Blueprint Medicines Corporation

If you would like to ask a question during this time, simply press star, followed by the number one on your telephone keypad. If you would like to withdraw your question, please press star, followed by two. Please plan to limit yourself to one question. Thank you. Cassie Sato, you may begin your conference.

Thank you, Nadia. Good morning, everyone, and welcome to Blueprint Medicine's 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 investor section of our website at www.blueprintmedicines.com. Joining me today are Kate Haviland, Chief Executive Officer, Felina Lee, Chief Commercial Officer, Becker Hughes, Chief Medical Officer, and Mike Lanceville, Chief Financial Officer, Fuad Namuni, 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 three, 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.

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 Avakit, our breakthrough medicine for patients with systemic mastocytosis. In 2024, we delivered $479 million in product revenue. representing impressive annual growth of 135%. Avakit's deep and sustained clinical impact and very strong safety profile have transformed the treatment paradigm in ISM. Today, we are pleased to announce our revenue guidance for 2025. We expect Avakit to achieve $680 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 Avakit 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 JP Morgan conference in January. We now project that Blueprint's SM franchise will reach a peak value of $4 billion with Avakit 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 Avakin. 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 five 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 two-fold 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 derms and GIs start to actively look for ISM patients, they are finding them in their practice. Many of these healthcare providers are motivated to manage these SM patients directly and build their expertise in SM. 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 Avakit 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 advocate revenue by 2030. Felina 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 advocate revenue growth, we have clear areas of focus to create value this year. This includes building a durable SM franchise with L-anestinib that will enable us to drive growth throughout the next decade. L-anestinib is our next generation KIT D816V inhibitor. With our phase three trial of LNS-Nib 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 LNS-Nib on significant ISM disease morbidities in the Harbor Registration Study. And we are confident we will be able to clinically differentiate LNS-Nib and deliver improved outcomes for ISM patients, putting Blueprint in the driver's 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 Blue808, our next blockbuster opportunity. The healthy volunteer data we presented last month showed that Blue808 has a wide therapeutic index and impressive pharmacodynamic impact. Blue808's clinical profile positions it as the best in class and likely the first in class oral kit inhibitor across a range of mast cell mediated allergic and 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 mast 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 Felina to dive deeper into Avakit Performance. Felina?

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 Avakit and Blueprint. Let's look at our results. In 2024, we achieved $479 million in Avakit net product revenues. Fourth quarter revenue was $144 million, with $124 million in the US and $20 million ex-US. 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 toward multi-year durations of therapy, underscoring Avakit'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 Avakit, 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 remains stable and similar to what we saw in Q3 as we expected. In Europe, our international team recently obtained ISM pricing for Avakit in Germany. The price reflects Avakit's proven benefit risk profile and sets a benchmark as we move through additional price negotiations. and launch ISM in more countries this year. Last, let's look at healthcare providers. In Q4, new and repeat Avakit 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 Avakit prescribing in the top 400 providers by patient volume. to show how first positive experiences with Avakit 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 Avakit for SM since ISM approval. There are a couple important points to highlight here. First, you can see in the chart on the left that the total number of Avakit prescribers has grown significantly. While we've seen growth in prescribing across the thousands of hemlock and allergy specialists we've been targeting, the number of allergists with Avakit 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 Avakit are driving repeat prescribing and broadening the lens on who is an Avakit 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 Avakit's profile easy to manage with nothing beyond their typical check-ins, two or three times a year. The large and growing base of Avakit 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 Avakit 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 four 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 Avakit 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 hemox 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 Avakit 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 to $710 million in Avakit 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 achieve 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 Avakit and stay on therapy putting us further down the path towards realizing $2 billion in advocate revenue by 2030. Overall, we couldn't be happier with where we sit today, with another year of tremendous achievement under our belt 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.

