Blueprint Medicines Corp (BPMC) 2022 Q3 法說會逐字稿

Please welcome to the stage Senior Vice President, Investor Relations, Jim Baker.

Good morning, everyone. Thank you for joining us in the room and on the webcast. We know that your time is really important. And we're grateful that you're choosing to spend your morning with us today. We're also thankful to all the Blueprint employees, who contributed to the presentation you're about to see and are listening in from home.

This morning, we announced financial results for the third quarter. And during the presentation today, we're excited to share a number of updates and our vision for achieving precision at scale. Our presenters include Kate Haviland, our Chief Executive Officer; Dr. Philina Lee, our Chief Commercial Officer; Dr. Becker Hewes, our Chief Medical Officer; Dr. Fouad Namouni, our President of R&D; Dr. Percy Carter, our Chief Scientific Officer; and Christy Rossi, our Chief Operating Officer; Mike Landsittel, our Chief Financial Officer is also here and available during the Q&A.

I want to take a moment to orient you to our agenda this morning. This morning, our program is divided into 2 sections. First, we'll talk about our plans to bring AYVAKIT to patients with systemic mastocytosis. And this section will conclude with a panel discussion and Q&A with 3 disease experts. We'll then take a short 10-minute break. After the break, we'll return for Part 2, which will include presentations on our programs for EGFR mutant lung cancer and our portfolio -- our research and portfolio strategies. After these presentations, we'll have a Q&A with company leadership. And to keep us on track from a time perspective, we ask that you hold your questions for the company until we get to the Q&A period at the end of our program. For any of our sell-side analysts who are on the webcast, you can e-mail me questions directly during the Q&A, and we will do our best to work them in.

We'll be making forward-looking statements today. And I'd just direct you to our SEC filings, including our recent updates and risk factors, including our 10-Q filing for the third quarter, which we'll be filing post market today.

And with that, I'd like to introduce Kate Haviland, our Chief Executive Officer.

Good morning, everyone. So nice to see you all in the room, those of you who are here in person. And I would also like to extend a warm welcome to all of those who are sign in on the webcast. And thank you, Jim, for that introduction.

Blueprint Medicines was founded just over 10 years ago on the belief that precision medicine can improve and extend people's lives. Okay. The next one. Thank you. I joined Blueprint 7 years ago based on my conviction through my experience in rare genetic disease and rare oncology, that targeting the underlying genetic driver of disease is a powerful way to profoundly improve the health outcomes for patients. And at the same time, dramatically improve their quality of life, by limiting difficult and sometimes intolerable side effects, that you often see with more indiscriminate treatments. At Blueprint, our mission has become a reality. We are now a fully integrated company who is delivering our innovative therapeutic medicines to patients directly. We have a strong sense of who we are and what we can achieve by delivering the right drug to the right patient at the right time. This reality is best understood in the stories of individual patients we have impacted, including the patients that you see pictured here.

Let me take a moment to introduce you to Suki, who is living with non-advanced systemic mastocytosis, or SM. Suki traveled to Blueprint 1.5 weeks ago to help us commemorate mast cell disease awareness day. She generously shared her story with us. And she started by talking about how she lived in constant fear that she was one anaphylaxis attack away from the end of her life. This concern was so palpable, intangible to her that she wrote letters to her husband, in each of her 4 children for them to open in the event of her death, telling them how sorry she was to miss out on their lives, on their major achievements and milestones and how much she love them. She described the first anaphylaxis attack she ever had. It came on so quickly that all she could do before she lost consciousness was text her husband, "help me." Luckily, he had his phone with him, and he was able to locate her quickly. He rushed her to the ER where she coded 3x. It was this anaphylaxis attack that led to her diagnosis of non-advanced systemic mastocytosis. After her diagnosis, she describes a life of being isolated at home.

She talks about it feeling like her life was on pause indefinitely. And that she went through a grieving process for what her life used to be before SM entered it. She also told us about the impacts that SM has had on her family. During yet another anaphylaxis episode that overtook her very quickly, her 8-year-old child had to administer an EpiPen to her while her 10-year-old called 911. Suki did not hesitate to sign up for the PIONEER clinical trial. She describes her quality of life of being so poor that every treatment she had tried did not provide benefit or relief, and she desperately wanted to have a life at (inaudible). For Suki to travel to see us at Blueprint 1.5 weeks ago is quite a feat. And she told me that she couldn't have imagined getting on an airplane a year ago. But she felt strongly that she wanted to meet our team and that she wanted to thank us. She let us know that for the first time, she has hope -- hope that she will see her kids graduate, hope that she will be at their weddings and meet her grandchildren.

And she's once attend -- and once again, engaging in life attending family events, attending her kids school events. She can even go grocery shopping. She thanked us for the impact we have had on her. And importantly, she thanked us for giving her kids their childhood back as they are no longer living in a daily fear of potentially losing their mom. We will hear directly from Suki shortly in a patient video. And we are very lucky to have Dr. Pankit Vachhani here to talk about Suki's clinical case as he was the investigator at the site where Suki participated in the PIONEER clinical trial. Suki's story and stories like hers is what motivates us every day. It keeps our team at Blueprint pushing the boundaries of innovation, choosing to take on more difficult and important medical problems in persisting in our efforts to educate health care providers on the diagnosis and treatment options for a rare disease like systemic mastocytosis.

Sorry, you guys are just a little slide -- our success in bringing forward the first fundamental new treatment for Suki and patients like her offers insights into how expanding AYVAKIT to treat patients with non-advanced SM represents a tremendous near-term growth opportunity for our business. This is a really important topic and one that we will delve into some detail today this morning. But another goal we have for today is to help you all understand that the treatment of SM is just one component of Blueprint's compelling value proposition. This is Blueprint's second Investor Day. Our first, we held almost 3 years to the day in early November of 2019. Since that time, we have significantly advanced our business, and we have built a strong foundation of enterprise capabilities and infrastructure.

We will share with you today what we believe are Blueprint's defining achievements as a young company and what we believe differentiates us. We are poised to leverage this foundation to increase our impact on patients globally. And we will also share with you today our vision of what we are aiming to achieve in the next 5 years.

In my first year as CEO Blueprint Medicines, with the opportunities we have in front of us and with a team we have in place, I have never felt more optimistic about what we can achieve as we expand our impact and transform the outcomes of thousands of patients globally.

So let's start with our foundation. What we have achieved in the last 10 years is remarkable. We're going to step through each one of these. We have nominated 14 therapeutic development candidates, 2 of those have gone on to become approved medicines, 8, are currently in development, either by our team at Blueprint or in partnership and collaboration. And 4, we have stopped for various technical or shifting market opportunity reasons. We have defied industry odds with an 80% success rate from IND to clinical proof of concept. We have taken on serious medical conditions, and we have developed important data that has led to 5 breakthrough therapy designations. And we have moved with urgency, getting FDA approval in less than 4 years from enrolling our first patient in the AYVAKIT and GAVRETO clinical trials. We know that the one thing patients with advanced cancer and rare diseases do not have is time. We have made history by bringing 2 innovative medicines to approval from our labs in the first 10 years since our founding. And we have expanded the reach of these medicines through 5 separate FDA approvals.

Success like ours is rare in this industry. We are very proud of these accomplishments, and importantly, they give us the confidence that we can impact many more lives with our existing portfolio of medications and also deliver many more transformational medicines in the future.

Above and beyond our research and development capabilities, we have now also established commercial infrastructure. Becoming a commercial stage company has been an important evolution for us at Blueprint Medicines. We are well-positioned for near-term commercial growth based on 3 key distinguishing factors. The first is that the opportunities we are pursuing are large. We are ready to scale the impact of AYVAKIT by addressing the medical needs of a substantially larger portion of patients with SM with our potential label expansion into non-advanced SM in the middle of next year. The market opportunity for AYVAKIT across the spectrum of SM is at least 15-fold the opportunity we are pursuing today. This is a blockbuster opportunity. And importantly, it is also a specialty market. We can access this much larger opportunity through economies of scale with only a modest increase in our field-based teams. At the same time, we are growing our geographic footprint and expanding our customer base to regions beyond the United States. We are launching directly with our own team in Europe, and we are working with partners to bring our innovative medicines to patients around the globe.

The second key distinguishing factor you see in the middle of this slide, is that we have the necessary commercial experience and expertise in place. We have established teams of highly experienced professionals, driving disease awareness, appropriate diagnosis, treatment adoption and patient access. We have the right team of people in a range of organizational components to scale our impact across both advanced and non-advanced SM.

And third, we have deep expertise in SM that will enable us to continue to expand our leadership in this area, and we are driving the direction of innovation in this space. We have built [substantive] knowledge to our years of clinical development and our community engagement. And we are now expanding those insights to the interactions of our field-based teams. You cannot underestimate how important is to be at the table -- it is to be at the table with a broad group of physicians who are treating patients with SM, which gives us that real-world understanding of how SM presents in physicians' offices. It allows us to anticipate and understand the data needs of physicians who are treating these patients. And we bring those insights back into the work we are doing in clinical development and medical affairs to develop the long-term treatment impact of AYVAKIT and to publish and disseminate important and relevant data for all of our health care providers.

We are in the early stages of building the SM market. We know that as a commercial stage company, we need to earn our place every single day by defining the exciting opportunities we are pursuing by setting reasonable and achievable near-term goals and by consistently meeting those goals. And this is what we will be focused on doing as we drive our core commercial performance.

Standing here today, Blueprint offers an incredibly compelling value proposition. We will spend most of the morning providing details that support this value proposition and our strategies for driving growth and delivering value to all of our stakeholders, including all of you, investors. With our existing commercial portfolio and the opportunity to drive revenue acceleration with a potential expansion into non-advanced systemic mastocytosis, we have a certainty of value and a tangible near-term opportunity for growth.

Today, we also announced our Q3 financial results, reiterating our overall total year guidance where we expect to achieve the high end of that range and revising downward our AYVAKIT revenue guidance for this year. Philina will walk you through the reason for our change in AYVAKIT guidance shortly.

The second major aspect of our value proposition is our clinical stage portfolio of best-in-class investigational therapies that are focused on addressing difficult, important medical problems in much larger groups of patients. This portfolio will enable us to substantially scale our impacts on patients globally.

Adding to our commercial and clinical portfolio is our proven drug discovery platform. This platform generates new programs with a higher-than-industry average probably success as we saw on the previous slide and will allow us to continue to drive long-term organic growth. The diversity of our fundamental value drivers creates numerous opportunities for growth and upside potential across all aspects of our business. As a fully integrated company, we have critical mass and we can scale efficiently. Revolutionizing the treatment for patients with SM at a larger scale is just the beginning for Blueprint Medicines.

So what do we mean when we talk about precision at scale? Precision at scale to us means that we will double our impact in half the time. I want to zero in on the goals on this slide. In the next 5 years, by 2027, we are aiming to have 4 approved medicines. There are very few companies who have been able to achieve this. And the pipeline positions us well to meet or exceed this goal. And in the process, we aim to establish leadership position in two additional therapeutic areas beyond systemic mastocytosis. We aim to double the number of programs we have in late-stage clinical development and to substantially increase the number of therapeutic development candidates we bring forward annually. What will be achieving these goals mean in real world terms? It means that we will be serving almost 20x more patients with our innovative precision therapies globally in 2027 than we are today. We have the confidence that we can achieve these goals because of the foundation that we have in place.

So another way to think about our time together today and the agenda that we have put together, is to the lens of the questions that you all have been asking us over the past few months. And the 3 key questions are summarized here. The first, what is the opportunity in non-advanced systemic mastocytosis? And how does our current experience in the advanced systemic mastocytosis launch in [format?] The second, do we have a winning approach to change the outcomes for patients with EGFR-driven lung cancer? And the third, how will we leverage our expertise in our infrastructure to drive continued innovation and growth over the long-term? We have answers to all these questions, which we will share with you today. The short answer on SM, we are well on our way to being able to treat the majority of patients with SM and we are building what will become a blockbuster therapeutic category. Philina and Becker will take us through this in more detail.

Our confidence has grown in this compelling near-term opportunity to expand the impact of AYVAKIT into non-advanced SM because of the deeper and evolved market insights we have been gaining. And importantly, based on the strong clinical profile of AYVAKIT from the PIONEER study. Becker will present some new data from PIONEER further characterizing Ayva's clinical benefit in patients with moderate to severe non-advanced SM. We will then have the unique opportunity to hear from 3 leading physicians who treat patients with SM, including Dr. Frank Siebenhaar, Dr. Pankit Vichhani and Dr. James Wedner.

So for our second question, do we have a winning strategy to change outcomes in patients with EGFR-driven lung cancer? The answer is yes, we do. We have the EGFR opportunity in our sites and with our strategy, our emerging data and our innovative capabilities. We are progressing a comprehensive portfolio with the potential to transform the treatment of EGFR-driven non-small cell lung cancer. Fouad will provide an updated overview of this portfolio.

In EGFR, we have big goals and big opportunities. Importantly, our strategy is comprehensive, but it is also modular. We can achieve significant commercial success with each of our individual molecules, while on the way to revolutionizing EGFR-directed treatment through a combination of Blueprint compounds as the first line standard of care.

And for a third question, we will turn to research and how we are building on our track record of success. Percy will describe how we are now broadening our discovery efforts to expand the range of high-value targets we can pursue and to increase our already very impressive research productivity. Percy will also describe how we are integrating our robust and scientifically driven discovery efforts with our clinical expertise and our commercial capabilities and infrastructure, to build (inaudible).

(presentation)

Good morning, everyone. My name is Philina Lee, and I'm the Chief Commercial Officer. That patient video we just saw today is an incredibly important anchoring moment of our day. This is the type of patient impact we aspire to achieve for patients living with systemic mastocytosis. Suki and Melanie's story provides a great example of the debilitating impact SM can have on patients and families. We first shared Melanie's story 3 years ago at our Investor Day. And since then, AYVAKIT has truly impacted her life. We aim to make this type of impact on many more patients living with systemic mastocytosis. And today, we're going to share how we're going to do this.

I've been involved in AYVAKIT's development and commercialization since the beginning. And from the start, we've partnered closely with the SM community, resulting in a winning product profile that addresses the needs of patients, providers and payers. By targeting KIT D816V, AYVAKIT has achieved profound disease-modifying activity. enabling deep durable responses in advanced disease, clear symptom improvement in non-advanced disease and a favorable safety profile that opens up the potential for chronic lifelong treatment. With this strong product profile now in hand, we feel a tremendous sense of responsibility to deliver on this promise for patients.

So here are the most important take-home points I'll speak to today. AYVAKIT has the potential to benefit patients across the spectrum of systemic mastocytosis. This represents a compelling commercial opportunity with blockbuster potential. We are early in this journey, beginning with the advanced SM ongoing launch, and with a strong PIONEER readout, we are now well-positioned to move into non-advanced SM with the anticipated approval and launch. We are very well-positioned to launch AYVAKIT for non-advanced SM. And in my 15 years of commercial experience, I can't imagine a more exhilarating moment than where we stand today. The culmination of many years of development effort with that early optimism to seek to address patients across the spectrum of SM. And yet we're still only getting started. And what truly inspires me is the opportunity to work with our commercial and medical teams who are out there, living their patient focus and persevering every day as they engage with providers to change this treatment paradigm. And so we are early in this journey, starting with advanced SM, and we are moving in parallel to prepare to capture the much larger non-advanced SM patient opportunity, and there are several levers for continued growth over time.

Before going into this in more detail, let's just step back and take a moment to examine some important differences between advanced SM and non-advanced SM. Advanced SM is managed primarily by oncologists. An ideal treatment goal is to improve the overall survival of these patients. The disease is highly heterogeneous with 3 distinct subtypes. And most of these patients have SM along with an associated heme neoplasm or AHN, where a proliferation of additional cells creates complexity in the management of these patients today. It's a highly medically complex disease. Non-advanced SM is much more prevalent. It's managed primarily by hematologists/oncologists as well as allergists/immunologists who are highly attuned to patients' symptom burden with the treatment goal of improving their quality of life. Non-advanced SM has a much more homogeneous disease biology, 1 disease, 1 cause, KIT D816V. There is heterogeneity that results in terms of the severity of symptoms and the types of symptoms that present from patient to patient.

And so let's dive in first by talking about our efforts in advanced SM. In the context of our performance -- and so taking a look at our first year of launch of AYVAKIT in advanced SM. We have established AYVAKIT as the standard of care in patients who are treated for their advanced SM and our first 4 quarters of growth illustrate this. We've reached a point in our launch cadence where continued growth requires the ability to grow the number of treated patients, most of whom have SM as well as that concomitant AHN, and we'll speak to these challenges in a bit more detail.

In Q3, we generated net product revenues of $28.6 million. This represents 65% growth over Q3 of last year but not the same degree of growth we had seen in the first 4 quarters of our launch. If we laser into the key drivers and challenges behind our Q3 performance in more detail. On the driver side, we have, in fact, further strengthened AYVAKIT's position as the standard of care in treated advanced SM patients. We have grown the market share of patients who are treated from slightly over 50% to approximately 60% within Q3. This type of market share growth is impressive within 1 quarter. Our team has accomplished this by growing the share of treated patients, starts and switches, to 75%. And importantly, the number of advanced SM patients on therapy continues to grow.

Finally, we continue to broaden provider experience with AYVAKIT, growing the number of total accounts treating to 350 since launch by adding more than 50 new accounts during Q3.

The key market challenge we are focused on is that the initial penetration in patients with SM-AHN has been lower than other subtypes. And this goes back to the complexity of SM-AHN where today, providers must decide between treating the SM or prioritizing the AHN, which they're historically used to doing due to the lack of effective treatment options. We are -- with these market insights in hand, we are updating our full year revenue guidance to $108 million to $111 million. This represents twofold year-over-year growth, and we expect this growth to be able to continue albeit at a more measured pace within advanced SM.

There are 3 important reasons to believe in this continued growth within advanced SM. The first being, as I mentioned, the total number of treated patients continues to grow. Secondly, the majority of SM-AHN patients are anticipated to be addressable with AYVAKIT over time. And finally, the real-world experience has been very positive with duration of therapy trending still towards 18 months. And importantly, in the patients who have recently started AYVAKIT treatment, these patients are trending towards an even longer duration of therapy. And these patients are also primarily TKI naive.

