosed SM patients today. We expect that to not only increase penetration into the existing diagnosed patients, but also continue to grow the market as they’re motivated to diagnose additional patients.

Operator: The next question goes to Mark Frahm of TD Cowen.

Marc Frahm: One, just kind of following up again on the med derms and GI docs. Just do you expect over time that population starts becoming the — either a major or the major driver of growth? Or is this over time, just incremental opportunities relative to kind of continuing to drive growth within the original target markets? And then also just on the 2025 guidance, just can you walk through your assumptions around U.S. — additional ex U.S. reimbursement agreements and kind of when we might expect this?

Kathryn Haviland: Yes. So Philina, do you want to take Mark — the first part of Mark’s question just around the specialties. I mean I know we continue to think allergy immunology is going to be the most predominant specialty in managing the largest number of patients here. But how do you think about med derm and GI. And then Christy, you can talk a little bit more about international.

Philina Lee: Yes. Thanks for the question, Mark. I would say the growth is really multidimensional across a lot of fronts, right. We have tremendous headroom to grow across both existing as well as the new specialties. We would expect to see in that breadth and depth chart as those grow, we would expect to see more new hem/oncs and allergists come on as well as deepen. We have, at this point, I think, a relatively small number of med derms and GIs, but I wouldn’t be surprised to see if we start to see a few more of those. And in addition, what’s really important is these specialties are motivated, and they’re managing and recognizing and diagnosing more SM patients, and we expect them to be taking on a greater role in the future.

Christina Rossi: And I can comment a little bit on the international piece. First of all, if we look at 2024, really pleased with the performance of our international team, which drove really nice strong revenue growth. As we know, Germany is the only market right now outside the U.S. where we have ISM reimbursement. We. Did say at JPMorgan, we expected another 5 markets to come online as we go through the year. Those are many of the usual suspects, right? So we’re following kind of a similar cadence with ISM as we did with advanced SMs and some of the other major European markets. We expect to come online through the year at sort of a steady pace. And that’s one of the variables, honestly, as we think about the guide that we kind of incorporated.

The timing around that is not something you want to put a firm stake in the ground on right now, given we certainly don’t fully control those negotiations with some of our European payers, but I certainly think we’re in a good place. The price [indiscernible] in Germany actually, I think, is a really nice recognition of the value of AYVAKIT and ISM and I think puts us in a nice spot as we approach those negotiations. So I’d expect additional markets coming online. Overall, from a revenue perspective, last year, we said that international, we expected to be sort of in that 10% to 15% range. That’s where we were through the year, obviously, with quarterly ups and downs, as you would have expected, I think, this year, that’s probably the right range as well.

So we’ll see nice growth both in the U.S. as well as outside the U.S.

Philina Lee: And I want to actually just — this is Philina, again, I want to add 1 additional maybe color comment to your question around the potential to grow the market by engaging these broader specialties. And as we look at medical dermatologist, a lot of SM patients, the majority, in fact, present with skin involvement. And so cutaneous mastocytosis in adults, we know is actually a reservoir of undiagnosed ISM patients, which is immediately actionable by the med derm. We also have a number of patients who are showing up within GI symptoms, sort of IBS-like symptoms. And so a lot of those educational efforts focused on both the GI as well as a more systemic symptom as a flag can continue to drive and grow this market over time.

Operator: The next question goes to Laura Prendergast of Raymond James.

Laura Prendergast: I was curious if you think it’s possible to maybe have some BLU-808 data potentially in urticaria by year-end ’25. And then the MCAS angle here seems super interesting, particularly for you guys. Do you see a potential total symptom score like your proprietary methodology needing to be used for BLU-808 studies in MCAS? And how are you ensuring that your potential MCAS patients with the D816V mutation are being identified and potentially put on AYVAKIT ultrasensitive testing involved here? Any color there would be helpful.

Kathryn Haviland: Yes. Thanks, Laura, for the questions. I’ll take the easy one and then give Becker the hard stuff. In terms of data, yes, we do expect data by the end of the year, coming out of these studies. What we’re going to give you guys more on both the design and when more specifics around what you can expect there as we get these trials off the ground, we start enrolling patients. But yes, we do expect data and then Becker, do you want to talk about MCAS and just how we’re thinking about it?