Thanks, Belina. 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 three-year follow-up data from the pioneer study of Avakit in ISM. We now have a very large body of Avakit data, including pioneer results beyond three 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 Quad AI, 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 six-month registrational portion of the Pioneer trial, and no patients discontinued treatment due to side effects. we will share data on the positive impact of Avakit on bone health from a subset of patients and pioneers who had bone scan data available. As Felina 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 Avakit. These data also underscore our decision to prospectively include rigorous assessments of bone density in the HARBOR study of alanestinib, which we designed in collaboration with the FDA. Now moving to Blue808. At the JPMorgan conference last month, we were incredibly pleased to share positive healthy volunteer data showing Blue808 was well-tolerated with dose-dependent pharmacokinetics and rapid, robust triptase response. These data were exactly what we were hoping to see from Blue808 in the clinic and positively differentiate Blue808 from other programs targeting wild-type kits. Blue808'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. 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, 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 development by exploring various doses and dosing regimens. In chronic urticaria, where wild-type kit targeting has been de-risked by others, our studies will include several arms to measure the impact of various dosing approaches. In allergic rhinitis and conjunctivitis, we'll also be looking to de-risk 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 Avakit and Blue808 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 Blue808's unique profile and our differentiated approach can unlock true pipeline and 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.

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 Avakit, representing robust year-over-year growth. In addition, we reduced our operating expenses in 2024 compared to 2023 as we focused investment on our mass-sell franchise programs and efficiently operated the business. As Felina 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 re-verification process challenges common across our industry that are now impacting a much larger base of patients on Avakid, 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 increase investment in commercial infrastructure and progress development of L-anestinib and Blue808, Importantly, the inflection in avocate 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?

Thank you. At this time, I would like to remind everyone, in order to ask a question, please press star, then the number one on your telephone keypad. Please link yourself to one question. We'll pause for just a moment to compile the Q&A roster. The first question goes to Brad Canino of Stifle. Brad, please go ahead.

Hi, good morning, and thank you. The simple math on the guide calls for adding $215 million in advocate 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 four of the ISM launch and beyond? Thank you.

Thanks, Brad, for your question. You know, we are incredibly pleased to be able to project the midpoint of our 2025 range of 45% growth rate, which is, you know, really puts us, again, in pretty rare, rarefied air relative to other rare disease launches. And to see this type of growth is really incredibly exciting. Christy, do you want to talk a little bit more about Brad's questions relative to RAMP?

Yeah, sure. So, you know, as Kate said, we are really pleased with the growth that we see coming for Avakit in 2025. This growth rate, you know, 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 Avakit. We've spent the last 18 months 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 seeds that are going to drive that growth over the next several years. I also think some of the investments that Felina mentioned in terms of expanding our commercial field infrastructure, are really putting that foundation in place to drive growth into 26, 27, 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, you know, we're very much at the early stages of this. There's a ton of headroom for growth. And, you know, we really see strong, steady growth to get to, you know, 2030 and the $2 billion goal that we've set.

Thank you. The next question goes to Salveen Richter of Goldman Sachs. Salveen, please go ahead.

Good morning. Thanks for taking my question. Post-reporting 808 data in Healthy Volunteers, could you just speak to us about how de-risk 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, your read-through as well as when we might see these data sets. Thank you.

Yeah, thank you, Sylvie, for that question. As we said at J.P. Morgan and as Becker just mentioned, we're just incredibly pleased with the profile of 808. It's exactly what we were hoping to see from a 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 de-risking of the healthy volunteer data and then also just what we hope to see this year?

Yeah, sure. So, Sylvie, 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. And this includes a single dose, dose 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 into 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 two or at least one of the first two programs in the latter half of this year.

Thank you. The next question goes to Michael Schmidt of Guggenheim. Michael, please go ahead.

Hey, guys. Thanks for taking my question. I just had a follow-up regarding 2025 guidance. How much of the expected growth in 2025 is driven by your expectation of continued use of Avakit in existing patients versus adding new patients? And when I look at the chart of the slide, Sarah, and it looks like a lot of the prescribers have only one patient on therapy, how much opportunity is there to, you know, prescribed the drug to additional patients at those existing prescribers versus adding new prescribers to drive some of the growth? Thank you.

Yeah, thank you, Michael. You know, I think what we're really pleased about is that we're off to an incredibly strong start. And as we said, you know, we believe that less than 10% of the currently diagnosed SM population is currently on Avacat. 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. Felina, do you want to talk a little bit more about that?

Yeah, 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 Avakit's experience appeals to a broad base of customers across all specialties and settings. We see adoption across both hemox 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 Avakit, 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, you know, in short, I would say we would expect to see growth across all of these dimensions.

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 Felina mentioned this in her prepared remarks. We had typically looked at the top 400 providers by what we look at as SM volume. We're now showing you everyone since, you know, ISM approval who has been prescribing Avakit. And I think what you see here and what we've always said is we're calling on, you know, multiple thousands of these providers, and we're seeing uptake not only in those highest concentration providers, but also throughout the middle and tail of this, to Felinda's point. So Avakit'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.