We have taken time to assess the market dynamics at play in this SM-AHN highly complex patient subset. And we are applying these insights to an action plan. Our team is redoubling our efforts focusing on this enhanced action plan. And the plan has 3 important components. First is provider education, using both the efforts of our field team and peer-to-peer education to inform on the rationale to treat the SM -- the urgency to treat the SM component, especially in these SM-AHN patients. Secondly, we have rolled out enhanced real-time patient-level data alerts to enable our field teams to understand exactly where there are advanced SM patients in need of a new therapy who are much more likely to start on AYVAKIT therapy.

And finally, we continue to drive forward our data generation efforts to follow long-term follow-up on AYVAKIT, as well as to embark on combination studies that will be important to treat the SM-AHN components. In addition, we are incrementally expanding our field team in preparation for the non-advanced SM launch. And this will broaden our reach to address an additional number of providers who are treating advanced SM patients today.

Let's dive into 2 of these key initiatives in a little bit more detail. On the left-hand side of this slide, you can see the significant overall survival benefit AYVAKIT has shown compared to best available therapy in a retrospective study. This data was recently published and just this month, actually, I should say, just in October, was added to the NCCN guidelines, which will further increase the awareness of these important data. Over on the right-hand side, we have leveraged machine learning to increase the predictive power of our patient-level data alerts that we equip our field teams with. And using these tools now, we are able to identify patients who are now more than 10-fold likely to start on AYVAKIT. Importantly, this enables us to continue to move forward, these types of tools enable us to continue to move forward with a highly efficient and effective commercial model because our teams know where to go to engage with providers who are engaging -- who are managing these patients in need.

So looking forward, we expect to continue to grow. If we apply pattern recognition from other rare disease launches, we wouldn't be surprised to see some variability from quarter-to-quarter, but the year-over-year will be strong. And most importantly, our key inflection point that we anticipate next year is the anticipated approval and launch into non-advanced SM.

So let's now dive into that in more detail. The PIONEER readout in August has been one of the truly most rewarding moments in my career. We are now shifting our strategy to prepare for non-advanced SM. And let's remember those key differences between non-advanced SM and advanced SM. The first is size, non-advanced SM is far more prevalent. The second is there's little to no disease heterogeneity in terms of the underlying cause of the disease. And the third is that goal of treatment is to improve symptoms and quality of life. And we have not only hematologist/oncologist, but also allergists/immunologists who are heavily involved in managing towards this.

In my years at Blueprint, this opportunity has never felt as tangible as it does now. And let me tell you why. So one of the questions that we commonly get from investors is how many patients with non-advanced SM could be amenable to treatment by AYVAKIT? And so we've looked at this question closely using the most comprehensive claims data set in the industry. And what we have found is that we can see within the U.S., 7,500 patients diagnosed with moderate to severe non-advanced SM who are diagnosed, actively seeking treatment and receiving therapy with symptom directed polypharmacy today. We can look further using the resolution and the power of our claims data to further stratify these patients into 2 disease segments, more severe as well as more moderate disease presentation. And we've done this, looking at factors that include the degree of burden of disease, so the frequency of anaphylaxis, organ involvement as well as the degree of polypharmacy burden.

So whether the patients are using more TKIs, cytoreductive therapies or long-term use of steroids, Cromolyn or antihistamines. We anticipate the earliest adoption in our launch will come from the more severe segment of these patients. followed by adoption into the more moderate patients over time. This level of resolution into a patient population who are in need and seeking new treatment options. This puts us on a clear path to achieve the potential for AYVAKIT.

So let's dive into these data in yet more detail. And so what you're looking at here is individual patient-level journeys with systemic mastocytosis. And so we've shown the journeys for 4 representative patients with advanced SM on the top followed by a severe non-advanced SM patient journey, a moderate non-advanced patient and another non-advanced SM patient. And so every single dot you're looking at represents an interaction with a health care provider, or a change in therapy, a tuning of that symptom directed polypharmacy to try to improve symptom control. There are also dots that indicate acute events such as ER visits, or multiple additional prescriptions of EpiPen. I'll direct you to the second row where the severe non-advanced SM patients has had multiple episodes where this patient had to be prescribed additional EpiPens. And in the third row, a moderate non-advanced SM patient who had multiple interactions to adjust their symptom directed polypharmacy, including EpiPen prescription.

The first important take-home message from all of this is how it illustrates the incredible high burden of disease within these patients. And the second important take-home message is how actionable these types of insights are. Again, by having this individual patient-level resolution, we are able to provide actionable alerts to our field teams so that they know when and where to engage with providers who are treating these patients in need. Again, maximizing the efficiency of our commercial build. This is part of our Blueprint Edge.

Let's move next and talk a bit more about that launch strategy. Our launch strategy is focused on the ability to drive growth across every single phase of the launch. We are actively engaged in prelaunch preparations, and we're getting ready for launch anticipating mid-2023. Beyond this, there are several levers to continue to accelerate growth, deepen provider experience and broaden adoption into broader patient segments over time. The 3 core tenets of our launch are highly targeted provider engagement in order to build the disease awareness, the urgency to treat and the rationale for AYVAKIT. And secondly, to leverage our strong access foundation to ensure unencumbered patient access to therapy. And the third core tenet is patient engagement. We know that patients are at the center of their care. And so educating and empowering these patients to seek more information about their disease and about treatment options will be critical.

So let's dive into each of these in a bit more detail. On the provider side, our strong analytics, once again, enabled us to segment the providers who are treating the 7,500 patients visible in claims data today into 3 distinct segments. And there are 3 ways that our go-to-market model is going to enable us to interact and engage these providers in a highly targeted and efficient manner. The first is in the prelaunch phase where we're focused on engaging these top 350 providers who are sort of on the top of the peak. These providers are managing 1,500 patients who are actively seeking care today. Upon approval, we'll equip our field teams with patient-level data alerts that enable them to engage with providers across all of these segments, but at the right moment in time when they are treating these patients in need. And finally, to address the tail of the providers who include additional referring specialties like GI and derm, we'll apply methods such as nonpersonal promotion and other cost-effective approaches to educate, interact and engage with this tail.

So turning to patient access. So two questions we get frequently from investors are how are you going to price AYVAKIT? And how are you going to ensure good patient access to therapy? What patients and providers truly care about is access and affordability. What will be the cost of this medicine to my patient? How easy will it be for me to get this medicine and how quickly? Importantly, our model is set up to address both of these important drivers. When we look at the advanced SM -- at the SM market today and engage with payers, we see that payers don't currently distinguish between advanced SM and non-advanced SM. That's an important point as the access to AYVAKIT today for advanced SM is extremely favorable and provides a strong foundation. And so let me walk through four important points when it comes from an access perspective. The first is all 5 doses of AYVAKIT are available on the market today, and they're being reimbursed. They're being reimbursed with virtually unencumbered payer coverage.

The third point is that we see an exceptionally rapid time to fill AYVAKIT in less than 5 days. These types of metrics are among the best in the industry. And the fourth important point comes from our early research and engagement with payers that show us that payers understand SM is a rare disease, they understand that AYVAKIT will be the first and only approved therapy for non-advanced SM at launch, and they don't anticipate managing this category in a way that restricts access to appropriate patients. The bottom line is, we expect strong coverage.

And building on this are YourBlueprint patient support program streamlines the access process for patients. When we look at the number of patients who are receiving AYVAKIT, approximately half are enrolled in YourBlueprint. This exceeds standards for oral oncology. We also see that the majority of patients receiving AYVAKIT receive co-pay assistance when they qualify, whether or not they're engaged in YourBlueprint. And so the bottom line is patient access is a critical priority for us at Blueprint and the access capabilities we already have in place provide a strong foundation for non-advanced SM.

Moving towards patients and caregivers. An educated patient can be a catalyst for treatment. We saw in the patient video how Melanie was carrying literature in her purse, so that she could educate the providers who are caring for her. And so it's incredibly important to engage with this patient and caregiver community. One example of how we've done this is our it's something patient and caregiver education campaign, which launched earlier this year in March, and has secured industry-leading metrics in terms of the outreach. And this just truly illustrates how highly engaged this community is and how hungry they are to seek more information. Beyond this, we have also engaged in long-standing partnerships with patient advocacy groups, such as the Mast Cell Disease Society for many, many years. And so stepping back, there is a highly tractable path to address the needs of these patients who are diagnosed that we can see today. And beyond this, there are multiple opportunities to drive further growth and patient impact with AYVAKIT.

I'm proud to share some of the metrics that we've seen as Blueprint has partnered with the SM community over many years, resulting in a steady growth in the number of SM patients who have been diagnosed and who are visible to us in U.S. claims data. One of the things I'm most excited about is the ability to help these patients who today are wandering through the health care system, looking for a diagnosis, helping them get to that diagnosis faster and helping them find better treatment options.

And so in close, we see a clear path to a highly compelling opportunity. While in the near-term, we're focused on the advanced SM ongoing launch and growing that treated patient population, we're also focused on the far greater non-advanced SM opportunity. We are exceptionally well-positioned for this launch. With a winning product profile, leadership experience from nearly a decade of involvement in the SM disease area. And finally, a highly experienced team who are in the market today already for advanced SM and engaging with providers.

So thank you for your attention. And with that, I'll transition to Becker and our key opinion leader panel. We're going to share more about why we're so confident in AYVAKIT's profile in non-advanced SM.

Thanks, Philina. Good morning, everyone. I'm Becker Hewes, Chief Medical Officer. It's good to be back in New York. I did my training here. I was New York Hospital for residency, and I saw my first cancer patients at Sloan Kettering. And what I appreciate about New York is give me the facts. And I know that's what you're here for. So today, we're going to take a deeper dive into non-advanced systemic mastocytosis. We're going to look at some PIONEER data, including a bit of new data. And this is to help you put into context the cases that you'll hear about from our physicians that have treated systemic mastocytosis for many years.

So -- but before we do that, I wanted to provide my perspective on this program. So I've been developing drugs for 17 years, and I've had the privilege of bringing 2 patients, 3 drugs that have been transformative for breast cancer, leukemia and lymphoma. But I got to tell you, this is different. And the reason it's different is because for the first time, patients in an underserved population have an option or will have an option that modifies the disease and improves their lives. And what you'll see is that this is a serious debilitating disease. So in that process, we are defining how to treat the disease. We're learning a lot more about the biology, and this includes the complex biology of the advanced SM, where patients were thought to have 2 malignancies at the same time. And then a different kind of complexity in the non-advanced SM, where a single driver drives a number of different types of symptoms, and we'll get into why that is in a moment.

And so we're learning more about the disease and what we're really starting to learn more about is the impact on the patients and you saw a couple of patients talking about this today. But what you're going to also learn today is that this is not -- these are not outlier patients. These are typical non-advanced patients. And so we'll hear from our treating physicians to provide more evidence about that.

So in order to first set the understanding and make sure that we're all on the same page, we're going to take a look at systemic mastocytosis. So we understand why it's such a devastating disease and how these mast cells are causing such difficult lives for these patients. So first, we've got to think about what a mast cell is and why it's here. Mast cells are the first line of defense for all of us against really foreign invaders. And so there aren't many of them in the buy, but they exist where you interact with the outside world. So they're in the lungs, in the GI tract, in skin and in the blood to a certain extent. And they grow or they come from the bone marrow. And so I think of these as the Navy seals of the immune system because they have to be ready for any attack, and they have to be able to react very quickly. And they don't have time to divide and migrate.

And so they have the most powerful armamentarium in the immune system in their granules. And what they do is when you get an insect sting or you eat something that you just shouldn't eat, their only goal is to make sure that, that substance is diluted and out of your system as quickly as possible. And so you'll get itchiness to get that stinger out of the skin, you'll get vasodilatation and you get wheel and flare in your skin and hives. And this is all to redirect this venom outside away from where it's sitting in your skin. In the GI tract, you see peristalsis, you see -- you get pain from the inflammation from the release of these histamines and leukotrienes. These are the most powerful chemicals that our immune system has. And so -- that's the normal function. But then when a D816V KIT mutation occurs in these mast cells, the KIT molecule, the KIT protein is the control center for these mast cells. And so these with the mutation, are always on.

They are releasing granules with the little stimulation or sometimes no stimulation. And this becomes a chronic inflammatory condition because these cells not only cause vasodilatation, but they also recruit other immune cells to the area. So I'll show you in a moment how this shows up in patients that have had systemic mastocytosis in the non-advanced form, particularly those who've had it for a long time. So the first place that often shows up is in the skin. As we've heard, there'll be little brown spots. But these aren't just hyperpigmented lesions. These spots have a lot of mast cells in them. And that's why you see Darier's sign. Darier's sign is when you just cause physical stimulation or you rub the skin, you get a release of histamine and you will see a hive. So these are masses of mast cells that are poised to release their mediators. And on the top right of the screen, you can see the subcutaneous tissue and the chronic inflammation that you see in these patients.

Now let's talk about anaphylaxis. Suki talked about having anaphylaxis that was the worst that in the ER had seen. And the reason that it's so bad, we all are familiar with people with peanut allergies or they get a wasp sting and they get the swelling and the difficulty breathing, but there's a particular kind of anaphylaxis that these patients have, which includes hypotension. So not only can you not [breath], but you don't have any blood pressure. And so it can be particularly scary, particularly life threatening, and this can happen over and over again for patients. So they use multiple EpiPens in many cases. And they have the anxiety of worrying about walking through department stores, selling some perfume and having this kind of a reaction in up either just in the ER, and that's a good day or in the ICU on a bad day.

So let's talk about the manner. As said that these cells are prevalent in the GI tract. So what that looks like? If you see the bottom left of the screen, you'll see thickening of the GI tract, and this is the chronic inflammation. So Suki described when she would eat, she would get belly pain, and then the diarrhea would come afterwards. Imagine trying to lead a normal life and go to work and you knew that when you went to lunch, you were going to spend the rest of the afternoon with diarrhea despite all of the medications that you might be taking. So chronic inflammation in the GI tract and really debilitating diarrhea and nausea and pain in many patients.

So I said these cells are produced from the bone marrow. So as they continue to divide and if you don't stop the actual KIT mutation from causing these cells to divide, they will continue to divide and go into other tissues. And that's why this disease often gets worse over time. So what you'll notice in these X-rays of the bones is there's not a lot of calcium, there's not a lot of white. And that's because the mast cells have started to eat their way through the bones in this patient with nonadvanced systemic mastocytosis. And it causes bone pain and then young people will have fractures as if they had osteoporosis late in their life. So this is debilitating in that they can't do their normal activities of daily living. They can't play sports, and they experience a lot of pain and take strong pain medications for it.

And then one of the most puzzling manifestations of the disease is the brain fog. So patients will describe an inability to remember people's names, to remember how to do activities that they do at work normally. And so they can't function normally. Some of them are able to get by, but they're nowhere near as sharp as they were before. And for some of these patients, this has happened over the years before they're diagnosed. And so they don't even realize that it's not just that they're getting a little older and a little slower, they are actually having brain fog from the disease.

And it's important to know, so in this CT scan, you'll see some white marks. These are white matter changes in the brain. We don't know whether those are mast cells in the brain, mast cells in the meninges or it's just the mediators or some combination. And at Blueprint, we are going to figure out whether you need a compound that crosses the blood brain barrier to deal with these brain fog symptoms. And then patients lose weight. They're tired all the time. And as Suki said, some of them "live in a bubble." So they don't -- not only do they not have a normal life, they don't engage with their family, with their friends, with their colleagues. So it's a really devastating disease.

So what's Blueprint done about this? So the PIONEER study was an ambitious attempt to do a few things. One is to show that a targeted KIT inhibitor that targets KIT D816V can reduce the disease burden, can reduce the activity of these mast cells, can therefore reduce the symptoms. And therefore, it will change the quality of life for these patients and to begin to establish AYVAKIT as a standard of care, the standard of care in nonadvanced systemic mastocytosis. And we've done all these things. And let me show you how we did it.

So on this slide, you see the PIONEER study. PIONEER study was 2 parts. So on the top left, what you see is Part 1. Part 1 was testing 3 doses, 100 milligrams, 50 milligrams and 25 milligrams of AYVAKIT in nonadvanced systemic mastocytosis patients. And the point here was to determine whether there was a dose response and what the safety of each dose was so that we could pick the best dose for optimum efficacy and long-term use. You can see in Part 2 in the middle of the slide, we took 25 milligrams, randomized patients 2:1 to either AYVAKIT plus all of the medications that they were on already, so best supportive care. Or placebo plus best supportive care. So it's not an inactive arm. And we randomized patients 2:1 and then we looked at 6 months, and we compared the mean reduction in symptoms between those 2 arms as our primary endpoint.

And importantly, after that 6-month period, patients who were receiving placebo plus best supportive care were able to roll over and receive AYVAKIT at 25 milligrams and continue on that as long as they needed. So today, we'll look further into the data and we'll answer questions about dose selection and whether we left efficacy on the table. And I can tell you now, we didn't, and I'll show you why. And why the placebo arm did better than in Part 2 than in Part 1. And whether this was a typical SM patient or not. And our clinicians will help us understand that. And also what's clinically meaningful, what's meaningful to prescribers and what's meaningful to patients. And as Kate said, I will show you a bit more data from the PIONEER study, and it's to bring into context what you hear when you hear about the cases that our clinicians will present and also to help answer some of these questions.

So let's talk about the top line efficacy. So what you see here is the primary end point and multiple secondary endpoints, all of which were statistically significantly positive in the PIONEER study. This is not very common, and it's particularly not very common in patient-reported outcome studies. And so these measure not only that mean change comparison, but the depth of response in patients and multiple ways of looking at objective measures of disease reduction. Remember, first time we're actually reducing the disease in these nonadvanced patients.

And so let's dive a little bit more deeply into the efficacy. So the primary endpoint, mean change in symptom score. You can see on the AYVAKIT arm, it was a 15.6% reduction in symptoms, and this is only within the first 6 months of treatment. And these patients have often had this disease for many years. In the placebo arm, we saw a 9.2 point reduction. And I can tell you that, that was primarily in the first month or 2 of treatment, and then there was a plateau in that score.