Becker Hewes: Yes. So MCAS is an amazing opportunity to really address a patient population with very little right now in terms of the understanding of their disease or therapeutic options. And with respect to the symptom measurement, we think that there will be a need to refine the way that we look at symptoms, but these are activated mast cells, very similar to what we’ve seen in or drive systemic mastocytosis symptoms. And so we think we’re already well on the way to being able to measure the symptoms in these patients. And as we select patients for our studies, that will be part of our focus. With respect to elucidating the extent to which the mutation is driving the disease versus patients who don’t have a mutation and have more classic MCAS already with the Digital Droplet PCR, you can identify patients that have the mutation that are being treated as MCAS patients.

And so really, increasing the awareness of this and using that testing is the beginning. We have talked about the rolling circle amplification test that is more sensitive for KIT mutations, and we are working with vendors to bring that forward. And we’ll say more about how we’ll incorporate that into some of our studies and then how it will be available in the future for broader testing as that story develops.

Kathryn Haviland: We’re really excited about MCAS. Christy, do you want to add no? .

Christina Rossi: Had a quick point. We’re obviously very excited about MCAS We think that this is a really interesting factor for growth, both for our mutated kit portfolio as well as for BLU-808. I think it’s important to remind everyone that when we talk about the SM opportunity, the number of diagnosed patients we see, the true prevalence this additional sort of reservoir potentially of patients that may be sitting in MCAS that is not yet detected that is sort of above and beyond, right? So I think it’s just important to remember that the headroom that we see for growth is in the current — our current view of the ISM patient population, and MCAS is really an opportunity, I think, for significant upside.

Operator: The next question goes to Mike Ulz of Morgan Stanley.

Michael Ulz: Maybe just one on BLU-808. It looks like you shared fairly comprehensive top line data from the Phase I study already. So just curious, any additional data points for Quad AI that we should be focused on?

Kathryn Haviland: Yes. Thank you for that question, Mike. I mean we’re kind of pulling together some of the data AAAAI now. It’s a poster. It’s got some limited real estate. So we’re going to — we’re figuring out from just a hierarchy perspective we want to put in there to make sure that health care provider kind of customers at that meeting get a really good sense of the profile of BLU-808. But we’re really looking forward to presenting that data at AAAAI and importantly, we’re going to see the long-term safety data from — an efficacy safety data specifically for AYVAKIT at 25 milligrams as well as now 10 months of experience for a subset of patients, but a meaningful number of patients with AYVAKIT at 50 milligrams. And again, that safety data just continues to look really strong and very kind of consistent with what we saw very early on in the program.

So that’s — safety only gets worse over time. So that’s a really amazing kind of an exciting presentation for us at AAAAI.

Operator: The next question goes to David Day of UBS.

Unknown Analyst: I just have a question on elenestinib just around the — some key differentiations of elenestinib compared to AYVAKIT. Maybe you can share some of the key efficacy and safety benefits over AYVAKIT.

Kathryn Haviland: Yes. And again, we’re really thrilled with elenestinib. I mean I think 1 of the things for us as a company is to have the assets and strategy in place to achieve our goal of continually improving outcomes for SM patients while also maximizing the longer-term potential of our overall SM franchise on the back of an opportunity that we’ve talked a lot about today is really compelling and growing. — is just an exceptional place for us to be. Becker, do you want to talk a little bit about what you guys are driving in the HARBOR study to differentiate on this?

Becker Hewes: Yes. I mean, I would first say that AYVAKIT leaves little room for improvement. And so the distinction here is not about a new compound that has an advantage over AYVAKIT. It’s really a distinction in the development. And we’re developing elenestinib to have a different profile than AYVAKIT in the future. And as I mentioned before, the 2 main areas that we’re incorporating into HARBOR are a really rigorous look at both bone health and then the episodes of anaphylaxis did occur in patients with indolent SM. So our plan is to have a distinct label for elenestinib and to really drive this notion that you need to treat patients early. We don’t want to wait until the symptoms are unbearable and then come after a lot of the damages already done. But you want to treat patients in a preventative manner with an elenestinib, both in the development program and in the label will drive those points home.

Operator: The next question is you Ren Benjamin of Citizen JMP. .