Thank you. The next question goes to Brian Cheng of J.P. Morgan. Brian, please go ahead.

Thanks for taking our question this morning. Just on 808, as you think through your first set of POC indications, what's your latest thoughts on the depth and also duration of tryptase reduction that will optimally deliver response and also have the minimal safety baggage. Thanks.

Yeah, thanks, Brian. We at Blueprint have been good students of trip days over the last decade and have probably gone deeper than most on this. I'm going to hand that over to Becker now.

So it's important to remember that trip days 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 is to 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 that 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 trip-based story throughout the program.

Thank you. The next question goes to Amy Fardia of Needham and Company. Amy, please go ahead.

Hi, this is Una. Thank you for taking my question. 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?

Thank you 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, Selena, do you want to take the field expansion and what you're hoping to see there?

So our view is that we have a lot of headroom to continue to grow avocate 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. 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 Avakid in the United States. Our view is that for the foreseeable future, the most significant competition for Avakid is symptom-directed therapy. And we are really catalyzing a new market where prescribers and patients are understanding the benefits of treating with a therapy that affects the underlying driver of the disease. So, you know, 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, you know, given the dynamics with Avakit where we see that when patients start on therapy, they are staying on for long durations of treatment.

You know, Fleeta, do you want to talk a little bit about what you're hoping to achieve with the field expansion?

Sure. 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 increase the number of interactions with our core hematologists and onxin allergists, as well as to broaden the breadth of providers that we're engaging with. And so there's investments, I'd put them sort of in two buckets, where we would expect both nearer term as well as longer term impacts. The field force expansion, you know, 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 starting in 2025 and through to 2030.

Yes, I think what you've heard is we're investing in more surround sound, building on our critical mass, And then, you know, as we increase the number of our field team members and we can reach more prescribers, you know, we expect we will increase treatment rates and we will see that, you know, really take effect predominantly next year as that team gets into place and really starts to get embedded in their territories. You know, 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, you know, and be able to leverage all of those dynamics.

Thank you. The next question goes to Derek Archila of Wells Fargo. Derek, please go ahead.

Hey, good morning, and thanks for taking the questions. Maybe just some follow-ups on the, you know, 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? Thanks.

Yeah, Felina, do you want to talk about just the relative magnitude of expansion here and then also, you know, what that benefit is going to get if we're actually going to be able to get to a significant number of more patients directly with the expansion?

Yeah, 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 SMs, but really also expand our ability to engage with med derms and GIs, which together, you know, we can see a couple thousand med derms and GIs who are managing two or more SM patients today. That piece is really important because hemox and allergists, while they manage, you know, they're the two 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.

Thank you. The next question goes to Mark Fromm of TD Cohen. Mark, please go ahead.

Thanks for taking my questions. One, just kind of following up again on this med derms and GI docs. Do you expect over time that that population starts becoming either a major or the major driver of growth, or is this over time just incremental opportunities relative to continuing to drive growth within the original kind of target markets. And then also just on the 2025 guidance, can you walk through your assumptions around XUS, additional XUS reimbursement agreements and kind of when we might expect this?

Yes. So, Felina, do you want to take 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 you think about med dirhams and GIs. And Christy, will you talk a little bit more about international?

Yeah, thanks for the question, Mark. I would say, you know, 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, you know, in that breadth and depth chart as those grow, we would expect to see more new hemox 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.

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 US where we have ISM reimbursement. We did say at JP Morgan, we expected another five markets to come online as we go through the year. You know, those are many of the usual suspects, right? So we're following kind of a similar cadence with ISM as we did with advanced ISM. So 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. You know, the timing around that is, you know, not something we want to put a firm stake in the ground on right now, given, you know, we certainly don't fully control those negotiations with some of our uh, European payers. Um, but you know, certainly think we're in a good place. Um, but the, you know, uh, price we agreed in Germany actually, I think is a really nice recognition of the value of advocate and ISM. And I think puts us in a nice spot as we, as we approach this negotiation. So I'd expect, you know, additional markets coming online, um, overall from a revenue perspective, you know, last year we said that international, we expected to be sort of in that 10 to 15%, um, range. That's where we were through the year, obviously, with quarterly ups and downs, as you would expect. And I think this year, that's probably the right range as well. So we'll see, you know, nice growth both in the U.S. as well as outside the U.S.