So let's talk a little bit about placebo effect and why this might happen. So first of all, it's common knowledge that when you go from a small to a large study, you often will have a larger placebo effect. And our clinicians who have done many of these trials have told us about that and can continue to -- can talk to you all about it as well. The other thing, and I think this is probably the most important part is you think about the world when we did PIONEER Part 1. That was a time when people didn't know that AYVAKIT could modify the disease. They didn't know that they were symptom improvement when you did modify the disease. And so patients came in kind of not knowing what to expect.

And then when we did Part 2, we had already seen the data from the advance program showing profound reduction of disease in the advanced patients. We had seen the Part 1 data where we saw all doses showing a reduction in the symptoms that was really marked and dramatic in some -- in many patients. And the patients pay close attention to what's developing here. Some of our clinicians have said, they come in every time and say, what's new doc? What's coming down the pike that might modify the disease? And so they knew that there was a chance that they could have benefit here. And then they randomized 2:1. So the fact that there was a more pronounced placebo effect in Part 2 is not a surprise when you consider the environment.

So then patients that went on in the AYVAKIT arm to treatment beyond that 6-month period onto a year, you can see a further reduction in their symptoms. And so this is chronic inflammation. Some of the symptoms take some time. We chose 6 months to look at their primary endpoint, but there has been improvement beyond that, and that's really important because we'll see these data emerge over time.

So let's talk about the disease itself and objective measures of disease. Tryptase is what we've talked about so far. So in Part 2 -- so let me talk a little bit about tryptase first. Tryptase is a good marker of kind of how many mast cells there are. It's not a perfect marker, but it's a decent marker. And so you need to see reduction in tryptase to know that you're modifying the disease. But what I can tell you, and I'll show you some data on this in a minute, is it doesn't track with either severity at baseline. So it's really common knowledge among patients and providers that your tryptase level doesn't mean if it's high that you're going to be really symptomatic and if it's low that you're not. There's not -- there's a disconnect.

One of the reasons this might be the case is that you can imagine a patient with a small number of very mature mast cells that are hyperexcitable. They can have high symptoms. And then as those mast cells divide more rapidly, they don't stay as mature. And in the advanced patients, they're not actually very mature at all. So the number of or the amount of histamine and leukotrienes per mast cell can go down. So the symptoms and the tryptase can be quite disconnected. But what we've shown here is that over half of the patients have at least a 50% reduction in their tryptase level. And this shows that AYVAKIT at 25 milligrams is profoundly impacting the disease burden by 6 months.

So let's talk about safety. So in Part 2 of PIONEER, we saw a pristine safety profile, really consistent with long-term dosing. And this is important because patients are going to be on this drug, we expect, for a very long time. So a few things I want you to notice about this. First of all, the adverse event rate on both arms is about the same. And this tells you that the disease itself and the drugs that are used as best supportive care will give -- will cause a lot of side effects or a lot of adverse events. And so the thought of giving patients high-dose antihistamines, you can imagine, I'm sure most of us have taken antihistamines and tried to have a normal day at work after that, and it's really difficult because it makes you sleepy, makes you groggy, and these patients are not only taking these things routinely, but they're taking higher doses than normal. And so the adverse event profile in both arms is about the same.

There was a bit more low-level mild grade 1 edema on the AYVAKIT arm, but this edema was not something that caused people to need to dose adjust. So it really was consistent with long-term dosing. So this safety profile is one that we're very pleased with, and we know will be consistent with long-term dosing in these patients. But when you see a safety profile like this, the first question that some people -- some of you have asked is did you use the right dose? Did you give them enough? Did you leave efficacy on the table? So let me show you why we did not.

So I haven't shown you these data before. This is new, and this is from Part 1, the deeper dive into Part 1. So on the left side of the slide, you'll see the symptom reduction score for each of the doses tested in Part 1. So we've got 25, 50 and 100 milligrams. And at 6 months, that symptom reduction was pretty much the same in all 3 arms. So there is no dose response curve here. Now when you look on the right side, we're looking at tryptase, and you can see there are a few patients with a bit more tryptase reduction by 6 months at 100 milligrams than at 25 milligrams or even 50. But this does not correlate with symptom improvement. And I'm giving you some reasons why that might be the case. So there is no correlation here between tryptase reduction and symptom improvement. We picked 25 milligrams, which was at least as efficacious as 50 or 100 milligrams and took it into Part 2.

Now in Part 2, I didn't think that the question was finally answered in Part 1, so we looked again. And I can tell you, I've asked for a number of exploratory analyses to look at correlations between tryptase and symptom reduction. And this is new data. But what we saw -- and in this case, despite the large reduction in symptoms, we took patients with very high tryptase. So in this case, above 50, and asked whether there was a correlation between their tryptase reduction and their symptom reduction. And this correlation coefficient of 0.38 is pretty weak. So a correlation coefficient of 1 would be perfectly correlated, 0 means there's no correlation. But 0.38 is quite a weak correlation coefficient. So again, showing that tryptase does not reflect the symptomatology in this disease.

So how can we measure patient benefit beyond just the symptoms? Well, quality of life is something that we incorporated into the trial in a number of different ways. And here, I'm showing you some data from -- I will show you some data from the EQ-5D. And the reason I chose the EQ-5D was because this is a tool used across a number of different disease types. And so it measures a number of different ways of looking at your daily living, your health state, how you're feeling, how are you anxious, can you move around. So it's a series of multiple questions that come up with a score between 0 and 1.

And what I'm showing you in the middle is that the average American has a score of about 0.8. And then there's a disease -- intermittent porphyria that doesn't include a great deal of symptomatology. And those patients are not that far below the normal American score of just over 0.8. Now you look at lung cancer, and that's in the 0.7, middle 0.7 range. And this also shows you that it's a very sensitive measure of quality of life. And so a reduction in that 0.1 points is very significant. And then you look at the patients on the PIONEER Part 2, and you can see that they have a lower score in the midpoint 0.6 or low 0.6 range that's lower than even the lung cancer patients. So what happened on treatment?

So the placebo arm reported about a 3% increase in their quality of life. While the patients treated with AYVAKIT at 6 months reported an 11% increase in the quality of life. This isn't just symptoms, it's like how they're living their quality of daily life. And I can tell you, based on other studies and other diseases, this increase of 11% here is quite clinically significant. And we'll show you more information or more detail on that in a future medical conference.

So we've got quality of life. We've got symptom reduction. Another way to think about benefiting these patients is reducing the number of medications that they're taking. So here we look at the typical medications that are used in these nonadvanced patients. And these are high doses that are given multiple times a day. So I've talked already about the sleepiness that you can get from antihistamines, and we've got steroids involved. And then the GI drugs are particularly worth talking about because oral cromolyn, for example, is one of the most loath drugs that these patients are on. So let's take a deeper dive into that.

So cromolyn is a mast cell stabilizer. It doesn't do anything to decrease the mast cell burden, but it keeps the granules from releasing as readily. And it was initially developed for asthma and it's been reformulated into high-concentration vials. And patients have to take those vials and they have to dilute them in a large volume of water, take them 4 times a day. They got to take them before every meal and at bed time. I can't remember to take things once a day sometimes, much less 4 times a day. And the reason I'm showing you the stack of boxes is because a lot of these patients will lay their medications out and put them on the blogs and this is just to show how much they have to do just to get by. And so in PIONEER Part 2, we had 58 patients who were taking oral cromolyn at baseline for their GI symptoms. This is also new data.

So what we saw is just within that first 6 months, there were about 1/4 of the patients reduced their oral cromolyn dosing. And this is important that it was in the first 6 months because these are patients who were trying not to change much because they didn't want to impact the primary endpoint. But nonetheless, this is such an onerous drug that they decrease their intake of oral cromolyn. No patients on the placebo arm did that. So quite a distinction.

So that -- those are the new data I'm going to introduce today. And now I'm going to bring up our experts in treating systemic mastocytosis -- nonadvanced systemic mastocytosis. They're going to go through a couple of cases. And then after that, we'll have an opportunity to ask them some questions about the cases they presented.

Thank you guys for making the trip. Why don't we first start with a brief introduction and maybe you can talk a little bit about your practice, how many nonadvanced SM patients you see, and whether you've had experience with AYVAKIT or not. So let's start here with Dr. Wedner.

So my name is Jim Wedner. I'm a Professor of Medicine at Washington University School of Medicine in St. Louis. I just started my 51st year on faculty at Wash U. We have about 100 patients overall with mastocytosis.

And have you used AYVAKIT before?

Not yet.

And Professor Siebenhaar.

Hi, everyone. My name is Frank Siebenhaar. I'm a dermatologist and allergist by training. I work in Charite Hospital in Berlin. We have found an interdisciplinary mastocytosis center a little bit more than a decade ago in Berlin. And since then, we have seen a couple of hundred patients with systemic and cutaneous mastocytosis. We are knowing about 850 patients in Berlin, and we see them on a regular basis every year. And we do have experience with AYVAKIT because our center took part in the PIONEER trial.

Great. And I'm Pankit Vachhani. I'm an Assistant Professor of Medicine at University of Alabama, Birmingham, Alabama. I'm a hematologist/oncologist by training. I am the Director of the UAB, MPN and Mastocytosis Clinic. I have experience with avapritinib for both nonadvanced SM as well as advanced SM. And as written on the slide, I am an investigator on the PIONEER study.

Great. Thank you. Before we dive into the cases, maybe I can ask each of you what stands out to you in this data and what you think is most important. So maybe Dr. Vachhani, we can start with you.

Absolutely. I think the first and most important piece is, of course, the symptom reduction. Both Melanie, Suki and numerous other patients who we have never talked about, who are waiting out there talking with each other on Facebook groups, they are very symptomatic. Sometimes the word nonadvanced doesn't capture how much the patients are suffering. We think of it as indolent, but there is nothing indolent about this condition. These patients are truly debilitated, they live in bubbles. So any symptom improvement is a big win. And avapritinib actually improved symptoms significantly more so improve the quality of life of these patients. So that is a big achievement in and of itself.

In addition to that, the reduction of tryptase burden, mast cell burden, these are very important findings. And it tells us that the drug is disease modifying. It's not just improving the symptoms all by itself.

An additional point that you touched upon in the previous slide was the use of other medications or polypharmacy. That is a big point as well. These other medications, H1, H2 blockers, PPIs, cromolyns, steroids, omalizumab, these add up. Many of our patients are on many of these medications, bringing down the burden is a very important point, both from cost effect of those other additional medications, but also from the adverse event profiles of the other medications as well.

Great. How about you, Dr. Siebenhaar?

Yes. Well, I can just echo that. And there's one additional point. I mean not only the patients, also we as doctors, we're actually waiting for such a drug. Treating patients with systemic mastocytosis over the last 10, 15 years was just frustrating, not only for the patients, also for the doctors because we're giving them a lot of different drugs and none of them in many patients were actually able to really bring down the symptom burden. Why? What we had available is mainly antihistamines, leukotriene antagonist, trying to block whatever the mast cell mediators that are released from the mast cells in these patients causing their symptoms.

But we don't have a drug to block all the mediators. There's about more than 200 mediators that potentially could cause symptoms in these patients. And with this is not surprising that even we gave 5, 6 different drugs to these patients, it was not able to control the symptoms in many of them. And AYVAKIT is one of the first in class drugs that now comes a bit earlier. It's not trying to block whatever comes out of the mast cells, it prevents mast cells to release their mediators. It decreases the mast cells burden in patients. More or less, yes, it's really disease-modifying, and we haven't seen such an action of a drug before in mastocytosis.

And Dr. Wedner, I know you haven't used AYVAKIT before, and you've only seen the PIONEER data that everyone in this room has seen. So what impresses you?

Well, I think the 2 things, one is the symptom reduction. I mean these people whether or not we treat them, and as you'll see, we have patients with 5, 6, some of them taking 7 different medicines. And as I want to say, they have brain fog and yet we give them drugs that cause brain fog, which doesn't make much sense, but it's the only thing up till now that we have. And the quality of life is much better based on the data, and that really makes a difference for patients. These patients are unhappy, they don't like their disease. They don't like to have to take a lot of medicine. And more importantly, they don't like the fact that they cannot exist in society, the same way everybody else does.

And you've participated in a number of studies like this with PRO outcomes. What are your thoughts on the performance of the placebo arm here?

Well, every study I've ever done, and we've done many, okay, probably over 50, has a placebo effect. We talk a lot about the placebo effect. But remember, some patients magnify their symptoms a little bit, so they get in the trial. I mean we have patients who would love to be in another trial of AYVAKIT. So that means that when they tell us their symptoms are up here, they're actually here. And then when we ask them, they get better. So that's the placebo effect.

And then there is the anticipatory effect. So people don't know which drug they're getting. These are all placebo controlled, all appeals look like. The physicians don't know which drug so -- and so there is the anticipation that I'm going to get better. And so just the anticipation makes them better. This data is not at all surprising. What would have been surprising if there's no placebo effect, then we'd start to think about it.

Great. Thank you. So maybe we can go into the first case now. And so Professor Siebenhaar, let me just turn this over to you.

Yes. Sure. So this is one example, one patient that was on the trial. He was a young man -- or he is a young man. And he actually started early even in his childhood with being diagnosed with allergic disease as allergic rhinitis and asthma. He suffered from his early childhood. And then over his adolescence, more and more symptoms started being bothering him. And then finally, when he was 20 years old, he got diagnosed with nonadvanced systemic mastocytosis in our center. So he was carrying the D816V mutation. His tryptase was elevated, not very high. So it was below 20%, which means it doesn't count as a criteria for diagnosis. But anyways, as you said, doesn't reflect actually the burden of symptoms.

And his burden of symptoms were like a lot. So mainly, he suffered from GI symptoms that made him recurrently suffering from unpredictable diarrhea. He was brain foggy, also headaches, he had a lot. His skin more and more got covered by these spots and lesions. And he also suffered from bone pain. And as we have heard before, also this patient was on several drugs. There was even more. We [trialed] him. He was for a while on leukotriene antagonist. He even had some short course steroids, which can be given long term, but it was -- he was taken off because they were just not effective and not do anything else to him than the drugs he already was taking. He also was on cromolyn. And he carried the EpiPen as most patients because he also had a risk of anaphylaxis.

And what was most intuitive in this patient is that he was diagnosed very young, and he was lucky enough. He told me once that when he started his professional career, he was actually able to work from home. He is working in IT, and he was lucky to have like a company and a boss who accepted his disease influences. And he said, if I need to use a bathroom, I can have my bathroom right away. If I feel foggy, I can just lay down for an hour and then continue working. So when he started the trial, he even said it was kind of difficult to him to rate the severity of his symptoms because he was so used to them.

And maybe we can go to the next slide and look at his symptoms. So on the left-hand side, you see his total symptom scores divided by the different symptoms. And you see that the spots on the skin, the fatigue, the itch was among the most annoying. And also then in the middle, you see his disease-specific quality of life measured by the mastocytosis quality of life tool. And you see that many of his most disability symptoms improved, mainly the fatigue and also the gastrointestinal symptoms. And this is much -- most reflected by the improvement of this quality of life. So the black lines are the baseline and the red lines actually how he improved over the study, and this is really significant. Also shown by the EQ-5D, which is a more generic and not disease-specific quality of life measure to.

And yes, last but not least, also his spots and his skin lesions disappeared. This for us is a clear sign of the disease-modifying effect. So you have explained how these spots occur on the skin. So this is a marker of having increased numbers of mast cells on the skin. All these reddish brownish spots is kind of a nest where the mast cells sit. And we were trying in the past to treat the itch, to treat the flush. Even UV irradiated patients ages ago, but nothing was actually able to reduce the number of spots to improve the picture and the symptoms of the skin, and AYVAKIT is able to do this. And this is a very representative example of a patient in which we see the skin lesions fading over time, which is clearly reflecting the reduction of the number of mast cells in the skin.

Thanks. And Dr. Siebenhaar, are -- you developed the MC-QOL. So can you just comment on the depth of the quality of life changes that you're seeing and maybe put it in perspective for us?

Yes, yes. Well, I mean, as you have mentioned for the EQ-5D, we are not at 0, all of us. There is something in our life that also impacts our quality of life. So you cannot just bring this to 0. But this patient, particularly having an improvement of over 50% really is significant. So if you translate it to the severity of impact, it means you come from very severe to mild, actually. So this is what the patients also tell us. It's the first time in my life that I actually realized how impactful this disease is for my life. Now I can go and meet my colleagues more often in person, I can go and meet my friends. And this is what clearly also then the question reflects improvement of large quality for this patient.

So what you just said, reminded me of a term that I heard from a couple of patients and providers, which is a new normal. And these patients have lived for a long time with what they consider normal. But then when they're treated, they feel even better than that. And Dr. Vachhani, have you seen that in your experience with AYVAKIT?

Absolutely. So patients, both before and after treatment. So prior to going on the treatment, patients have had this condition for many years. And they get used to a new normal at that point, which is far away from what we would be. They are living at home. They have made many adaptations. For example, Suki just decided not to go outside. That became her new normal. That's not what we would want to be. Even some low-grade symptoms like, for example, diarrhea, which if any of us had 1 or 2 episodes of diarrhea, we would probably not be able to be here because that could happen anytime. So that's prior to going on treatment. And then after going on treatment, patients improved, and this is very heartening to see, they reach a much better new normal. Yes.

And Dr. Wedner, this case, does it seem typical of the patients that you're seeing?

This is a very typical case. I mean the only thing maybe not typical is the time it took to get diagnosed, which is like all rare diseases. It takes a long time for these people to get diagnosed. As I've told you, we had 1 patient in whom I was the 72nd physician that they saw. And we finally were able to get her diagnosed.

And had -- you told me that yesterday, but how did you know there were 72 people before you?

She actually came with her entire medical records about that high, brought in several boxes and said, "This is what I've done. You have to find out what's the matter with me."

Great. All right. So maybe we can move to the next case. Dr. Vachhani?

Absolutely. I think you guys all saw the video, but this is my patient, Suki. She is a 39-year-old mother of 4, as you heard. Her symptoms and her journey began in 2017, but if you ask actually, maybe some of the skin lesions erupted even before that. In 2017, she had the episode of anaphylaxis that led to the ER visit and coating and ICU stay and she was eventually diagnosed of nonadvanced SM in 2019, so almost 2 to 3 years after her initial presentation, which, by the way, is also a shorter time period compared to the 7 or 8 years that Dr. Wedner was referring to. And she has found to have the KIT D816V mutation. That's a classic mutation for systemic mastocytosis. I had tried out of desperation, a wide variety of medications, me and my allergist/immunologist colleague.