Reni Benjamin: Congratulations on the quarter, and of course, at on the guidance. As Avocet becomes available and more of an ex U.S. opportunity, can you talk a little bit about what percentage of the 2030 revenues that you’ve highlighted and peak revenues comes from the ex U.S. opportunity. . And then just as a follow-up to a prior question, do we expect any interim data from part 1 of HARBOR? And when do we think the Phase III portion might ultimately read out? .

Kathryn Haviland: So Christy, do you want to talk little bit about international and then Becker talk a little bit more about the HARBOR study.

Christina Rossi: Yes. So as we said, international has become an important part of our top line revenue is certainly an important part of our revenue growth. we expect it will lowly tick up over time in terms of contribution. But even in 2030, my expectation is that the U.S. is driving the majority of our revenue opportunity. Obviously, we won’t get out into the next decade. We’ll see how things evolve. But with these types of markets, the U.S. tends to be driving the most significant top line revenue whether that ends up being 70-30, 75-25, we’ll see. I think there’s a number of different scenarios that get you there and obviously, how some of these pricing and reimbursement cards slip will also drive that. But the bottom line is under any circumstance, we will still have a lot of headroom to penetrate both in the U.S. as well as outside the U.S. to make these numbers in our view, very achievable.

Kathryn Haviland: And Becker, do you want to talk little bit more about how the HARBOR study and expectations and timing there?

Becker Hewes: Yes. So as Kate mentioned earlier, the HARBOR study is underway,; bringing the sites up with the new design is the phase that we are in right now. And then with respect to time lines and readouts, we’ll update you later as we get a better sense of how things are going out there. It’s very early in the process. .

Operator: The next question goes to Colleen Kusy of Baird.

Colleen Hanley: I know you made some comments on seasonality expectations for 1Q ’25. But were there any seasonality you saw in 4Q? and then with the derms and GIs you’ll be targeting, are they typically more rapid adopters are more conservative than their hem/oncs and allergists colleagues? And any notable differences in the type of patients that these docs are seeing versus the hem/oncs and allergists that might drive differences in prescription trends?

Kathryn Haviland: Yes. Thanks, Colleen. Maybe Mike to talk a little bit about the kind of quarterly dynamics, particularly on Q1 and Philina to go to how we’re thinking about the different providers. I mean 1 thing I’ll say, Colleen, is that we now have a very good sense of these quarterly dynamics since we have a whole year of iosemitar about from 2024. And this is a chronic disease, and we do see at times around vacation points that patients do delay starting therapy for a couple of times until they come back from vacation. We’ve talked about that in the summer, we talked about that we’re baking that in now. So we’re — that’s part of our expectation and it’s incorporated into guidance generally over the course of the year. Mike, I don’t know if you want to hit a little bit more on just the Q1 dynamics that that we all experienced in second [indiscernible].

Michael Landsittel: I mean, Kate touched on a little bit of the seasonality piece. I think Q1, I think, as everyone knows, is kind of unique in the industry. We often see financial headwinds. And I noted that in the in the formal remarks, but essentially, you have all the reverifications that take place for insurance purposes. . And that’s like we’re confident in that, but it is a process you have to go through. And when we have a larger base of patients. That’s increased effort, but that’s a good problem for us to have. Additionally, a couple of other things that we’re facing, we’re seeing, I think everyone knows is just with the movement in the dollar. We’re seeing some FX headwinds. And I think one other one to call out is just like quarterly ordering dynamics that we have a much better handle on now as we’ve learned more about the business.

And in Q1, like a couple of our large customers actually will have like 1 less ordering day than we typically see in a normal quarter. So I think all that kind of leads into some potential headwinds, but that doesn’t change our outlook on the year. That is absolutely baked into our annual guidance, and it’s just really our understanding of the seasonal and quarterly dynamics that we see.

Philina Lee: And to your question about the broader specialty derms and GI. So I think we would expect to see 2 growth impacts of this. One is both growing the size of the market by catalyzing even more diagnosis. And the second is by growing the treatment of these patients and get sort of more recognition of the burden and the urgency to treat with AYVAKIT. Really, if we look at the specialties, as I talked about, derms are going to be seeing patients who are coming in with skin involvement as sort of part of their symptom presentation of cutaneous mastocytosis is an actionable step to follow up and do the differential diagnosis and find the SM patients within that. They may also play an important role in comanaging these patients. And so really, the more arms we can get around this to see the burden and the impact that the ISM is having on patients’ lives. All of these are important weights on the lever to move more patients towards treatment.

