Blueprint Medicines Corp (BPMC) 2022 Q2 法說會逐字稿

Good morning. My name is Charlie, and I'll be your conference operator today. At this time, I'd like to welcome everyone to the Blueprint Medicines Second Quarter 2020 Financial Results Conference Call. (Operator Instructions)

Jenna Cohen, you may begin your conference.

Thank you, Charlie. Good morning, everyone, and welcome to Blueprint Medicines Second Quarter 2022 Financial and Operating Results Conference Call. This morning, we issued a press release, which outlines the topics we plan to discuss today. You can access the press release as well as the slides that we'll be reviewing today by going to the Investors section of our website at www.blueprintmedicines.com.

Joining me on today's call are Kate Haviland, our Chief Executive Officer, who will discuss our successes in the second quarter and a look ahead to the second half of the year; Philina Lee, our Chief Commercial Officer, who will provide a commercial update; Becker Hewes, Chief Medical Officer, who will provide a clinical update; Christy Rossi, Chief Operating Officer, who will review our 2022 milestone progress and upcoming catalysts; and Mike Landsittel, our Chief Financial Officer, who will review our second quarter 2022 financial results.

Before we get started, I'd like to remind everyone that statements we make on this conference call will include forward-looking statements. Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of SEC filings. In addition, any forward-looking statement made on this call represents our views only as of today and should not be relied upon as representing our views as of any subsequent date. Accept as required by law, we specifically disclaim any obligation to update or revise any forward-looking statements.

I'll now turn the call over to Kate. Kate?

Thanks, Jenna, and good morning, everyone. Thank you for joining the call today. At Blueprint, we continue to build one of the world's leading precision therapy companies with the diversity of growth drivers across all stages of our business, including 2 globally commercialized revenue-generating medicines, multiple important clinical development programs across a range of prevalent and hard-to-treat cancers, a prolific early discovery engine and a strong cash position.

Blueprint had a strong quarter with $36.5 million in total revenues, including $28.5 million in AYVAKIT net product revenues. The 20% AYVAKIT quarter-over-quarter revenue growth underscores the strength of our ongoing commercial launch as we continue to solidify AYVAKIT as the standard of care for the treatment of advanced systemic mastocytosis.

Our launch in advanced SM has demonstrated broad prescriber receptivity to AYVAKIT’s clinical profile, strong launch execution that has facilitated access and limited payer hurdles and an elevated patient awareness, leading to increased diagnosis and treatment rates. It has also continued to improve our understanding of the non-advanced SM market and the significant opportunity AYVAKIT has to meet the medical needs of these patients as we look to our registration-enabling, PIONEER Part 2 top line data readout later this month.

We ended the quarter with the announcement of a transformative $1.25 billion non-dilutive financing that ensures we have the resources and operational flexibility to drive Blueprint's long-term growth while maintaining our path to financial independence. This financing enables acceleration of our broad pipeline and an ability to continue to explore opportunities for synergistic and strategic business development. Business development has played a key role in Blueprint's value creation and long-term portfolio growth and has allowed us to fully realize the value of our prolific discovery platform.

Today, we are happy to announce that we have out-licensed our internally discovered KIT Exon 13 Inhibitor to IDRx, a newly launched clinical stage company. Christy will provide an overview of the transaction later during the call. And finally, we plan to provide additional insights into our breadth of growth drivers at our Investor Day, which will take place on November 1st of this year in New York City.

We look forward to sharing our strategic vision for Blueprint with our near-term focus on the important growth opportunity on SM as well as outlining how we are driving midterm value through our EGFR-mutant and CDK2-vulnerable cancer development programs and how we're creating long-term value through our research innovation and vision.

The depth and breadth of what we will cover at the Investor Day demonstrates our unique company profile and the strong position we have to continue to deliver significant value to patients and all of our other stakeholders.

With that, let me turn the call over to Philina to discuss our commercial updates. Philina?

Thank you, Kate, and good morning, everyone. Reflecting on our first full year of launch with AYVAKIT, I am most proud of the strong commercial execution our team has demonstrated as we deliver for patients living with advanced SM. We have established AYVAKIT as the standard of care in advanced SM secured a strong and growing prescriber base and enabled broad patient access with virtually no payer challenges.

We have driven 4 straight quarters of double-digit revenue growth. In the second quarter, we continued to build on AYVAKIT's launch momentum, generating net product revenue of $28.5 million, including $24.7 million in the U.S. and $3.8 million ex U.S. Our launch in Germany is off to a strong start with early adoption at Mastocytosis Centers of Excellence as well as in the community setting.