We had tried midostaurin, we had tried to interferon, IV famotidine and 7 or 8 other medications and maybe they helped for a brief while, maybe they helped for certain symptoms, but the effects would just not last to the point that was raised before by Becker, but also by Frank before that the tryptase level doesn't really correlate. Much like the previous case, this patient too has and had a tryptase less than 20, but was phenomenally symptomatic, right? So her baseline symptomatology included chronic diarrhea, sometimes 6 to 8 times a day. And when she would eat certain food that would lead to pain in the GI system. Brain fog was constant. She was a teacher before she had to quit because of all these symptoms. But in particular, brain fog was one of those.

We heard from her directly that she had numerous skin lesions erupting sometime around 2016, 2017, her trunk and her extremities were full of these very fine dots like the picture that were shown before. She had bone pain that was bone pain in some of our big bones, like the femur, the long bones or the hips and shoulders, and recurrent anaphylactic episodes. This is a big issue for patients with SM. We didn't see this in the top line information from avapritinib PIONEER study. But these anaphylaxis episodes are what really concern us as physicians. Nonadvanced SM may not kill you directly, but an anaphylactic episode can take your life. So she had numerous episodes to the point where 1 day, for example, when she was working in the school, some other children's parents were wearing perfumes and she had anaphylaxis in the school. She had to quit working eventually.

And the polypharmacy list is right there. The first one, oral cromolyn, famotidine, Zyrtec or levocetirizine, and you can read through that long list, which also includes omalizumab or Xolair. EpiPen, used 99 EpiPen injections in a year. Every time you inject, that's a nasty medication. It's not a good medication. You don't want to use it. It has bad cardiovascular effects as well. So in the dark blue bar, you are reading that she stopped working, she stopped traveling, she would just not go outside her home. Her only real exposures, which she was always very concerned about was visits to see me. And when she would come, I would make sure that none of my staff, none of our patients were even carrying food items which she was allergic to, that they were not wearing perfumes, that we were not using detergents to clean up our office space because any of those could be triggers and they were triggers for her. She had to isolate, COVID pandemic absolutely didn't help. And she, as you heard, was unable to attend our kids' events and multiple episodes of life-threatening anaphylaxis. Any of these could have taken her life.

As shown in the previous case, here, too, what you are seeing is that she was very symptomatic. So if you look at the total symptom score on the left side with the ISM symptom assessment form, she was very symptomatic on many domains, fatigue, brain fog, diarrhea, nausea, dizziness, abdominal pain, headache, itching, bone pain, and then what you're seeing in the inner spider plot is the red curve, which is what the symptom improvement was on treatment.

Now the first question that some of my fellows and residents ask me is, well, but it's not gone completely. It's still there. It may be. But what this means is that now you are better. This is not a complete response, but this is a great response, which allows people to get back their life. They can start doing things that they were not doing before, including, for example, a trip to as Becker and Philina and Kate mentioned, a trip to Cambridge, Massachusetts, 2 weeks ago. Even you may or may not know, but that was her first trip in years and years. So she's able to do those things with some improvement, right?

And then in the middle one, you are seeing the mast cell quality of life or MC-QOL score. Here too, you are seeing some improvements, which fit with her story. On the right side, you are seeing the EQ-5D scores improve. So on the black, which is the black bar shows her baseline, she was far away from the U.S. general population. That 38% increase is a tremendous increase for a patient who was accustomed to living as sedentary normal -- new normal life for her. This was great.

And I don't know if there's a future slide, but put together on avapritinib, she has been able to get rid of some of our medications. You showed data about cromolyn. So she has cut down her cromolyn use, Xolair. She doesn't need it as of a couple of months of being on avapritinib. She was on it for 2 to 3 years prior to that, and it still wasn't working, but now she has gone in herself off of that. So talk about polypharmacy use going down. And most important to me, at least, has been how she has been able to function back in society and now she's doing what I have always wanted her to do, which is apply for a job and get back to where you were before.

Right. And I met Suki as well and tell me if this is correct, but she described continuing to improve after that 6-month period.

Yes, this is a very important point. So maybe 2 or 3 months into her treatment course, we -- she started talking about the Xolair use going down and she felt like she didn't need it. But her symptom scores and her overall feeling though was not fully there. What really interested me and she noted in herself was that maybe around 6 months to 8 months into the treatment journey is when the brain fog lifted. So she saw that by being on treatment for a numerous number of months, there was a certain point around 6 months or so when things improved. So deeper responses can happen, sometimes just by being on treatment for a long period of time.

Professor Siebenhaar in your experience with AYVAKIT, have you seen that improvement over time?

Yes, definitely. I mean we have to consider that even if you are for 6 months on avapritinib, your mast cells are not 0. You still have mast cells, right? And depending on where you start at baseline and how severe symptoms are, it takes time to improve. And actually, we see all our patients improving over the time of 6 months. So it's a continuous improve of symptoms that even last longer than the 6 months' time we analyze the study.

So Dr. Wedner, as we said, you haven't participated in the trials. And so I want to get a better sense of how you're -- what your practice is like and where you see your patients from and what unmet needs still exist in those patients? So let's talk a little bit about your practice.

So I'm in St. Louis, and we have a rather large drawing area. So I have patients who come see me from the eastern border, Indiana to the middle of Kansas, some drive down from as far north as Chicago and up from Northern Louisiana. So we have a very, very broad referral basis, and our referrals come from a large number of other physicians. Some of them are other allergists who simply don't want to deal with the problem. We see from gastroenterologists for patients who have intractable GI problems that aren't responding to the standard therapies that gastroenterologists use. We have dermatologists who refer them because they have spots and maybe there's something in addition to the spots. The spots are very troublesome for many of our patients. And then we have neurologists because they see patients who say, there must be something wrong. I can't think this is the brain flog. And then the last group are patients who have symptom complex, they consult Dr. Google and Dr. Google says, maybe you have mast cell disease and they come to see us for that reason.

So you brought a case to show how difficult it is to control symptoms with what's available. But before we go there, what do you think of as the -- some of the most transformative newer medications that you've dealt with in the past, say, 5 to 10 years?

So the idea of what's called precision medicine. You've heard a lot of talk about it today. And that is to try rather than treat symptoms, which is what we do up until recently with many of our diseases, you want to treat the cause of the disease. So if you think about it, we have biologics for the treatment of asthma, brand new. There used to be 1 of them. Now there are 5 and more on the way. We have -- medicines for our patients with immune deficiencies that we give them back what they're missing. I treat a large group of patients with a disease called hereditary angioedema. And we've gone from literally no medicine for these patients to 3 prophylactic medicines and 4 on-demand medicines, all of them looking at the pathways that cause the disease and interrupting that pathway. So I think the idea in modern medicine is what's wrong with the patient from a genetic or biochemical abnormality and how can we fix that by attacking what we know cause the disease rather than just treating a whole bunch of symptoms.

And I've heard from all of you that treating the actual cause of the disease is important. And these new medications, sometimes we've heard questions about access to medications like that. So Dr. Wedner, what makes the difference in terms of getting access for patients?

Well, we have a large number of people in our practice who spend their time getting access. But having a program where all we have to do is send the patient's information to a central access registry, and they get medicine what's called a quick start program. You've already heard about it, in which they can get medicine in a couple of days rather than in the old days, a couple of weeks or even longer makes a big difference because now patients have the anticipation. They come to see us, and we say we've got this new wonder drug that's going to fix your disease or at least make it a whole lot better, and they want it now. They don't want it 3 months from now. So the kind of program that you guys have is really going to make a big difference in getting patients on medicine and keeping them on medicine.

Dr. Vachhani, in Alabama, what's been your experience with access?

The -- let me first talk about access to other medications and then about this one. So access to other medications can sometimes be an issue. You have to go through prior authorizations, you're dealing with many providers, and it's just not an ideal way of dealing with a single patient with many organ system involvement. In terms of access to avapritinib, we have not really had issues for nonadvanced or advanced systemic mastocytosis. Our social worker team, pharmacy team has always been able to get access whenever we have wanted to get access to the medication.

Great. So Dr. Wedner, let's look at your case. And then I have a couple of questions after that.

So this is a very typical case for us. It was a 41-year-old woman who was actually referred to us by the local emergency room because she had an unprovoked anaphylaxis. When she saw us, that was the reason she was there, but we took a history. She had frequent stomach upset. She had years of itching and flushing. She described how people would say, why your face is really red, what's the matter with you? And she had occasional shortness of breath. When we looked at her, she had skin spots. She was flushing literally as she was sitting in the clinic setting. She reported nausea, vomiting, frequent diarrhea, which she attributed to food allergy, of which I can assure you she had none.

She did have a classic Darier's sign when we stroke the skin. She had a chest x-ray, which demonstrated osteopenia. Her tryptase was elevated at 42. She did have the D816V positivity. She did have a bone marrow, which showed massive unusual shaped or spindle-shaped mast cells. This confirmed the diagnosis. She started off with a few drugs, which did virtually no good and she ended up on this list with cetirizine and famotidine and montelukast, that didn't work very well. So she was moved to Zyflo CR, she is on ketotifen, which is a very, very sleep-inducing drug. She takes Gastrocrom 4 times a day, and she has EpiPens and she has a lot of them. So she has one that she keeps in her purse. She has one that she keeps at home. She has 1 that she keeps at relative houses just to make sure that there's always one available.

And so you can -- at the bottom, you have persistent symptoms there. She's still living with this?

She lives with it. And she's one of the patients. She's very active and she -- every time she comes in, she wants to know when is this new medicine that she's going to make her better coming.

And Dr. Siebenhaar, you have the unique training in that you're both dermatology and allergologist as they call them in Germany. We've heard about spots in all of these patients. When you think about patients that come referred for cutaneous manifestations, how do you think about that with respect to overlap with patients that have more disseminated disease or indolent -- I mean, or systemic disease, how are those populations doing?

Yes. Well, I mean, first is that when we look at the adult population, most of the patients that are diagnosed with mastocytosis in the skin actually have systemic disease. You just need to look at. And 15 years ago, people weren't said, you may have a systemic disease. It was kind of nondangerous skin condition more or less, might be a bit itchy, then you take antihistamines and you will be fine. But so it turned out, patients are not fine. And now we do all the diagnostic workup in the other patients diagnosed with mastocytosis in the skin, and we find 95%, 98%, actually, indolent systemic disease in these patients.

And when you ask them, they also most of them have also other symptoms that are -- that couldn't be explained before, and there wasn't -- won't actually counted for symptoms of mastocytosis. But as a dermatologist, it's actually very interesting to see because many patients, they come because of their skin, not only, but they come because of their skin. And if you imagine young female or a young man or you're in your teenage time, in your early 20s and you are covered by these spots and nothing helped before. We weren't able to target these spots at all. And AYVAKIT is the first drug that is able to do this.

Great. And Dr. Wedner, you described some of your patients coming from dermatologists. And I think your point was that they ask about the skin and don't go beyond that?

Correct. Dermatologists look at skin. Nothing else -- but when you take a history, what Frank said is absolutely correct. All of a sudden -- but they've attributed a lot of their symptoms to something else. It's not unusual for them to say, "Well, yes, I came because I have spots, but I also have allergies to foods, and that's why I have GI symptoms. And I flush because I ate tomatoes." It's -- so when you put it all together, the vast majority of these patients have systemic mast cell disease, and that's what we have to treat. You just can't treat the skin because they just don't get any better.

And when you think about the spectrum of patients that you see, how do you bucket them into patients that would need a treatment like AYVAKIT or benefit from?

Well, a lot of them do. If you think about those, as Frank said, a lot of our patients, they have spots and the spots are getting worse. And women, in particular, will ask me, are these spots going to get on my face. And we say, "Well, I can't guarantee or not." But anything that could target the mast cell itself. Remember, we know what causes the spot, we know why they're there. Anything that would actually target the mast cell is going to make them better. And you're going to get a lot of people who be willing to take this drug simply because you can say it's probably going to make your spots better. The fact that it's going to totally change the symptom complex, you've seen that now. Quality of life gets better, symptoms get better. We're going to have a lot of patients who are going to be up to use AYVAKIT as a primary way of treating their disease.

And so Dr. Vachhani, what would you say to somebody who would argue that most patients are well served by available medications in this disease?

Well, they are not. Anyone who has seen even a few nonadvanced systemic mastocytosis patients will know that they are not well served. They are still very symptomatic on numerous medications and adding toxicities of those other medications be that drowsiness, be that the ugly taste and sometimes even diarrhea from cromolyn, let's say, or the steroids causing their own numerous other issues. And to me, what this drug avapritinib represents is one arrow with multiple targets in many ways. You are controlling a wide variety of organ systems or multiple symptoms with a single treatment.

Well, thank you all for your presentations. We're going to open it up for questions for the clinicians in just a second. But before we do that, I just want to remind you the things that I said you should remember, first of all, this is a devastating disease. I hope you're convinced of that now. Secondly, AYVAKIT makes a huge difference for these patients, and it does so by targeting the disease and that the more data we look at, the more in the focus, the profound dramatic benefit for patients comes into focus. So let's open it up for questions for the clinicians. We will have a more general Q&A session for the rest of the company later, but are there any questions out there for the -- if you could please identify yourself and your affiliation. Got a microphone coming around? Right. Jim, you got (inaudible)?

A quick question for the clinicians. Are there any biases towards referring physicians to you depending on severity of symptoms? So we see from the prior slides, oncologist visits, GI visits, et cetera, et cetera, do more severe patients come to you referred to by a GI doctor or oncologist? If you could help us out with that.

Yes. Right now, if you were to ask me, I think a vast majority of my patients come from allergist immunologists and/or dermatologists. But I've seen patients from gastroenterologists or even pulmonologists, 1 from neurologist because of how many neurocognitive issues they had. But I would say, allergy immunology and dermatology are the 2 primary big practices from where they come.

I am Bradley from Stifel. For the PIONEER investigators, you discussed the reasons for the placebo effect. But I want to ask for any of the patients you had on placebo on the trial can you characterize the impact from AYVAKIT when patients rolled on to drug at the end of the study? And then I have a follow up.

Yes. Well, I think what is quite good in the study design of PIONEER is that all the patients in the end, rolled over to a real drug treatment. And you see we have seen this placebo effects in the very first weeks which resembles what we think placebo if it is. You tend to rate yourself a bit worse to go into the trial and then you rate yourself a bit better because you hope you are on drug. But this is something which phases out after the first couple of weeks. And then you have these plateaus on placebo, but you have a continuous improvement on symptoms and quality of life on the patients that are on real drug. And you also see this when it comes to the rollover that then the placebo patients come and also come down to the same level of symptom improvement than the patients that have been on real drug before.

Okay. Great. So I want to ask in terms of the clinical meaningfulness, do you look at the clinical benefit of AYVAKIT on the basis of its absolute benefit, which was about 15 points in symptom reduction, or on the placebo-adjusted basis, which was about 6 points?

Yes. Well, I mean we actually do this on statistics or the placebo-corrected way. But I think what turned out even is that the disease is more than we can capture. It's actually not an easy-to-capture disease. There's many, many different symptoms, and we have talked a lot of anaphylaxis, for example, or osteoporosis, which is not even captured by the symptom scores. It may be captured by the quality of life, which is a more look at how the patient is doing and feeling. But since there's not 1 single symptom that applies to all, it's a very heterogeneous disease when it comes to the symptomatology. And therefore, the real improvement is even hard, I would say, one of the hardest diseases to capture in the setting of a clinical trial because all patients are more or less different, right? So this is why we also look at the total improvement, right? Because we know that there are things not very well captured by the PROs we have to use.

I just want to add 2 points to these excellent points. Patients don't care about the specific time point of the primary endpoint of a clinical trial. So the 15 or 16 points that you're referring to, in reality, it's more like 20 points for them with deeper treatment courses as we saw in the PIONEER study. That's one. And then the other thing I would add to it is that these mean symptom score reductions don't capture the entire story. As an example, let's say, if there is a patient who has a big burden of symptoms. But their primary issue, the one big symptom that is affecting them is, let's just say, the GI symptoms, nausea, pain in the abdomen and diarrhea. If that alone improves, that can make them more functional and have an improvement in quality of life. They may not necessarily have to have symptom burden improvement across all the domains. So that single number of mean total symptoms score, it doesn't capture what happens for every individual patient.

Yes. And maybe to add, don't forget that these were all patients being on polypharmacy before. Nothing were able to change or improve their symptoms. And then what we see with AYVAKIT is actually what comes on top. There's nothing we can compare this with, but this is an improvement of symptoms to patients that are taking 6, 7 different drugs and nothing was able to improve them.

Salveen Richter, Goldman Sachs. Blueprint has segmented this market into 3 groups. So the advanced SM and then the nonadvanced SM that are severe and moderate. Can you just help us understand who the adopters of the drug are within these patient populations? And what has played out so far with advanced SM? Has the bottleneck primarily been identification, just given the heterogeneity and how do you think this might improve over time?

Maybe we'll start with the question about advanced SM and Dr. Vachhani, hematologist...

Sure. Yes. Remember the drug avapritinib has been FDA approved for advanced SM only since June 2021. So it's what, 14 months right now, 14 -- 13, 14 months. So many of the community physicians are now more aware about the drug as compared to maybe even 6 months ago. That's one. The other issue -- the other point that I want to add is that there is far more awareness about advanced SM and SM in general. Advanced SM has 3 subtypes of advanced SM. So the field as a whole is learning more about these subtypes of advanced SM, and that is a learning curve that I believe we have been through at this point.

Now in terms of treatment adoption, as was the point brought up before, should we be treating systemic mastocytosis first or the advanced hematologic neoplasm, which is the biggest subgroup of the advanced systemic mastocytosis. Prior to avapritinib there just weren't as good treatment options as with avapritinib based on the EXPLORER and PATHFINDER studies. We have also learned that the c-KIT mutation is a multi-lineage, which means it's found in both the mastocytosis component of advanced SM as well as the other hematologic neoplasm component of advanced SM. With this knowledge and now with more awareness about avapritinib as well as advanced SM, we are seeing more and more uptake in the community for the use of avapritinib. It is the undoubted treatment of choice for patients with advanced SM.