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

Thank you. The next question goes to Laura Prendergast of Raymond James. Laura, please go ahead.

Hey, guys. I was curious if you think it's possible to maybe have some blue 808 data, you know, potentially new to CARIA by year N25. And then, you know, the MCAS angle here seems, you know, super interesting, you know, particularly for you guys, Do you see, you know, a potential total symptom score like your proprietary methodology needing to be used, you know, for blue 808 studies in MCAS? And, you know, how are you ensuring that, you know, potential MCAS patients with a D816B mutation are being identified and, you know, potentially put on Avacate? You know, is ultra-sensitive testing involved here? You know, any color there would be helpful.

Yeah, thanks, Laura, for the questions. I'll take the easy one and then give Becker the hard stuff. In terms of data, yeah, we do expect data by the end of the year, you know, coming out of these studies. We're going to give you guys more on both the design and 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?

Yeah, so MCAS is an amazing opportunity to really address patient populations 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 what drives 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 some 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 kit mutations, and we're 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.

We're really excited about MCAS. Christy, do you want to add on that?

Yeah, I just wanted to add a quick point. We're obviously very excited about MCAS. We think that this is, you know, a really interesting vector for growth, both for our mutated kit portfolio as well as for Blue808. 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, you know, the headroom that we see for growth is in our current view of the ISM patient population. And MCAS is really an opportunity, I think, for significant upside.

Thanks, Christy. Thank you. The next question goes to Mike Oles of Morgan Stanley. Mike, please go ahead.

Good morning. Thanks for taking the question. Maybe just one on Blue 808. Looks like you shared fairly comprehensive top line data from the phase one study already. So just curious, any additional data points for Quad AI that we should be focused on? Thanks.

Yeah, thank you for that question, Mike. I mean, we're kind of pulling together some of the data, Quad AI now. It's a poster. It's got some limited real estate. So we're going to, we're kind of figuring out from just a hierarchy perspective what we want to put in there to make sure that, you know, a healthcare provider kind of customers at that meeting get a really good sense of the profile of Blue 808. But we're really looking forward to presenting that data at Quad AI. And importantly, you know, we're going to see the long-term safety data from, and efficacy data, safety data specifically for Avakit, at 25 milligrams, as well as now 10 months of experience for, you know, a subset of patients, but a meaningful number of patients with Avacyn 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, you know, safety only gets worse over time. So that's a really amazing kind of an exciting presentation for us at QuadiAC.

Thank you. The next question goes to David Day of UBS. David, please go ahead.

Great. Thanks for taking my questions. And I just have a question on elanestinib, just around some key differentiations of elanestinib compared to Avakit. Maybe you can share some of the key efficacy and safety benefits over Avakit.

Yeah. And again, we're really thrilled with elanestinib. I mean, I think one 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. It's really compelling and growing. It's 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 illness?

Yeah. I mean, I would first say that Avakit leaves little room for improvement. And so the distinction here is not about a new compound that has an advantage over Avakid. It's really a distinction in the development. And we're developing LNS to have a different profile than Avakid does in the future. And as I mentioned before, the two main areas that we're incorporating into HARBOR are a really rigorous look at both bone health and then the episodes of anaphylaxis that occur in patients with indolent SM. plan is to have a distinct label for L-anestinib and to really drive this notion that you need to treat patients early. You don't want to wait until the symptoms are unbearable and then come after a lot of the damage is already done, but you want to treat patients in a preventative manner, and L-anestinib, both in the development program and in the label, will drive those points on.

Thank you. The next question goes to Ren Benjamin of Citizens JMP. Ren, please go ahead.

Hey, good morning, guys. Congratulations on the quarter and, of course, the rest on the guidance. As Advocate becomes, you know, available and more of an ex-US 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-US opportunity? And then just as a follow-up to the prior question, you know, do we expect any interim data from part one of Harbor? And when do we think the phase three portion, you know, might ultimately read out? Thanks.

Okay. So, Christy, do you want to talk a little bit about international? And then, Becker, we'll talk a little bit more about the Harbor study.

Yeah. So, you know, as we said, international has become an important part of our top-line revenue, certainly an important part of our revenue growth. We expect it will slowly pick 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, when we 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 7030 7525 we'll see I think there's a number of different scenarios that get you there, and obviously how how some of these pricing and reimbursement cards flip will will also drive that. But the bottom line is under any circumstance, you know, we will still have a lot of headroom to penetrate both in the US, as well as outside the US to make these numbers, you know, in our view, very, very achievable.