We are in the midst of country-specific reimbursement submissions in other key markets and anticipate launching in several more countries by the end of the year. Turning to the U.S., AYVAKIT is now the standard of care in patients being treated for their advanced SM with greater than 50% market share. It's the treatment of choice for more than 70% of patients who are starting on or switching to a new therapy.

We expect both these measures to continue growing. We've now seen AYVAKIT prescriptions from nearly 300 accounts since the launch in advanced SM. Our team activated 46 first-time accounts in the second quarter, and we continue to drive breadth in the community setting and depth in the academic setting.

Duration of therapy continues to trend favorably at about 18 months overall, and we expect many patients to benefit from AYVAKIT for even longer periods of time. The greatest opportunity we see to drive continued growth is to increase the proportion of patients who are being treated for their advanced SM, particularly SM-AHN, the most common subtype.

Patients with SM-AHN have a poor prognosis with a median overall survival of around 2 years. At EHA, we presented a retrospective study comparing overall survival for AYVAKIT versus best available therapies. Within SM-AHN patients, AYVAKIT demonstrated a median overall survival of 46.9 months versus 18.0 months for best available therapies. These data should further catalyze the urgency to treat these patients.

Advanced SM represents just 5% to 10% of all SM and with our strong launch momentum, we're only just getting started. We see tremendous potential for AYVAKIT to benefit many more patients as we set our sights on the non-advanced SM opportunity. Non-advanced SM leads to debilitating and potentially life-threatening symptoms, including uncontrolled anaphylaxis, extreme fatigue, diarrhea, skin lesions and brain fog.

Patients and caregivers undertake a significant burden to manage the disease, avoiding everyday triggers and coordinating complex therapy regimens that in most cases, fail to control the disease. There are no approved therapies today. Our goal is to transform the lives of patients living with this debilitating disease. Here's why we're excited about the opportunity.

First, the number of diagnosed SM patients is steadily growing. We can see over 16,000 unique diagnosed SM patients in U.S. claims data, and most of these patients have non-advanced SM. This represents a remarkable 63% growth of the diagnosed patients in the U.S. since the initial launch of AYVAKIT in January 2020. Second, approximately 60% of non-advanced SM patients in these claims take complex regimens of prescription medications, indicative of moderate to severe disease burden.

These patients use a cocktail of symptom directed therapies, including EpiPens, mast cell stabilizers, TKIs and cytoreductive therapies. These complex regimens of off-label polypharmacy highlights the serious medical needs these patients face.

Altogether, the claims data, combined with the breadth of patient and provider research indicates an addressable market opportunity of approximately 7,500 non-advanced SM patients with moderate to severe disease today who may be candidates for AYVAKIT. This represents a significant patient population who have and will continue to actively seek treatment for their non-advanced SM.

With the pricing strategy similar to rare disease analogs such as hereditary and angioedema, we believe non-advanced SM may represent a multi-billion dollar opportunity for AYVAKIT. We expect the launch trajectory will follow other rare disease markets. We continue to advance our market development efforts, working with the SM patient and provider community to accelerate the time to diagnosis and initiation of treatment.

We anticipate this will continue to increase the number of diagnosed patients towards the 32,000 prevalent SM patients living in the U.S. On a personal note, as I reached my eighth year at Blueprint Medicines, the non-advanced SM opportunity has never felt so tangible. We look forward to sharing more about this and how we'll capture this opportunity at our Investor Day in November.

With that, I'll turn the call over to Becker to review our expectations for PIONEER Part 2 top line data.

Thank you, Philina, and good morning, everybody. As you know, we plan to share top line results from our pivotal study of AYVAKIT in non-advanced SM later this month. As the first registration-directed study in non-advanced systemic mastocytosis, PIONEER is on track to provide a wealth of data and confirm AYVAKIT's potential to transform treatment of this more prevalent form of SM.

In June, we shared that the FDA requested we elevate mean change in Total Symptom Score or TSS, which was previously the key secondary endpoint to become the primary end point. As we've seen with recent approvals of other medicines, this approach is increasingly becoming the FDA's standard for randomized trials designed to assess patient-reported outcomes because it considers the full range of benefits seen in each arm.

Let's review our primary endpoint, the comparison of mean TSS reduction in each arm and a key secondary endpoint, the proportion of patients who experienced a response, defined as a 30% reduction in TSS score. These endpoints are correlated as illustrated by the Part 1 data.

Our primary endpoint, the comparison of group means is a measure of how the population treated with AYVAKIT felt compared to those treated only with placebo plus best supportive care. We'll refer to the control arm as placebo-controlled for simplicity. But as was the case in PIONEER Part 1, patients in both arms continued to receive best supportive care before and during the study.