And before we get into the nonadvanced, I think it's important to remember that we had a lot of patients with SM-AHN on the study. And there are patients where the AHN component will improve as well. And so that part of the uptake is a bit more labor-intensive than the patients who have the pure advanced SM. And so we do expect to make inroads both showing data that we generated in the PATHFINDER and EXPLORER studies as well as looking at combinations in that area to address both diseases at the same time in the future. So in terms of the types of patients, I guess, was your question that in mild, moderate and severe, there will be early adopters, what are your...

Well, I think we -- our advanced patients, we always treat in collaboration with our hematologist oncologist. The ones that are not advanced are largely taken care of by allergists immunologists. I think that the uptake for if the drug is approved for the nonadvanced will be in the allergy and immunology community. We're very tuned to this as a disease, and we're looking for better treatments for this group of patients. So I think you will get a lot of uptake once the drug is available.

Dr. Wedner, in the past, you said to me that some people think of a new drug as being first given to the most severe patients, but I think you have a different approach.

No, I don't think that's true. I think there is a little bit of hesitancy about the ones that are most severe. I wonder if they're going to get better. But the ones that are the mild -- the moderate are the ones I think where you're going to see a lot of use of this drug because you have a better chance of it working. And as physicians, we want our patients to get better. So when you see a patient, you're really certain that you have this new drug, they're probably going to get better. There's going to be a lot of uptake there. And then we'll move to the more severe patients because we'll, a, learn how to use the drug, we'll learn that it is a very safe drug. Remember, our more severe patients have more symptoms. So side effects would be more important there. So I think that the uptake will actually be in the moderate group, and then it will progress toward the more severe but nonadvanced systemic mast cell disease.

And maybe what I want to add is completely correct what you say, the field of allergist and immunologist, they're actually well prepared for this drug. Most of diseases as we treat are mast cell-driven or mast cell-mediated. So the awareness and the knowledge about what the drug is adding to the field is very well perceived in the allergist communities.

I think we have a question over here?

Ren Benjamin, JMP Securities. Can you talk a little bit about whether you see a complete resolution of polypharmacy, the longer patients stay on therapy? Or is there just a new level of polypharmacy that you see? And when you're looking at patients, especially like let's call it newly diagnosed patients, do you put them right away on something like ava? Or do you try polypharmacy first, see if you can get it in control and then eventually move to ava?

So well, from my standpoint, the fact that you see from the PIONEER data that these patients are getting better, many of them actually on their own. Patients don't like to take medicine. The human animal is not a really good medicine taker. And so they will, on their own start decreasing their medicine. And I think you see that. I don't need my omalizumab anymore. So I'm not going to come in and get my shot. So I think that one of the things that will happen as a result of a targeted therapy will that individuals will stop taking their medicine. We'll work with them as allergists and how to stop taking them particularly some of them you don't want to stop cold turkey if they're on, let's say, steroids, that's not a good idea. But I think one you're going to see is the fact that they don't need them means they will stop taking them.

Yes. I think it's important to remember that we -- they often try not to stop in the first 6 months, and we will present more comprehensive data about the long-term polypharmacy over time. But with respect to your management of a patient that comes in newly diagnosed, Professor Siebenhaar, what are your thoughts about either optimizing or...

Yes. I think the situation will adopt to the management of other mast cell-driven diseases we did before. For example, chronic urticaria, we have a treatment algorithm, international guideline. And of course, we always start with the antihistamines because they are available, they are cheap and they're helping some patients. But the vast majority of severely affected patients, they will not help them. But immediately, this is something you realize very quickly. And then it's the point to go to the more advanced treatment option. And as we are expert for the disease, we see most of the severe patients. So I think our decisions will be very quickly, and we have to experience that the antihistamines and other drugs doesn't work well. So we do the first shot. But if this doesn't work, we will come with the second shot right after that.

Also as physicians, we don't really like to send our patients to 4 different specialists for management. That's just a lot of burden on the health care system. Patients are then seeing 4 specialists, multiple medications, medications at very high doses compared to what's usually given. So it's not just polypharmacy. So I -- much like what was mentioned before, I see adoption at an early phase in a patient's journey rather than using it after numerous other medications.

And what are the patient's opinions about this, whether they want to try other medications or they're interested in something that hits their disease?

They definitely want this, Becker. I welcome you to come to the UAB MPN Clinic. After the PIONEER study completed enrollment, I still had patients who wanted to go on. They are eagerly waiting to either get the drug once it's FDA approved. ARGON, Blueprint, other clinical trial, which we can -- I'm sure the team will talk later.

Other questions?

Yes. Arthur Weise, Kingsland Investments. It sounds like diagnosis of the disease can take many years. Can you comment on what we may typically see? And do you think that now that there is a treatment that time frame to diagnose correctly will shorten?

Yes. Well, this is not unique to mastocytosis. It's unique to rare diseases. So for most rare diseases, the time from onset of symptoms to diagnosis is about 9 years. The hope is that as you have better and better therapies, one of the things that I often say is nobody's going to ever make a diagnosis they don't think of. So the hope is that we will interact with the community, with the physicians that we deal with and make their awareness of this disease greater so that we can shrink the amount of time from the onset of symptoms to the diagnosis.

Yes. But maybe to add to this, I think this is even about to change, right? We have learned so much more about the disease in the last 10, 15 years. And the experience we have now, patients telling us it took 9 years till I got diagnosed is patients that are having the disease for really 30, 40 years. So at that time, it was what it was. But there was so much awareness about this disease in the last 10 years. There's mastocytosis -- is in the head of every allergist or a dermatologist or even other doctors. So I think nowadays, even so it hasn't been captured, sorry, by numbers, but I think nowadays, the disease is diagnosed much, much more quickly.

Yes. Great. Well, thank you all for your time, and thanks for your participation in the trials and your many years of knowledge about allergy disorders. So thank you. And we'll take a short break right now, about 10 minutes, and then we'll come back with the next part of the presentation.

(Break)

Please take your seats and silence your devices. The meeting is starting now. Thank you. Please welcome to the stage, President of Research and Development, Fouad Namouni.

Hello, everyone. As you heard from the voice of [God], I'm Fouad Namouni, President of R&D at Blueprint Medicine. 2 years with Blueprint Medicine and I will share with you today my perspective on our R&D and how our R&D is going to achieve the vision that Kate Haviland, our CEO, shared with us for 2027.

I will also give us an update on our EGFR, 945 and all the EGFR pipeline data and how are we setting the strategy for this opportunity to really address a high medical need for this very complex disease. Then I will invite Dr. Percy Carter, our Chief Scientific Officer, to come and take us through a full research update, including our new platform of targeted protein degradation and how at the Blueprint we are using our expertise in this field to leapfrog in these new technologies.

With 2 approved medicines in multiple indications, with 14 development candidates, with a high success rate from IND to POC and with 5 breakthrough therapy designations by the FDA, Blueprint have established a robust and productive R&D capability. But the most important question I asked myself over the last 2 years, why is that? What are the drivers for such a robust and productive R&D capability? And I was able to identify 4 key things.

One is the scientific rigor and the scientific decision-making. That's what the teams at Blueprint do.

Number two is the focus on precision medicine and built a platform that is designed to give highly selective and yet potent tyrosine kinase inhibitor with the discipline to look at target product profiles that achieve high bars and stick to them or replace them through our platform.

Number 3 is our highly experienced research and development teams. They're not only highly experienced in the research and development, they have been acting over the last many years as talent magnet. I witnessed personally during the very difficult period of our industry during COVID how tough was to be able to attract talent. And the teams at Blueprint yet continued to do that on a regular and consistent basis.

The fourth one, a very important one, is an efficient management of resources. In a company our age and our state, it is important that we allocate our resources and finances the right way where we think we can make the difference and be very, very much focused. As we continue to focus on high medical need diseases, now we are moving to doing it in more and more patients with scale in mind to help even a broader population of patients.

A few key things I would like to highlight on this slide. Building on our KIT mutation experience that you heard about earlier from a number of presenters, including leader and experts in the field of systemic mastocytosis, we are expanding our research to wild-type KIT to address in the space of allergy some very important challenges such as chronic spontaneous urticaria. We are building on our experience in lung cancer with GAVRETO to use our pipeline of agents and address the complex challenge of the resistance EGFR-driven lung cancer.

In breast cancer, in hormone positive breast cancer, we are focusing on one of most exciting approaches targeting CDK2. And we are also looking at CDK2 outside of breast cancer in CCNE1-amplified tumors in the GYN space like endometrial cancer and ovarian cancer. In addition to our collaboration with Roche on immuno-oncology, that Percy will update us on where we are there, our teams are studying multiple undisclosed research program covering a variety of targets in a variety of areas with medical need.

How are we continuing to scale our R&D and how are we continuing to prepare us for that 2027 high bar goal that we are -- that we'll be able to achieve?

In terms of platform, and in support of our tyrosine kinase inhibitor platform that continue to give and give highly selective agents, very potent agents for geared towards the use of single agents or even with combinations with other agents, we are adding targeted degradation platform. Targeted degradation platform is a very crowded area. A lot of people are interested in this new approach to [ready] drug, very important targets. Percy Carter later on will show us how Blueprint, building on our experience, we think we can leapfrog the field in this space.

We are using more and more translational data as I will take you through the EGFR experience, as an example, to really help us make scientific or science-driven decision to help us accelerate the cycle of development of our pipeline and to help us bring precision medicines to the right patients very quickly.

Our culture of innovation is key to us. It is important that we'll continue our scientific rigor and depth in anything that we do. Urgency to patients will see how we are moving fast with our EGFR and other program has been key to us, and will continue to be key. I heard this morning from the presenters, severe diseases whereas oncology, hematology or rare diseases are so severe, patients do not wait.

The last but not the least, as a company with our age and our size, it is important for us to really use our resources in the most efficient way, make some choices, sometimes some tough choices, but be scientifically driven, be focused and go for where is our highest ability to impact and to win for patients.

Let me move gears to update on where we are on EGFR, look at the overall medical need area, where we think our pipeline can impact and set the direction for our EGFR molecule, so we know where -- what are we focusing on moving forward. It goes without saying that lung cancer is a devastating and a deadly disease. And with all the progresses that have been made over the years, many, many, many patients continue, unfortunately, to die of this disease.

In the gene driver space, EGFR is the most frequent driver in this disease with about 60,000 patients worldwide coming every year to first-line therapies. First-line of therapies, regardless of the progress that was made in the first-line space, EGFR is not -- is still a high medical need disease.

There are 2 activating mutations driving the EGFR as a disease. One is the L858R activating mutation. For simplicity, I will call it LR during the presentation. And the other one is exon 19 deletion. Regardless of the progress that we have seen, L858R, or LR, continues to be a high need in this space of EGFR-driven non-small cell lung cancer.

At Blueprint, we are using our pipeline to address this complex and high unmet need situation with a pipeline that is built as a complementary and synergistic pipeline, but also, as you heard this morning, as a modular pipeline with a number of medicines or number of molecules that could become impactful medicines.

Regardless of the progress that was made with osimertinib as a third-generation TKI in the treatment of non-small cell lung cancer driven by EGFR, there are still a number of issues that we see and we will continue to see over time. Three key ones are, first one, the benefit in the LR activating mutation population. We continue to see a lack of benefit or a lower benefit in the LR population compared to the exon 19 deletion probably due to an incomplete inhibition of EGFR LR-activating mutation by the third-generation tyrosine kinase inhibitors.

And when the treatment continues with tyrosine kinase inhibitor, we do see more and more resistance mutation emerging over time, driving the resistance in the EGFR clones or parts of the disease. Therefore, we believe at Blueprint and working with our investigator that the most important thing, it's not to go and face this mutation. This resistance mutation is in the very late stage in the complex and heterogeneous disease, but it's go very early on in the treatment and try to prevent the emergence of these drugs.

In addition to the EGFR resistance, there is what we call off-target resistance and a number of driver genes, as you see on the slide, will be driving resistance in the late-stage population of patients. And when I talk about late stage, I mean, second line and beyond, which you don't see a lot of it in the first-line setting of EGFR-driven non-small cell lung cancer.

Let me zoom in here on what we learned from the osimertinib experience in the L858R activating mutation or LR. Clearly, from the osimertinib registrational study in first-line non-small cell lung cancer, patients with LR activating mutations have a much lower benefit than patients with exon 19 deletion as an activating mutation with a difference of more than 6 months in PFS being shorter on LR compared to exon 19 deletion.

And in fact, patients with LR have one year shorter median overall survival compared to patients with the other activated mutation exon 19 deletion. Data suggest that an incomplete inhibition of third-generation TKIs is probably behind this, as you can see in 2 cell-line models comparing exon 19 deletion and L858R where we can see a full inhibition on exon 19 on the right side of the slide and an incomplete inhibition with LR.

At Blueprint, we developed our pipeline from our productive TKI platform to address the complexity of EGFR mutations. Let's go through what we have been developing at Blueprint. BLU-945 has been designed to focus on the driver mutation. And in particular, with the high potency on the LR as an activating mutation to also cover 2 resistance mutation, T790M to third-generation TKIs and -- to first-generation TKIs and C797S to third-generation TKIs. Importantly, this agent has also been designed as the best-in-class in terms of selectivity over wild-type EGFR. BLU-945 is selective almost 900 falls over wild-type EGFR in biochem experiment and is more than 500-fold selective over EGFR wild-type in several experiments.

BLU-701 and its backup, BLU-525, have been developed for full potency on the driver of mutation or the activating mutation, but also a strong potency on the resistance mutation to third-generation TKIs, the CS mutation. More importantly, it's probably the best-in-class strategy in terms of brain or CNS penetration as we have described in the past. So highly brain penetration.

For exon 20 insertions, we have set the bar at the Blueprint at a very high level. And remember, I just said when we go through our TKI platform, we set the profiles, we set the bar high and either we can make them or we try to find something that really corresponds to the high bar we set to -- that our research team set.

We're looking for 4 criteria: oral agent; covering major insertions of exon 20; selectivity over wild-type EGFR; and solid CNS penetration or a brain penetration.

Through the acquisition of Lengo Therapeutics earlier this year, we have been able to identify BLU -- what has become BLU-451, that in the preclinical data, fulfilled all the criteria we have described in our TPP. And I'm happy to share with you also in addition to 945 data, some BLU-451 very early signal from the ongoing CONCERTO Phase I.

So before we go to the 945 data from the Phase I trial, SYMPHONY, I would like us to look at what are our key takeaways and how are we using the monotherapy data, the preclinical data and the early observation from the combination data to really guide our strategy and how to help this population of non-small cell lung cancer with LR as an activating mutation.

What we have seen with BLU-945 data is a very low adverse events in terms -- related to wild-type EGFR. We have seen in terms of activity, a major decrease. In fact, I will be able to show you clearance of ctDNA in the majority of patients with a variety of mutations. We have seen clinical responses and clinical activity with BLU-945.

The clinical activity was not durable. As we have been dose escalating in the late-stage patients, third line, 4 lines of therapy, sometimes all the way to 6 or 7 lines, these patients have the EGFR component, but they also had bypass mechanism as you would expect. And therefore, the EGFR responses were not durable in time. But that gives us enough confidence and proof of concept for what BLU-945 as a single agent is doing.

We talked about the medical need in EGFR LR. We also talked about the first-line EGFR lung cancer that is different from all the other lines in terms of EGFR being the major driver of the disease. And we generated some preclinical data that showed us the combination of osimertinib and BLU-945 not only improved the -- or blocked the tumor growth, but also in preclinical models improved survival versus each single agent.

We are not seeing a major impact of EGFR wild-type adverse events. In fact, we are seeing low EGFR adverse events from the early cohorts of combination of osimertinib and 945. And we believe because of all these aspects that in order to help patients in the most efficient way as soon as we have a recommended Phase II dose for the combination is to move right away to look at patients in first-line with LR as an activating mutation.

This is the first time we present data on BLU-945 from our BID cohorts, monotherapy. This data will obviously be fully presented and described at a major oncology conference. But let me update you on what we have been seeing in this dose escalation study. BLU-945 was generally well tolerated with very limited EGFR wild-type related toxicity or adverse events. We have reported some DLTs through the dose escalation process, but all the DLTs were not wild-type EGFR-related. In fact, we have seen, as you would expect, with TKIs, LFD elevations, fatigue, nausea and vomiting.

Now when we look at the activity data, there we can see on the left side of this slide, a major level of clearance of ctDNA. And remember, these are very late-stage patients with multiple mutations. This clearance of ctDNA was seen in LR CS regardless of TM, with or without TM. We have seen also some triple mutation patients with exon 19 del as a driver and so on. This major clearance of ctDNA in these late-stage patients also was matched with the clinical activity in the majority of patients in this population of patients, including 2 partial responses in this very late-stage heavily pretreated population of patients.

As I mentioned, for off-target reasons, the durability of response was not long. But that does not really hinder the fact that the full inhibition that 945 is doing, these delayed stage patients, is one of the belief system we have in terms of taking it in combination to the first-line -- bypass resistance, off-target resistance in late-stage EGFR-driven non-small cell lung cancer.

At baseline, for patients when they enter BLU-945, we have been able to see the majority of patients consistently. A number of drivers that are listed all here. They may not come as a surprise in terms of driver because we knew we're going to see some of these drivers [again]. We had not only seen them at baseline, but many patients had them also had additional bypass or off-target driver of other disease at the end of therapy.

In fact, 24% of patients had multiple drivers at the same time. This is telling us that EGFR-driven lung cancer is a very heterogeneous disease. More we go to late-stage patients, the more we see other things that are not related to EGFR. And therefore, in order to prevent the disease progression we need a robust EGFR inhibition as early as in the frontline setting or in treatment-naive patient before all these off-target region started multiplying and appearing.

Now that we set the direction for 945 and its combination with osimertinib, now we have set the direction based on the totality of the data from the monotherapy that was not enough. We have set this direction also based on preclinical data and what we are learning from the combination in first-line -- in combination in lung cancer.