And Becker, do you want to talk a little bit more about the harbor study and expectations and timing there?

Yeah. So as Kate mentioned earlier, the harbor study is underway. Bringing the sites up with the new design is the phase that we're in right now. And then with respect to timelines 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.

Thank you. The next question goes to Colleen Cousy of BED. Colleen, please go ahead.

Hi, good morning, and thanks for taking our questions. I know you made some comments on seasonality expectations for 1Q25, 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 or more conservative than their hemlock and allergist colleagues? And any notable differences in the type of patients that these docs are seeing versus the hemlock and allergist that might drive differences in prescription trends?

Yeah, thanks, Colleen. Maybe Mike should talk a little bit about the kind of quarterly dynamics, particularly on Q1 and Selena to go to how we're thinking about the different providers. I mean, one thing I'll say, Colleen, is that, you know, we now have a very good sense of these quarterly dynamics since we have a whole year of ISM at our belt from 2024. And this is a chronic disease. And we see, you know, 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've talked about that in Q4. We're baking that in now. So that's part of our expectation set 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, you know, we all experience in the world of biotech and pharma.

Thanks, Kate. 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 remarks in the formal remarks, but essentially you have all the re-verifications that take place for insurance purposes. And that's like, we're confident in that, but it's just a process you have to go through. And when we have a larger base of patients, that's, you know, increased effort, but that's a good problem for us to have. Um, additionally, you know, a couple other things that we're facing, we're seeing, I think everyone knows is just with the movement and the dollar we're seeing some FX headwinds. And I think one other one to call out, it's 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 one less ordering day than we typically see in a normal quarter. So I think all that kind of leads into some, you know, 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.

And to your question about the broader specialties, DERMs and GIs, so I think we would expect to see two growth impacts of this. One is both growing demand 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 Avakit. Really, if we look at these 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 ISM. Cutaneous mastocytosis is an actionable step to follow up and do the differential diagnosis and find DSM patients within that. They may also play an important role in co-managing 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.

Thank you. The next question goes to David Lebowitz of Citi. David, please go ahead.

Hi, guys. John on for David. Thanks for taking our question. From a high level, can you help contextualize how you expect your $2 billion 2030 advocate estimate translates to the $4 billion franchise peak? Specifically, what are the key drivers for that incremental growth? How should we be thinking about general timelines and Yeah, how you expect advocate and know an estimated share evolves during that time.

Thanks for the question. I'll hand it to Christy. We love that you guys are modeling out in the 2040s. Really excited about beyond 2035, let's just call it. That's awesome. Christy, do you want to talk more about that?

Sure. So I think maybe just at a high level, the guide around 20 or sort of the view of the $4 billion, I think really just reinforces our view that in 2030, if we're the $2 billion opportunity for Avakit, 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 to continue to be penetrated. As I said earlier, you know, 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, you know, diagnosis is going to continue to grow. So, you know, 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 Avakid and LNS-Nib obviously, you know, 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 in hand and get a little closer. I do think it's worth noting that, you know, we don't really see a lot of credit for LNS in there, but anyone's modeled at this point. So, you know, we do think, you know, this is a really significant opportunity that will extend a multi-billion dollar franchise in the next decade.

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, you know, to where we need to get to and beyond.

Thank you. The next question goes to Matt Begler of Oppenheimer. Matt, please go ahead.

Hey guys, thanks for the question. Maybe another one for Mike on the financials here. You know, guiding the 2 billion in sales by 2030, are we at a point where we can start to triangulate to cash flow positivity? Thanks.

Yeah, thanks, Matt. Great question. You know, I think 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 were well over $400 million. 2024 was under 200 million. We expect to see a, a, 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 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 this. And at some point, those curves cross. We'll be cash flow positive, but we're not going to put a specific date on that right now.

Thank you. We have time for one more question. The final question goes to David Nierengarten of Wedbush Securities. David, please go ahead.

Hey, thanks for squeezing in. 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 simply a pharmacokinetic, pharmacodynamic property of your molecule. Thanks.

Yeah, thanks, David. We're glad to get you under the wire here. I know, Becker, we only have like 30 seconds. Sorry, we can always follow up too, but do you want to answer?

Yeah, 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 AO8 has an optimized profile, honestly, even better than expected. So we're really pleased to go forward with it.

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

Thank you. 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 thank you this concludes today's conference call you may now disconnect