Operator: The next question goes to David Lebowitz of Citi.

David Lebowitz: John for David. From a high level, can you help contextualize how you expect your $2 billion 2030 AYVAKIT estimate translates to the $4 billion franchise peak? So specifically, what are the key drivers for that incremental growth? How should we be thinking about general time lines and how you expect AYVAKIT in all estimated share evolved during that time?

Kathryn Haviland: Thanks for the question. I’ll hit it to Christy. We love that you guys are modeling out into 2040. So really excited about beyond 2035, let’s just call it, that’s awesome. Christy, do you want to talk more about that?

Christina Rossi: So I think maybe just at a high level, the guide around 20 — or the sort of the view of the $4 billion I think really just reinforces our view that in 2030, if we’re a $2 billion opportunity for AYVAKIT, we don’t think we’re at peak, we don’t think we’re close to peak. We think that this market still has a lot of room. They continue to be penetrated. As I said earlier, if you just kind of make some high-level assumptions about how many patients may be on therapy in the U.S. in 2030, it is still a significant minority, and we expect that diagnosis is going to continue to grow. So the $4 billion view just really reflects the fact that we think we will continue to penetrate into ISM in the next decade. What exactly that looks like between AYVAKIT and elenestinib, obviously, will depend upon strategic choices that we’ll make and I’m sure we’ll have more of a view on that when we have the HARBOR data at hand and get a little closer I do think it’s worth noting that we don’t really see a lot of credit for elenestinib in anyone’s models at this point.

So we do think this is a really significant opportunity that will extend a multibillion-dollar franchise in the next decade.

Kathryn Haviland: So we’re getting a growing piece of a growing pie, and we have all the assets and strategy in place within the same portfolio to enable us to kind of drive this to where we need to get to and beyond. So…

Operator: The next question goes to Matt Biegler of Oppenheimer.

Matthew Biegler: Maybe another one for Mike on the financials here. Guiding to $2 billion in sales by 2030. Are we at a point where we can start to triangulate to cash flow positivity?

Michael Landsittel: Yes. Thanks, Matt. Great question. I think we’re — we haven’t put a firm stake in the ground into guidance as to like when we’re going to achieve profitability. But I think when you see our 10-K later today, like we significantly reduced our operating cash burn in 2024 from 2023. I think 2023, we’re well over $400 million. 2024 was under $200 million. We expect to see another significant reduction in cash burn in 2025. And as you grow revenues, like our goal is going to be to operate this business with financial discipline and discipline. And we firmly believe we’re going to be able to grow revenues faster than operating expenses,; while still being able to invest in the exciting growth opportunities ahead of us. And at some point, those curves cross will be cash flow positive, but we’re not going to put a specific date on that right now.

Operator: We have time for one more question. The final question goes to David Nierengarten of Wedbush Securities.

David Nierengarten: I had a question actually on the science and chemistry behind 808 And just how if you could help us out on how you’re avoiding some of the neutropenia and other side effects that folks have seen or if it’s — or if it’s simply a pharmacokinetic, pharmacodynamic property of your molecule?

Kathryn Haviland: Yes. Thanks, David. We’ve got to get you on the wire here. I know Becker, we only have like 30 seconds. Sorry, we can always follow up to you. Becker, do you want to answer?

Becker Hewes: Yes, David. So as we said earlier, there’s an extremely wide therapeutic index. I think we all know that if you take any KIT inhibitor and push it to very high doses, you’ll eventually get on target inhibition. But what we saw was a really robust reduction in tryptase in a range where we did not see side effects that would limit dosing. Compounds are different, antibodies are different volume of distribution matters, and we don’t always understand why we see a better profile from one to the other. But what we do know is 808 has an optimized profile honestly, even better than expected. So we’re really pleased to go forward with it.

Operator: Thank you. That’s all the questions that we have time for today. Kate Haviland, I’ll turn the call back over to you.

Kathryn Haviland: Thank you, and we have a really exciting year in front of us, and we are more confident than ever in our future potential. So proud to be on this journey with the best team in the industry here, and we appreciate your continued support. Thank you all.

Operator: Thank you. This concludes today’s conference call. You may now disconnect.