The unique profile of 945 that was built with high level of selectivity allows a high level of inhibition of all the mutation LR, CS, TM or LR CS or even LR as an activating mutation in a way that is much higher than what we see with first generation gefitinib or third generation osimertinib from the biochem data on the left side of the slide.

It is interesting to see over time when the third-generation TKIs have been developed. There was really a shift of the selectivity profile to be more selective and more potent on the exon 19 deletion compared to the LR population of patients, where BLU-945 will have to play an important role. This is another element that is making us think that putting them together, osimertinib and 945 could achieve the full inhibition of LR.

Most recently, actually last week, at the EORTC-NCI-AACR, or triple meeting in Europe, our teams were able to show some new preclinical data focusing on LR in treatment-naive patient-derived xenograft. We'll look at tumor growth in this representative PDX for the disease we are targeting and we are looking on monotherapy BLU-945, we're looking at single agent osimertinib and the combination of both. And you can see strong additivity over time for the combination versus each single agent in terms of controlling the tumor growth in this PDX model. On the right side, we have also seen an improvement or increase in overall survival in this preclinical experiment of the combination of osimertinib and BLU-945 compared to each single agent.

So where are we from our early SYMPHONY trial dose escalation for BLU-945 and osimertinib? Since we started the dose escalation back this past summer, our teams have been really moving with speed and efficiency fully recruited 2 cohorts for the combinations in QD, 2 cohorts in BID and just opened the 400-milligram cohort in QD for the combinations of osimertinib and BLU-945.

First, osimertinib is used at its approved dose of 80 milligrams. Second, the population of patients we are looking at in this is really more geared towards dose escalating, looking at safety and getting a recommended Phase II dose, and these are late-stage patients. we are allowing patients to enter this dose escalation with -- they have to had one more prior TKI, but I can tell you that many patients have a number of lines of therapy coming to this dose escalation.

We are happy with the progress of this dose escalation. We are seeing minimal evidence of wild-type EGFR-related toxicity. We have not reported DLTs to date. And our goal is to continue this work to get to a recommended Phase II dose. And in the right way, expand in our target population of patients, which is the EGFR LR non-small cell lung cancer.

So overall, I think the totality of the data from monotherapy from what we are learning in terms of safety of the combination, continuing the dose escalation from preclinical data, whether it's biochemical cell or preclinical pharmacology models, is telling us that the need in the L858R population of patients in first-line non-small cell lung cancer can be addressed with the combination of 945 and osimertinib. Now let them finish the 945.

Let's move gears to our plans for the 525 backup to 701. The Phase I HARMONY, which is a dose escalation trial looking at 701 as I described earlier has been through dose escalation for 4 cohorts, 2 in QD, 2 in BID with early signs of clinical activity and translational activity through ctDNA.

The metabolism pathway did not allow an increase of the dose to a level where we think was our projected doses from the preclinical work that we have been doing. But having been watching this, the team has advanced the backup 525 that Percy will take us really through the detailed profile of 525 and would put it side by side with 701. This backup uses a different metabolism pathway has similar or strong potency on the activating mutations and the resistant mutation has an improved selectivity profile and has also an improved brain penetration. So I mean, you call it a backup, but the more I look at the data the more, I think this is probably next gen or potential best-in-class agents, as you will see from Percy's presentation.

The plan is to start the Phase I with 525 in the first quarter of 2023. And I have to be very clear that patients who are benefiting from 701 now in the Phase I trial, obviously, will continue on their investigator decisions as we would be winding down the 701 trial.

The third part of our EGFR, synergistic and yet modular pipeline is BLU-451. Just remember, the acquisition of Lengo Therapeutics was finalized at the beginning of this year. And this Phase I study named CONCERTO started at the end of the first quarter this year. This is one of the fastest Phase I in lung cancer, in oncology, I have personally experienced.

We started the dose escalation at 200-milligram -- at 100-milligram, excuse me, and we are now at the dose of 400 milligrams. No DLTs have been reported so far with BLU-451 and no treatment-related Grade 3 or more adverse events have been reported to date. We started seeing some activity, and we are seeing responses at different dose cohorts as the escalation continues.

We also started seeing some brain or CNS activity with this agent. But I chose to share with you this particular patient case, given how heavily [affected] this patient, and this patient now is 5 cycle in the treatment. This is a 63-year-old female with exon 20 insertion in non-small cell lung cancer who had 3 lines of therapy.

The first-line of therapy was a combination of pembrolizumab and chemotherapy. That was discontinued for progression, for progressive disease. The second line was CLN-081, that was discontinued for toxicity reasons. And the third line therapy was BDTX-189, discontinued for progressive disease. The patient entered the study at the second dose cohort of 200-milligram and the only related AEs she had was a Grade 1 rash, which is a wild-type EGFR-related AE with a decrease of 58% in its target lesion.

And you can see on the scan, how large was the tumor, 88 x 40 millimeter on the left side, shrinking almost by 60% in size on the right side, at cycle 2. This is one of the most rapid responses you see when you treat patients in oncology where it's in the first scan that you see this regression.

More data from this study with full data will be presented next year. This is an early signal. It is very encouraging, and this is why I chose to share this patient case with you.

So when we look at the totality of what we have been doing in the EGFR space to address a very complex, very complex, a very heterogenous disease, we focus our BLU-945 and osimertinib combination development on the highest need in first-line. And that's where we believe we can impact based on the data we have. Back to what I said from the R&D strength for Blueprint over the last many years and to continue is use the data, use the translational data, use the clinical data and follow the science and made some strategic and tough choices where we believe the impact will be the most important patients. That's 945 story.

BLU-525 clearly is data-driven choices and decisions from a PK, what we learned from 701. But more importantly, it's a speed story, urgency to patients. This has been developed really in a very short period of time to probably become a best-in-class as Percy will describe it. And we can see, when I say speed of story, even with this replacement and moving with 525, the impact on the overall time line is minimal.

Lastly is really for BLU-451 is setting a target profile from what we learned from our library and put the high bar for the target profile and stick to it. And was not available to Blueprint in-house, we were able to find it outside. This comprehensive and modular pipeline will help us address the most difficult questions in the EGFR-driven non-small cell lung cancer.

And to the earlier question around do we have a winning approach? Do we have a solid approach to address EGFR-driven non-small cell lung cancer? The answer is yes. We do.

I want to thank you and invite Percy Carter, our CSO, to take us through the research update. Percy?

All right. Well, thank you, Fouad, and good morning. When we think about research innovation at scale at Blueprint, it begins with our talent. And therefore, it's my privilege to present to you our science leadership team. These 8 individuals each have deep expertise in the basic science that underpins modern drug discovery. In addition, each of them has extensive experience in the applied and translational sciences that underpin science-led nonclinical development.

So collectively, they represent an expert group of collaborators for our colleagues in clinical development and an expert group of leaders for our colleagues in research. And it is indeed this collective research team, bench scientists, computational scientists, experimental planners, experienced program leaders, who work together to take advantage of our 2 integrated platforms and literally create the next generation of precision medicines at Blueprint.

When we consider our portfolio, we think about both the R and the D together. And so indeed, when we think about new opportunities, we begin with our knowledge of our development programs. What are we learning in the clinic? What opportunities do we see? What have our colleagues from commercial informed us about as they've learned more about the needs of the patient population? And so we take that knowledge and bring together and ask first the question is there are another molecule that we can bring in to one of our existing therapeutic areas that will help us provide still more patient benefit? And then, of course, as you might expect, we're also very happy to think about new program opportunities, new science that can lead in the future to the creation of new therapeutic areas.

Recently, you have heard us speak about externally partnered programs on the lower right-hand portion of this slide. And this is something that we've done not only recently but also historically. And what this entails is taking molecules from our research engine and partnering them for clinical development with other colleagues in the industry, biotechnology companies, pharmaceutical companies.

In the past 12 months, we reported on 2 new bioscience transactions highlighted on the top portion of this slide. That is to say, collaborating across research and development with our colleagues in business development to bring in new molecules to the portfolio. One very dramatic example is the one that Fouad just highlighted for you, the acquisition of Lengo Therapeutics, leading to the introduction of BLU-451 into our non-small cell lung cancer portfolio for EGFR-driven mutations. A more recent example we announced in February, which is to say our collaboration with Proteovant and VantAI for purposes of protein degradation. And I'll talk to you more about that later on.

Before jumping to the science, let's think about how we view the overall portfolio from a research perspective. And what I'd highlight for you is the focused approach that begins with these 4 criteria. Can the project lead to a transformative medicine? Does the project have a patient selection methodology? Do we have defined decision points, both at the early stage and projected for the late stage? And then lastly and critically, do we have an edge? Does Blueprint have the ability to apply its focused small molecule drug discovery platform to the project? If we can answer all 4 of those questions in the affirmative, then we proceed. But of course, we're constantly checking in on these questions even as the project progresses to make sure that we're still allocating our resources behind what we believe will be projects that produce medicines that matter for patients.

So today's update, I will cover 5 topics. Two, from our development portfolio, our EGFR backup candidate and our CDK2 program. I'll then turn to our research portfolio, where I'm pleased to talk about our wild-type KIT program and provide a brief update on our immuno-oncology collaboration with Roche. And then we'll come through the presentation at the end with a brief summary of our recent efforts on targeted protein degradation.

So let's jump to the science. Our EGFR portfolio has the potential to address the full spectrum of activating and associated resistance mutations in EGFR-driven non-small cell lung cancer. Fouad has spoken to you about 945 and also BLU-451 at the top. And I will focus my remarks on BLU-525.

This slide shows you a table that is summarizing data that my colleague, Chiara Conti presented on behalf of the team last week at the triple meeting. What the table shows you is that BLU-525 is fully active against both the LR and exon 19 activating mutations -- exon 19 deletion activating mutations, as well as being fully active on the CS resistance mutations. Shown in the square brackets are the selectivity of the molecule of a wild-type, and you can see that selectivity is high.

At the bottom row of the table, it shows you that the molecule also is fully brain penetrant, which was a crucial part of our target product profile. Because as we know, brain metastases represent a significant need in lung cancer.

The bullets on the bottom of this slide highlight for you the key advantages we see in BLU-525 relative to BLU-701. First, it has a differentiated chemical structure by design in order to alter the metabolic group and provide us options in that regard. And we anticipate this will lead to an increased exposure of the parent molecule in the clinic. Secondly, it has improved kinome selectivity. And you can see that quantitatively on the second row from the bottom where you can see the S10 score is 0.015, literally only hitting 1.5% of the kinome at a concentration of 3 micromolar, highly selective molecule.

The totality of these properties came together for us in our nonclinical toxicology studies, both the non-GLP and the GLP studies, which showed in rodent and non-rodent superior selectivity and activity and safety margin relative to BLU-701.

As we think about BLU-525 moving forward, as Fouad said, we're very excited to enter -- file our IND in the first quarter of next year. However, we're also looking forward to the full scope of the development path. In the future, we can imagine the combination of BLU-525 and 945 shown on the right-hand part of this slide. And what I'd urge you to think about is that together, these molecules will cover not only the common activating mutations, but all associated resistance mutations, while providing activity in the central compartment. In addition to being combined with 945, we anticipate that BLU-525 will combine with osimertinib as well as select forms of chemotherapy and indeed even possibly select antibody drug conjugates.

Okay. So now let's move to our CDK2 program. This is a program that has different therapeutic applications from 525 and instead focuses on a broad range of CDK2-dependent tumors. And when we think about CDK2-dependent tumors, we think in 2 contexts. First, serving as a critical node, the checkpoint for the transition from G1-to-S phase. We know that CDK2 or cyclin-dependent kinase 2 is misregulated in the context of genetic amplification of CCNE1. This leads to a barren CDK2 signaling and rapid progression through the cell cycle. And in fact, therefore, tumor growth and proliferation.

And so when we think about part of the application of our CDK2 inhibitors, we think about the precision medicine opportunity shown on the right-hand portion of the slide. Specifically in ovarian cancer, where up to 20% of the patients have CCNE1 amplification and also in endometrial cancer, as well as some of the other indications shown below.

A second major application for CDK2 inhibitors is in the context of HR-positive, HER2-negative breast cancer where CDK2 has been shown to serve as a resistance mechanism to the CDK4/6 inhibitors that are used in combination with endocrine therapy, right? So we very much look forward to studying both of these indications in the clinic, as I'll mention in a moment.

This broad activity of CDK2 and potential of CDK2 was exciting to us. And so we were thrilled earlier this year to have Victoria Brown representing the entire team present the profile of BLU-222, which I've simply reprised for you on this slide. As you can see, the molecule is fully potent, selective over CDK1, as shown in the Phospho-Lamin and the phospho-Rb cell assays, selective in the enzymatic context against other CDK family members. And then as shown on the final row of the table, highly selective against the kinome. In addition, the molecule has ADME and toxicology profiles that are projected to enable clinical combinations, which as I've just described, we believe will be important in the clinical applications for CDK2.

In the center and right-hand portion of the graph or the slide, I show you that in fact, the molecule does what we would expect it to do in a CCNE1 amplified context. Specifically, in the OVCAR-3 cell model, which is a genetically amplified context for CCNE1. We see the expected effect on cell cycle with increasing concentrations of BLU-222, which was shown through intervention of single-guide RNA to be dependent on retinoblastoma.

In the center panel, we see a dose response of BLU-222 in the OVCAR-3 cell-derived xenograft. Critically in this model, what the team was able to demonstrate was full activity in the model at concentrations of BLU-222 that cover the IC90 for phospho retinoblastoma without inhibiting Phospho-Lamin. So just to reprise that, strategically what that shows you is while sparing CDK1 and fully covering CDK2, we saw full activity, right? As disclosed in the poster, we also see great combination activity with this molecule.

My colleague, [Terry] (inaudible), will represent the team's recent work in preclinical breast cancer models at the upcoming San Antonio Breast Cancer Symposium. I've had the privilege of seeing that data early, and I encourage you to tune into that meeting. I think that's going to be an exciting disclosure.

When we think about the VELA trial, this is the opportunity to demonstrate the potential of BLU-222 in the clinic. Currently, VELA is enrolling the Phase I dose escalation. And we're setting, of course, multiple dose cohorts looking for safety, early signs of clinical activity, as well as validation of the patient -- potential patient selection strategies. The molecule is being studied in both monotherapy and in combination. We expect this to lead to the determination of a recommended Phase II dose, which will allow us to begin our Phase II expansion studies that are planned.

As you can see, the strategy for these studies follow from the science that we've just discussed. Specifically, we will be studying the activity of the molecule in patients with ER-positive, HER2-negative breast cancer as well as patients who have genetically amplified tumors with first -- sorry, genetic amplification of CCNE1 in their tumors, specifically in ovarian and endometrial cancer. In both cases, we will look at combination profiles for the molecule.

I'd like to draw your attention to the bottom of the slide to our translational medicine collaboration that we announced last year with MD Anderson. This is part of our broad effort to achieve the full clinical development utility of BLU-222. And in this collaboration, we are studying new biomarker hypotheses, rational combinations and critically indication expansions that will allow us to identify future important medical utility for BLU-222. This collaboration is going well, and we look forward to reporting results from it in appropriate scientific conferences and papers.

And so now let's come back to KIT. You've heard a lot about KIT today, and it's my pleasure to be able to talk to you about a new KIT program as well. But first, let me just remind you in the upper left-hand corner of this graph, our scientific leadership in KIT began, of course, with avapritinib, which you've heard a lot about today, and I won't reprise other than to say that I personally am thrilled to be part of a company that's doing such great work with this molecule.

My colleague, Christy Rossi will tell you about our strategy for BLU-263, which is a next-generation KIT D816V inhibitor, currently in study for systemic mastocytosis. Recently, we announced a new molecule, (sic) [V654A], shown in the upper right-hand part of this slide. This is a KIT exon 13 inhibitor, which the team designed to be used in combination with other KIT inhibitors for treatment of KIT-driven GIST. And as you heard in our announcement, we out-licensed this to a company called IDRx, a new company, a new biotechnology company. This molecule, you'll now see referred to as IDRX-73 in the future, it will be studied we hope in combination in the clinic, and we look forward to hearing the results of those studies.

So now let's move on to wild-type KIT, the fourth program in our KIT portfolio, which gives us the opportunity to still further expand our leadership in mast cell mediated diseases. So as you know, wild-type KIT plays a central role in mast cell survival, proliferation and activation. And as you've heard, quite eloquently expressed by my colleague, Becker Hewes, mast cells are primary effector cells in a number of severe allergic inflammatory diseases. And Becker, I think, described why they play such a key role in these diseases very articulately.

And when we think about diseases, it really is a very broad spectrum in multiple organ systems. They include severe asthma, atopic dermatitis and the focus of this slide, which is chronic urticaria. This disease occurs in 2 forms, the inducible form and the spontaneous form, which you may have previously heard referred to as the idiopathic form.

What is chronic urticaria? Chronic urticaria is a debilitating inflammatory skin condition. You've probably think about it most clearly from its association with hives called technically wheals, right? But these are these bumps that form in your skin that are very itchy because there's a lot of histamine releasing them.

There's tremendous actual disability caused by this disease because of the sort of chronic nature of this inflammatory condition in your skin. Your skin is an exceptionally important organ, covers obviously your -- the full surface of your body. And as these patients get progressively more and more hives covering more and more of their body, the amount of itching becomes extremely disturbing, right, leading to sleep disruption, stress, anxiety, and in some cases, depression, right?

In addition, there are further complications that are possible with the disease, including appearance of hives in untoward places such as your mouth, the airway or your genitals. And in addition, Anaphylaxis is also part of the disease score on the severe instances. The bottom of the slide, I summarize for you some chronic urticaria statistics to help you understand a bit more about the disease.

Our total estimated point prevalence based on published data is about 2 million patients that is at a moment in time in the U.S. and 4 major EU companies -- countries in the U.K. The lifetime incidence of the disease has been estimated at 1.4% globally. And when you look into that primary data, you'll see that the regional distribution of the disease varies quite a bit. Notably, 37% of patients are reported to have not only the wheals or the hives, but also Angioedema which, depending on where that's expressed can be life-threatening. Imagine the swelling of the eyes, the swelling of the airways, the swelling of the lips. And a full 1/3 of patients report poor control with sort of frontline antihistamines or topical steroids. So clearly, a very significant opportunity for Blueprint to benefit patients by bringing forward a new medicine. And we believe that a wild-type KIT inhibitor can be such a medicine.

This slide gives you our ideal target product profile in the center across a number of parameters, and this is just a selection of parameters. The right-hand part of the table summarizes the actual data for a molecule [BLU-8758]. As you can see, this molecule brought forward by the Blueprint team is fully active in blocking phospho-KIT in cells; proliferation induced by the KIT ligand, SCF; exhibits excellent selectivity both over specific kinases such as PDGFR and FLT3, as well as broad kinome selectivity as shown through the S-10 score.

And then the last 2 rows, I simply summarize the pharmakinetic profile of the molecule. Of course, this is an orally bioavailable molecule, as you would expect from Blueprint. But I've noted also that it has low or moderate potential for drug-drug interactions. And importantly, it is fully peripherally restricted with a KPU of 0.04. The team has identified multiple examples of compounds that meets the target product profile, I'm showing you just one. And advanced candidates' safety and ADME profiles consistent with either single agent activity or combination therapy. And we look forward to reporting more about this program in the future.

Before moving to protein degradation, I'd like to provide one slide to summarize our collaboration with Roche. As you know, this collaboration was initially announced in 2016 and it is a strategic collaboration with the potential to transform the field of cancer immunotherapy.

In 2019, we reported that the collaboration had explored 4 targets. And today, I'd like to tell you that the overall collaboration has together explored 5 targets in total and identified 2 targets for progression. One of those you've heard about before, MAP4K1. Here, the development candidate has been identified and advanced and we look forward to achieving first in-patient in 2023.

I'm also excited to say that the second target development -- sorry, development candidate for a second target, still undisclosed, is anticipated likewise in 2023. And so we've been very pleased with how this collaboration has gone forward with Roche, and we look forward to its continuation.

Now let's turn to targeted protein degradation. So you know Blueprint for its expertise in the discovery and development of kinase inhibitors, right? And that's shown on the left-hand portion of the slide. What we reported in February of this year was the expansion of our discovery platform to include degraders.

Why did we do this? Well, so there were 4 benefits that we expected. First, success with challenging kinases. Kinases for which either complete inhibition was difficult to obtain or we believe that, in fact, actual degradation of the kinase, actual removal of the kinase, would provide additional pharmacological benefit. In some instances, we expected to achieve enhanced selectivity for the profile or differentiated pharmacology. And then lastly, when applied across the entire portfolio, we view this would give us optionality because, again, I want to reemphasize, we will continue with our kinase inhibitor portfolio. In fact, we are continuing with our kinase inhibitor portfolio, while we've added in the degraders.

We took a bifurcated approach to this with internal investment on the one hand to give us flexibility across programs we were all already running -- ready running and new programs we might wish to start as well as the announced collaboration with Proteovant and VantAI, which introduced expertise and also expanded the reach of our efforts by allowing us to start two additional programs.

Let's think about this a little bit more scientifically and say, what are we doing here? Why does Blueprint have an edge in this response, in this area? And what I would say is that it begins again with leveraging the Blueprint kinase inhibitor library. As you know, this is a library of proprietary, potent, selective and drug-like ligands that have been optimized to work at different individual kinases across the kinome and for which we have fully annotated so we know at the outset, their kinome selectivity.

We can then optimize target degradation by [pending] an E3 ligase recruiting element. So these 2 elements are shown in red for the kinase binding element from our ligand. And in blue, the blue square in the center, for the E3 ligase recruiting element. These 2 items are connected by a linker to form a heterobifunctional degrader, right? And that linker can be optimized by the chemistry team to optimize globally the physical, chemical properties, potency and selectivity of the molecule. We are applying this strategy not only to our internal programs, but also to our external collaboration with Proteovant.

I'll give you a simple example from a recent work in this program, and this is an example where we're working on a kinase. We can just call this kinase A or Paralog A in the table. I'll direct your attention to the left-hand side of the table where we show the discovery of Blueprint degrader 1, which is active for degrading the kinase with a DC50 of 60 nanomolar and a Dmax of 63%, right? This kinase degrader was shown to proceed through the expected proteasome pathway and proceeded to induce this degradation through the expected ligase. And this was derived directly using the strategy I showed you on the previous slide, that is to say, by taking a proprietary Blueprint inhibitor and converting it into a degrader.

What the team was able to demonstrate was that through modification of the overall degrader molecule, they were able to convert this molecule, quite surprisingly relative to what we had expected based on the inhibitor SAR, to a potent, selective molecule that degraded Paralog B, a relative of Paralog A. You can see this on the right-hand part of the table [where now in] this molecule does not degrade Paralog A at all, but rather degrades Paralog B with full activity at 37 nanomolar DC50 and 86% Dmax. The team, of course, also quickly explored the possibility of identifying molecules that did both. And in fact, they were able to identify, [and I'm going to] show you one such example, with Blueprint degrader 2.

So this is a simple early initial example but one that has us quite excited. We had long been thinking about starting a program for Paralog B, and now we can do so opportunistically and, in fact, are exploring that now. And I will simply say and summarize from a portfolio impact, we've already started 5 degrader programs: 3 internally, 2 with our collaborations with Proteovant and we look forward to advancing those in upcoming months.

As we reflect overall on what the introduction of degraders has done, I would say it's done 3 things for us. One is by introducing degraders, we've had this portfolio benefit. Two, we have the ability to have altered profiles for any given target. And what I would urge you to consider is to remember that in some cases, a degrader will be optimal because an inhibitor will have submaximal efficacy. In other cases, an inhibitor will be preferred either because we want to fine-tune the percentage of time that we're inhibiting the target or because, as recently been reported in some instances, the inhibitor-bound enzyme actually itself goes on to exert independent biology and degrading it would be untoward. So it's important that we maintain and drive forward both of these platforms.

A third benefit that we've seen from introducing this is in the recruitment of new talent with new skills and the introduction of new technologies, which have actually not only enriched our degrader platform but also our approach to kinase inhibitors. In the future, we can imagine then the integrated platform is having unparalleled productivity, being fully scalable and also allowing us to approach new target classes. And we look forward to disclosing that activity in the future.

I will close with this slide, which summarizes for you our preclinical portfolio and contains many of the projects that I've mentioned today. BLU-222 is not on here because that's a clinical-stage program. But you'll see BLU-525, wild-type KIT and the I/O portfolio with Roche as well as targets that are undisclosed and I haven't had the time to speak to you about today.

And as shown on the final slide, when addressing the question that was put forward by Kate in the beginning of the talk, are we able to leverage our expertise and infrastructure to drive continued innovation and long-term growth, we believe we have, as illustrated to you in this discussion. And so with that, I'm going to turn the floor to my colleague, Christy Rossi, who will speak to you more broadly about our portfolio.

Thank you, Percy. Good morning, everyone. Great to see everyone who's in the room, and thanks to those on the line for joining as well.

Kate started us off this morning by laying out a compelling vision for Blueprint in 2027, by which we are going to double the impacts that we were able to achieve over roughly the first 10 years since our founding over the next 5. The engine that will deliver that kind of growth is, of course, the portfolio. And we've already spent time today talking about some of the most important aspects of it: the opportunities in SM and EGFR, our discovery platform and our early-stage pipeline. And so now I want to take a few minutes to zoom back out and talk about the sum of the parts and address the question that we often hear from many of you, which is what is our overall portfolio strategy and how will it get us to that 2027 vision.

There are 4 key principles that define our portfolio strategy at Blueprint. The first is to start with the science, and I think we heard that pretty loud and clear throughout the day. This was part of the founding vision of the company. Kate talked about the idea around what benefits precision medicine could bring to patients. This was true when I joined Blueprint 4 years ago, and it remains just as true today. Percy talked a bit about the aspects that drive our initiation of new research projects and programs. And they all start with an idea around a target that's important where we can bring, as Percy put it, a Blueprint edge to bear.

The second key driver of our strategy is to diversify risk, and again, we see this play out in several ways through our portfolio. We make routine use of backup programs and next-generation strategies, particularly against opportunity areas that we see as being very compelling. And at a portfolio level, we also look to balance risk and return. We like to think of this as a portfolio that contains a mix of opportunities: some singles and doubles, where we may have more defined risk and more defined upside; with triples and home runs, where we're willing to take on additional risk for the potential greater return. And we'll talk about some examples of that in a minute.

The third principle is to build scale, and again, we see this play out in our portfolio in a few different ways. Already today, we've seen this at the target level where we have built incredible expertise and know-how around important targets like KIT, like EGFR, that have informed multiple programs in our portfolio. We also see this in terms of the clinical and commercial infrastructure that we are building in disease areas of interest to us. And this enables us to gain efficiency and increase our return on investment. And we're starting to see that play through in our financial results as well as we see moderating OpEx growth as we begin to see some of those economies of scale bear fruit.

Last but not least, we don't do any of this alone. We know that we are part of an ecosystem, and we've been very intentional about leveraging partnerships, whether that's in the traditional business development sense or in other senses to help us accelerate the impact that we can have on patients. So let's look at these more specifically, and I think EGFR provides a great example of some of these principles and how they've informed decisions that we have made.

First, we have a portfolio here that is deeply rooted in the science. Where we stand today started with research programs that were initiated at Blueprint because we had a high degree of conviction that we could improve patient outcomes by better targeting driver mutations as well as potential mechanisms of resistance. We also see in this portfolio that balance of risk and return. We have opportunities like the opportunity to completely transform the care of frontline patients through a combination of BLU-525 and BLU-945 sitting alongside a more traditional driver mutation opportunity in exon 20 insertions with BLU-451. And we have a number of opportunities right along that continuum.

This also shows how we allocate resources and use that balance of risk and return to inform those decisions. For example, we are not prioritizing continued investment in BLU-945 combinations in later-line disease because we don't see that balance. We see greater clinical risk for a more limited potential upside. And we have many more opportunities, as Fouad walked through, that we're excited to direct our resources against.

We also see in the EGFR portfolio this idea of balancing risk at an asset level with the strategic use of backup and next-gen programs. So we talked about BLU-525 already, which is an example of a backup program that was in place against a high-value target, and where we're now prioritizing its development because as Fouad said, we believe we have potentially a best-in-class profile here. BLU-263, on the other hand, is an example of what we think of as a next-generation program, one where we intend to develop it alongside avapritinib to maximize the potential value of our SM franchise over the long term.

And this is where this idea of scale really comes into play, that third key principle. I can think of perhaps no more notable accomplishment of our portfolio to date than the leadership position that we have developed in SM, and we spent a lot of time today talking about SM. We have amassed hundreds of patient years of clinical experience, and we brought forward AYVAKIT to patients with advanced disease and are on the cusp of bringing avapritinib forward to patients living with non-advanced SM.

And through these years of work, becoming really part of the fabric of the SM community, we've developed, I think, a unique perspective on the SM landscape. And that enables us to have a vantage point on where we see opportunities for innovation. And we hear a question often from all of you, which is where is SM going and what does that mean for the role of 263? So let's spend a minute on that.

We have developed deep insight into SM across the continuum from deep biological insights to insights on regulatory strategy, clinical development approaches, strategies to help diagnose and eventually make sure the patients get access to treatment commercially. And the totality of that insight informs our view on where this landscape is headed. And I think it's helpful to think about this and break it down between advanced SM and non-advanced disease as we think about the role potentially of new assets like BLU-263.

So let's start with advanced disease. I think Philina put this into context very well earlier. We know that advanced SM is a smaller proportion of the overall opportunity, and that informs our thinking when we think about how best to bring a new therapy forward like BLU-263. We also know that AYVAKIT has set the standard of care here based on a data set with high overall response rates, deep and durable responses and a favorable benefit risk profile. AYVAKIT also has full approval in this indication. So this, in total, creates a pretty high bar. We've moved past the point we know where single-agent ORR data is going to really move the needle.

So how do we think about this in terms of bringing forward a potential next-generation agent like BLU-263? There are some opportunities that we see for innovation beyond, of course, head-to-head data against AYVAKIT to demonstrate superiority, which we know could be a challenge. Certainly, one area is to continue to generate long-term data and show the impact on overall survival, which is still important here. And this is an area where, again, AYVAKIT has significant head start in terms of the amount of clinical data and experience that we generated.

Philina talked earlier about the OS data that was recently published and added to the NCCN guidelines. We are excited to be sharing updates from our EXPLORER trial and following patients out for a longer period of time at an upcoming medical meeting. We now have patients on PATHFINDER who have been on therapy for almost 4 years. And so this is certainly an opportunity we see for continued innovation, but one that we'll likely prioritize with AYVAKIT because it's hard to imagine any therapy catching up to where AYVAKIT already is.

So what are other opportunities in the advanced space? Well, another one that we see is combination data. And again, Philina teed this up nicely earlier, particularly for SM-AHN patients. This is a more defined opportunity in the overall landscape, but clearly an important medical need and one that we are working to address both with data generation with AYVAKIT but we're also going to be looking at for BLU-263.

So what about non-advanced SM? Clearly, that's the bigger proportion of the overall opportunity that we see, where might we go there? Well, here again, we know and we heard earlier with Becker's presentation and from our esteemed panelists that we have a profile in AYVAKIT that is well positioned, we believe, to help a wide variety of patients living with non-advanced SM. We also know that AYVAKIT is going to have a multiyear head start on any new therapy, including BLU-263. And as someone who has worked in chronic rare diseases in my previous life, I know that the hurdle to switch for patients can be very high. Showing differentiation is going to be really important.

So what does that mean for our next steps with BLU-263? First, I want to emphasize that we continue to see an important role for BLU-263 in our SM franchise over the long term. It can play an important role in extending the life cycle of AYVAKIT. We're also in a fortunate position at Blueprint where we are now sitting on what is probably one of the most robust data sets in the SM space between the data that we have from PIONEER and then we'll soon augment with data from HARBOR. And that gives us a unique position to be able to really evaluate some of the interesting questions that are percolating in the treatment of this disease. For example, what is the relationship between tryptase reduction and symptom improvement that we talked a little bit earlier about today. What is the role of brain penetrants potentially in addressing the cognitive impacts of the disease?

So our plan is to, again, follow the science, start with that first principle; digest this data as we continue to work through it from PIONEER; augment it with HARBOR as we get those top line results and then follow those patients out into next year; and then make a really data-driven decision about the best way of bringing AYVAKIT forward, likely prioritizing non-advanced SM, which is where we see the largest opportunity, but continuing to look for those opportunities in advanced disease where we can address those remaining unmet needs.

So our fourth key principle that we outlined today was the role of partnerships. This has been a key driver of our portfolio strategy and will continue to be as we go forward. And we've seen the role that both inbound and outbound BD has played in our portfolio. You see it in lung where the deal that we did in 2020 for GAVRETO with Roche derisked that asset and put us on a completely different path from a financial perspective as a company; our acquisition of Lengo Therapeutics, which gave us access to BLU-451, which, as we heard earlier from Fouad, we're incredibly excited about the potential for that agent going forward.

It's also helped us enable programs that may not be core to our strategy to continue to move forward and impact patients. Certainly, our collaboration with Ipsen around BLU-782 is a great example of that. The IDRx collaboration with BLU-654 is another great example. We've used partnerships and business development to expand our geographic reach as well. So we've accessed the opportunities in China with collaborations with CStone and Zai. We are engaged in distributor relationships with AYVAKIT to help bring therapies forward to patients in Eastern Europe and Israel.

And then finally, we know that it takes an ecosystem to maximize the potential of precision therapies. And so we've been very intentional about engaging in partnerships clinically and commercially, whether that's with national labs, community oncology networks, et cetera, to accelerate the impact that we're able to have with patients. It's also important to note that business development has been an incredibly important financial lever for Blueprint. It has helped fortify the position that we're in, and it contributes to a key strength of the company, which is the diversity of revenue sources that we have. And again, we see this playing through in the financial results and guidance for this year where we've reaffirmed our overall top line revenue guidance, in part, due to that partnership and collaboration revenue.

So I've outlined the 4 key drivers. How does this actually tangibly pull through as we think about the evolution of this portfolio? Well, we see all of these drivers at play in our vision to get to 2027. First of all, we see that important principle of continuing to follow the science. Even as we target larger and more complex diseases and opportunities, we continue to see a portfolio that, at its heart, has every single program connected by a clear idea of which patients may benefit from therapy and why they may benefit.

We see the benefits of scale when we start to really build and consolidate leadership positions in areas like mast cell disorders and lung cancer. We see partnerships at play throughout this portfolio, and we expect that both inbound and outbound BD will continue to be really important levers in getting us to that 2027 vision.

And finally, we see this balance of risk and return I talked about earlier, and what for me is particularly interesting is to look at the evolution over time here. If I think about our portfolio, it has evolved from one that was perhaps a little bit more weighted traditionally to precision medicine opportunities as we think about them more traditionally, which are some of the more defined opportunities with maybe smaller patient populations like [PDGFRA for GIST]. And now what we see over time is a portfolio where those opportunities continue to play an important role, particularly where we have scale but where we're augmenting them with larger opportunities to impact more patients. And we see this acceleration where we are going to potentially be able to impact 20 times as many patients by 2027 versus where we stand today.

I also think it's just worth taking a step back and looking at the sum of the parts in the context of the landscape that we're operating in right now. All of us in this room are part of this biotech endeavor in some way no matter what role you play, and I think we all know that the work we're collectively doing is important and it's hard often. And I think it's interesting to look at what's up on this slide and just reflect on the unique position that Blueprint is in. It can be challenging for companies to bring one product forward or 2 products forward and try to build a company around that. I can't think of many organizations that are in the position that we are sitting in right now where we have the integrated capabilities end to end, we have the infrastructure, we have the talent and the people, we have this portfolio and we have the financial resources to be able to really have a shot at realizing that long-term vision.

So we zoomed out, before we move to questions, which we will in a minute. Let me just zoom back in, and we touched about the big picture. Now let's talk about the next few months and what milestones we have that are upcoming. And I just wanted to reiterate a few. I will also say that at JPMorgan, we will put forward our view on next year, as we often do. So stay tuned for that. But just to clarify what's to come here, and we talked about most of these things already.

We are on track to submit our sNDA for AYVAKIT before the end of this year. We are eager to present the data from PIONEER. That will either be at the end of this year or early next year. And we will be reporting initial 12-week top line data from HARBOR. And again, we'll look forward to presenting a more fulsome view on HARBOR data as that evolves at a medical meeting next year. We talked about BLU-525 and the IND in Q1. And then for both BLU-451, BLU-222, reiterating our guidance to present additional data in the first half of next year.

So with that, I would like to invite all of our speakers back up. We're going to do a company Q&A. (Operator Instructions) And I believe Jim also is accepting questions online from our covering analysts.

Can everybody hear us? I know we had some -- a little bit of audio issue at the beginning, we heard. I think we've gotten that resolved now. I hope everybody hear us okay, hopefully, on the webcast. If you can't, please send a note to the team.

Marc Frahm from Cowen. Maybe start on the EGFR with -- during the presentation, you presented a waterfall plot there, there were a couple of PRs. Can you just confirm whether -- were those PRs confirmed or not? Then you mentioned durability was kind of impacted by tolerability. But you're hopeful that it will be better in the first-line when you combine with osimertinib. Can you just explain that rationale a little bit better?

Yes. So thanks for the question. With BLU-945, we have seen really robust activity as you first have seen through clearance and quite frankly, of ctDNA in the majority of patients. We have seen clinical activity in the majority of patients. 2 PRs, I believe one is confirmed.

And we have seen also responders in the QD that I have not updated, but will be updated at a conference when we show the totality of the data. And I really believe what we are seeing -- and it's not something that we were surprised going to late stage, but actually, doing ctDNA, we have seen a large number of target gene drivers or bypass mechanism. We actually have seen more of that increase in bypass mechanisms at the end of treatment, and we believe that's behind this heterogeneous disease, and that's behind the lack of durability in that very late-stage population of patients.

We also believe that activity profile with ctDNA clearance and with the clinical activity, and more importantly, also with the safety profile for the monotherapy, the early day safety profile for the combination with osimertinib in late stage, I think the medical need in the LR activating mutation mark, I do believe we have a robust plan to go after RP2D, expand in the LR population in first-line and impact there.

I can tell you, I was talking to our lead -- clinical development lead on the program, Brenton Mar, who has been spending a lot of time with investigator on expert. And the idea of going quickly to try to have a complete inhibition of LR and prevention of -- and resistance in the first-line was not only encouraged but made much more sense to the lung cancer community experts than just go into very late stage with a single agent in a heterogeneous disease.

And just for emphasis. So the durability issue was not due to AEs, it was due to bypass mechanisms, just for clarity.

Ren Benjamin, JMP Securities. Just thinking about 525 and 701. I know you have a much better binder, but how do they differ in terms of drug metabolism? Have you been able to evaluate that since that was an indication as to why 701 has been deprioritized? And just going back to Marc's question, in terms of the combination with osi, how do you evaluate between a straight-up combination versus treating with osi first and then upon like response or resistance then being treated with 945?

Percy, you can start with the 525 and then...

Let me take this. Sounds good. Yes, so thanks for the question. So just to be succinct, the metabolic pathways for the 2 molecules are different and not overlapping, right? So -- and that was by design. We're not -- we'll disclose that in a scientific platform in the future.

And for the second question, Ren, I think the -- in the first-line setting, tyrosine kinase inhibitor of third-generation like osimertinib, they do a good job, but not for all patients. When you look at the data from the L858R activating mutation, clearly, there is almost a year difference in survival. In fact, quite frankly from the Florida, there is no improvement of overall survival versus fitting in that trial in the LR population of patients. So there is a clear need to increase or augment the inhibition of LR.

So where we are today is continuing the dose escalations and generating the recommended Phase II dose, expanding in first-line. And we will need to see some robust data. We will also need to see not only robust clinical activity because first-line osimertinib is quite an active agent overall. And we would like to see clearance in ctDNA even better than what we are seeing in late stage. We'd like to see a safety profile that is not adding EGFR-related AEs to osimertinib.

And then when we designed that expansion cohort, to your question, we will take into account how to determine what osimertinib doing in that population versus what's the combination of both doing in that population, what's 945 bringing into that population.

And as Fouad said, I mean shutting down the EGFR pathway, the activating mutation is fully upfront, right, which -- with the LR and also present preventing the resistance for emerging rather than treating it once it does. We believe both of those strategies are going to lead to much deeper and much more durable responses in patients with LR-driven non-small cell lung cancer.

Peter Lawson, Barclays. Just regarding off-label ISM or used in ISM for avapritinib. Just the -- what was the contribution in Q3? And then are you getting any sense that KOLs is starting to use it off-label or starting to think about using it off-label?

So maybe, Philina, you can take that one.

Yes. Thanks for the question, Peter. So we are not seeing appreciable off-label use. It's just a very small handful of the current avapritinib prescriptions. Importantly, the small handful we do see are being reimbursed successfully.

We wouldn't expect significant off-label use in this type of chronic indication as opposed to in oncology types of indications. Certainly, our field teams and our promotional effort are focused entirely on the on-label use of the indications. In addition to that, the top line data at this point have not yet been presented at a medical meeting, and we look forward to doing so in the near future.

I'd like to share a question from Dane Leone from Raymond James via the webcast. "Could the Blueprint team please discuss what early antitumor activities you've seen for the 945 osi combination and how that might inform a view on the lower bound for the therapeutic index for the combination?"

Okay. Thanks, Jim and Dane. As we described this dose escalation of the combination of osimertinib and 945 is happening in the early stage of patients. We are requiring one line of TKIs. But from what we are seeing, the majority of patients have multiple lines. So it's not only EGFR component of the disease.

The reason we are looking at the safety, as you would do in any new combination in Phase I as you go to late stage. And then when you have an established recommended Phase II dose with a good safety profile, and then you go to the population where we expect to see the efficacy. We will see. I mean we could see efficacy. I mean it's very early in the dose escalation. But the goal is to determine the safety profile, the recommended Phase II dose and the right away to the LR population of patients in first-line.

And we'd expect a similar bypass mechanism. It's really the same or similar population as we're seeing in the SYMPHONY trial for the 945 monotherapy.

That's right, that's right.

Matt Biegler, Oppenheimer. Just a question on the -- Becker, you mentioned combination trials in AHN. What's the thought there, midostaurin or chemo combination? And do you guys think that that's really what's going to be needed to get the hematologists off the fence when it comes to prescribing AYVAKIT? That's it.

Yes. So Matthew, you bring up a topic that requires us to think a little bit about the division of SM-AHN patients. And so I think of it is that there are some patients that are SM-AHN and others that are AHN-SM. And so for a much more aggressive AHN, then a hypomethylating agent combination not midostaurin, but hypomethylating agent combination maybe required to address both of these disorders at the same time.

We're still trying to elucidate the extent to which they maybe permissive for each other. And so there may be situations where you improve the SM and that then makes it more difficult to AHN to thrive. There are other situations where the KIT mutations, as Dr. Vachhani mentioned, are actually in the HN. And so that's a situation where we believe the KIT inhibitor by itself could improve both malignancies.

So for the area where we've seen activity on both the SM and the AHN and true SM-AHN in patients where the AHN is not extremely aggressive, just looking at the Pathfinder data more closely and maybe some future data, we think that we can start to change patient -- change providers' behavior. There are a number of people that have used AYVAKIT for quite a while in the advanced setting, and their algorithm is to try the KIT inhibitor initially if they don't have an extremely aggressive HN. And often, they will see improvement of the AHN as well. And so we see that as the kind of the first beachhead.

And then with respect to combinations in the future, I think the hypomethylating agent combinations, we'll have to study. There are some shared toxicity with the disease in terms of pancytopenia there. So we're working that in future clinical trials out.

Let me just to add. I mean we are continuing to treat new patients with SM-AHN, albeit at a slower rate. And so as Becker just described, and we have some additional evidence we are looking to generate. We talked about the overall survival data that we just got into the NCCN guidelines. And so our field-based teams are going to be able to lean more heavily on that data as well as we look to continue to convert patients, as we can bring additional evidence generation to bear. So as Philina mentioned, we have a multipronged approach to continue to convert and change that paradigm of treatment for patients with SM-AHN.

Zhi Shu from Berenberg. Maybe first on AYVAKIT on the advanced SM, it seems like [6%] of penetration is pretty high for a rare disease. Is there any expectation for this rate to go up? And then for the non-advanced launch in 2023, what's the cadence we should be expecting?

Thanks for the question. And so I think the first part of your question was about the additional room to grow even within the treated advanced SM patients and whether there was headroom. So I think the short answer is we believe so. And so I think the primary reason to believe is the observation that right now, 75% of new patient starts and switches are on to AYVAKIT. And so if we sort of continue on that trend, you would expect market share to sort of reach that equilibrium.

I think your second part of your question was about the expected launch cadence for non-advanced SM. And I think there, I would say, I would lead with non-advanced SM continues to be a rare disease. And so we would expect a rare disease type of launch. What makes the ramp, I think, the most tangible to us is this notion of the 7,500 patients we can see today who are diagnosed and actively seeking treatment and where we expect earlier adoption into the more severe subset of those patients, followed by more moderate patients over time. And then beyond that, of course, multiple levers to grow further.

David Lebowitz from Citi. This past summer, the WHO kind of made some adjustments to diagnostic criteria for systemic mastocytosis. How does that impact AYVAKIT going forward into both the advanced and in non-advanced populations.

Philina, do you want to take that? I mean, I don't think -- we don't believe it's going to make much of a difference at all in terms of diagnosis, but I don't know if you want to add, Philina?

Yes. I mean, I think some of the updates that we've seen that have been encouraging coming out of the SM community have been these updates anchoring around the use of the TSS and the importance of symptom -- looking at the symptomology. And so I think if anything, these types of updates are highly beneficial to raise the awareness of the disease and the urgency to treat the SM. But I think back to the heart of your question, we don't foresee any changes or barriers based on the updates.

Maybe just to add one piece to that. One thing, one trend I think we were seeing overall is increased acceptance and endorsement of high-sensitivity KIT blood-based testing as a key lever in patient diagnosis. And I think that is something that we think will continue and will be an important lever to accelerate patient identification. That's certainly something that we're seeing in the field.

Dr. Vachhani, did you have something to add to that?

Yes, I would just say that there were 3 major changes to the...

Just give him the other mic.

Yes, there were 3 major changes to the WHO criteria from earlier this year. Those should not really impact the incidence or prevalence of SM. What -- how they might help is in starting on the B findings of systemic mastocytosis, which will then play a role in how we subtype the systemic mastocytosis. And also, there was one additional change in the WHO criteria, which will help in the diagnostic workup of patients. But overall, the incidence revenue should not change.

Brad Canino again from Stifel. Now that frontline EGFR is truly the priority, how far into clinical development does your collaboration with Astra extend for free Tagrisso supply? Would you look to expand partnerships for the frontline Phase III development to reduce the investment cost? And then second, just quickly on CDK2, how are you measuring CCNE1 positivity as a biomarker? Is there a gene copy number cutoff? Or are you also looking at protein expression levels?

Okay. So let me start with the -- moving to first-line EGFR. We are really excited about going to the right population of patients in the frontline setting, not all patients for now, but the LR activating mutation patients, where we believe our combination with osimertinib could lead to a complete inhibition of the activating mutation.

We have been collaborating in terms of drug supply with AstraZeneca in the late-stage Phase I. We have been very pleased with the collaboration, with the feedback we received from the team there as they really showed interest in that Phase I. I mean, I cannot comment on where we are heading yet because this is -- for now, the goal is really to make sure we have a recommended Phase II dose, to go to first-line and then start the POC cohort in first-line. We'll probably have more information in the future to share. So that's too early to talk about.

From a biomarker perspective, CCNE1 as the potential predictive biomarker for the activity of CDK2, BLU-222 in CCNE1 amplified tumors, obviously, all the work that we're doing is to determine what is the right copy number in terms of amplification of CCNE1 and the team are doing that in ovarian and endometrial. So we'll determine what's the copy number.

We are also actually, beyond the amplification, we developed an antibody test for IHC, and we will be looking at the expression levels of CCNE1 in the tumors, including in some late-stage breast cancer. Again, it's really the clinical work and the markers assessment that we are doing in the Phase I that will help us determine what is the cutoff that we would be using in the future.

And then Brad, in terms of your question on partnering, as Christy reviewed, we always are thinking about potential partners and how to really maximize the value of the assets we're bringing forward globally or accelerate the development. I think we have a lot of experience and expertise in lung cancer. We are well positioned to move forward and do a first-line study there.

I think where we will have to make some decisions is as the EGFR portfolio and the CDK2 portfolio continue to progress. If they stay kind of in track with each other, how do we want to think about where to partner and which program. And I think that is something that we are actively thinking about. And we are certainly continuing to develop relationships around both. And as you all know, these targets are of high interest to big pharma on both sides. And so we will have options.

Another question from -- or 2 questions rather from the webcast. So similar questions that I'm going to combine for simplicity, from Michael Schmidt at Guggenheim and Andy Berens at Leerink. Can you comment on the EGFR opportunity in the context of the evolving landscape including recent amivantanab data, FLORA-2, MARIPOSA upcoming data sets?

Thank you to the 3 of you. I think it's always good for patients and for the disease to see that there is a lot of research happening in the EGFR space. Asking different questions, whether or not adding standard chemotherapy to EGFR third-generation will improve the progression-free survival and the overall survival in these patients. Whether or not adding a MET inhibitor to EGFR agents will improve overall survival in first-line versus the standard of care. And these are important questions that needs to be answered.

For Blueprint, our focus is to develop a well-tolerated, oral combinations targeting specific populations with the right activating mutations and preventing the resistance mutation from appearing over time. Obviously, as we move forward our development plans, we will always take into account the shift in the standard of care and how this would impact our development. Then at this point, we believe that we have a differentiated strategy to deal with a part of the disease that we believe is the highest need for us where we believe safety and activity and durability of response are key.

I think I'll just add to that. I think it's important to remember that all the strategies don't address the insufficient inhibition of LR that we see with osimertinib. And so were the case that they add to osimertinib, they would add to a combination that does suppress LR better than osi does by itself.

And maybe just one additional point to add for context, I think we've outlined why we have conviction from a kind of technical rationale perspective around our strategy. I think another clear piece of feedback that we have heard as we've engaged with KOLs is what the patient experience is like in the frontline setting right now, which is patients are on an oral agent that is generally well tolerated often for several years.

And so as we think about combinations that require chemotherapy that potentially have significant tolerability issues, that is a challenge in that setting. And so we've gotten a lot of very consistent feedback that an all-oral combination that is well tolerated would certainly be preferred.

Mark (inaudible), Bloomberg Intelligence. On AYVAKIT and the Part 1 of PIONEER, I think you showed convincingly there was no dose response and you've clearly taken the lowest dose forward. I'm just wondering, I know in the context of oncology, FDA has been keen on, shall we say, encouraging sponsors to identify the minimal effective dose. Is that something that you think is possible here or something that you've thought about?

I mean, I think that what the FDA has been encouraging people to do is to look at a range of doses and then to determine a very safe, very effective dose, and that's what we've done even before they encourage this too with the Part 1 of the study. And so I think it's pretty convinced -- that we'll be able to convince the FDA that 25 milligrams is an optimized dose for this patient population.

And then I would add to Becker's answer, given the safety profile that Becker shared with you today with 25-milligram of avapritinib in non-advanced SM, it's hard to think how we could go lower to improve that safety profile that is really a typical safety profile you see for primary care agents to use.

One more question from the webcast from Eun Yang from Jefferies asking, in patients who are CDK4/6 experienced breast cancer patients, what is maybe the role or percentage of patients that might have CCNE1 play a role in their resistance?"

In CDK4/6 independent kinases in hormone-positive breast cancer made a major improvement in terms of outcome and benefit when added to hormone therapy. We believe from some early data that resistance to these agents either primary resistance or acquired resistance could be related to CCNE1 over expression. We are working on better understanding the frequency of CCNE1 as a marker of resistance and as a potential predictive marker for activity.

It's too early to tell. But as we are exploring not only our clinical trial, but data from databases and from collaborating on some translational data, we'll have a much better understanding. I think it's very early to determine not only the frequency but whether or not in breast cancer, CCNE1 is a predictive biomarker -- CCNE1 expression would be predictive biomarker.

Yes. I'll add a little bit to that. So just important to remember that Nick Turner's initial data showed that increased CCNE1 expression was a reason for resistance to the initial CDK4/6 treatment. So when you look at patients that have been on CDK4/6 inhibitors for longer periods of time, the prevalence of CCNE1 amplification may change. And that's what we're starting to understand now, but we clearly know that it's part of -- in about half the patients that were on endocrine treatment alone, that caused them to have a shortened time on the 4/6 inhibitor. So it is one of the earlier mechanisms of resistance in a lot of patients.

Any other questions? I know we covered a lot of information today. So we'll do a quick wrap up, I'll make that quicker. Let's see, I have one final slide here.

So today, you have heard about the significant opportunities we have in front of us and about the ambitious but achievable goals we are positioned to execute against as we work our way to scale the impact we have on patients globally.

The combination of our portfolio and our team puts us in an incredibly strong position to execute on the value drivers we have across the business by leveraging our foundation of expertise, capabilities and infrastructure. We are going to double our impact in half the time.

We look forward to updating you on our progress in the days and months and years ahead. I want to take a moment to thank our 3 key opinion leader physicians who joined us here today. So Dr. Siebenhaar, Dr. Vachhani, Dr. Wedner. I wrote down a couple of things from the -- from what you were able to convey and the insights and the experience of SM patients, such as there's nothing indolent about this condition and these patients cannot exist in society the way that we all can.

You all talked about how it hasn't just been patients who are waiting for a new treatment, it's also physicians who have been waiting for a targeted drug for this disease and we are excited about the opportunity to have a potentially new therapeutic option. And Dr. Vachhani described AYVA as one arrow with multiple targets impacting a wide variety of organ symptoms in a single therapy.

I think that -- those statements and the characterization of this disease really brings to life the impact of the opportunity we have to continue to scale and grow Blueprint Medicines. Thank you all again for being here today. Apologies for running a little bit over, and we appreciate the opportunity to catch up again in the near future on the milestones that Christy laid out that are coming right in front of us. So thank you again.