In PIONEER Part 1, we observed a 16.5 point difference between the 2 groups, which was correlated with 60% of AYVAKIT treated patients experiencing a response, something placebo was not able to achieve for any patient. While this response is striking, we've received consistent feedback from practitioners that if at least 1/3 of patients treated with AYVAKIT responded, this would be highly important and practice changing.

Furthermore, both responders and those with less than a 30% reduction in total symptom score often experienced profound improvement in their most severe symptoms, such as extensive rashes, persistent diarrhea and brain fog, all symptoms that make normal life all but impossible. These reductions in most severe symptoms can often be life-changing for patients.

We are confident that PIONEER Part 2, which is powered to measure a minimum difference of 7 to 10 points between TSS reduction. Half the difference observed in Part 1 will provide robust practice-changing results in all of these correlated measures of clinical benefit. In addition to the primary and this secondary endpoint and similar to our prior top line data readouts, we will report top line safety data. This will serve as the foundation for global regulatory submissions.

It includes comparative safety from PIONEER Part 2, the first large placebo-controlled safety data set for AYVAKIT in systemic mastocytosis to date. I'm extremely enthusiastic about the promise AYVAKIT provides for thousands of patients who've been suffering from non-advanced SM for many years. I'll now turn the call over to Christy to review upcoming data milestones and catalysts.

Thanks, Becker. Good morning, everyone. We've made significant progress against our corporate goals in the first 2 quarters of 2022, and we are looking ahead to a breadth of value-driving data catalysts planned for the second half of this year. Within our SM program, we plan to report PIONEER Part 2 top line data later this month as Becker shared and initial clinical and safety data from the HARBOR trial of BLU-263 in non-advanced SM by the end of this year.

We are also making rapid progress across our programs in EGFR-driven lung cancer, where we are working to generate data sets that inform further development and accelerate our path towards registration. At AACR in April, we presented early dose escalation and biomarker data for BLU-945 at once daily doses up to 200 milligrams. These data show tolerability and initial proof of concept consistent with BLU-945 preclinical profile.

Based on these data, we initiated development of BLU-945 in combination with osimertinib in the second quarter. We plan to report initial dose escalation data for the combination in the second half of the year with a focus on providing evidence that BLU-945 and osimertinib can be combined safely as well as translational data highlighting a combination's broad coverage of primary and secondary EGFR-mutations and early signs of clinical activity. We also expect to report a recommended Phase 2 dose for single-agent BLU-945 by the end of this year.

More broadly, and consistent with our prior guidance, we expect initial clinical data for BLU-701 in the second half of 2022 and for BLU-451 in the first half of 2023. Finally, we remain incredibly excited about BLU-222, our CDK2 program and its potential to impact many patients suffering from highly prevalent cancers and look forward to presenting initial clinical data in the first half of 2023.

As Kate previewed earlier, we are proud to announce that we have out-licensed our internally discovered KIT Exon 13 inhibitor to IDRx to advance the program into the clinic, evaluating it in combinations for patients with GIST. This represents our first development candidate of 2022. And because we believe in IDRx's focus on the combined ability of precision therapies, we received a 15% Series A preferred equity stake in exchange for our license grant.

We are also eligible to receive up to $217 million in potential regulatory and sales-based milestones as well as tiered royalties on net sale. This transaction is another example of our commitment to ensuring that valuable, scientific and medical innovation reaches patients regardless of the shift in our portfolio priorities.

I'll now turn the call over to Mike to review our financial updates.

Thanks, Christy. Earlier this morning, we reported detailed financial results in our press release. For today's call, I'll touch on a few highlights from the quarter. Total revenues were $36.5 million for the quarter, including $28.5 million in net product revenues from sales of AYVAKIT and $8 million in collaboration revenues.

We are reiterating our previous revenue guidance for 2022 of $180 million to $200 million in total revenues and $115 million to $130 million in AYVAKIT net product revenues, putting us well on track to realizing the blockbuster potential for AYVAKIT. Our R&D expenses for the second quarter were $128.3 million, including approximately $10 million of non-cash stock-based compensation expense, reflecting planned growth in R&D expense related to the strong execution of our clinical trials.

Compared to the first quarter of this year, R&D costs increased by approximately $25 million, driven by accelerated timing of expenses related to the startup and supply activities of 4 new clinical trials across our EGFR and CDK2 programs. Additionally, we saw increases driven by timing of certain early research activities.

These investments and new programs will drive the next wave of value inflection points for Blueprint and highlight our ability to sustain meaningful innovation through our best-in-class discovery platform. SG&A expenses for the second quarter were $58.7 million, including approximately $15 million of non-cash stock-based compensation expense and were flat compared to Q1 of this year.

Looking forward, we expect that overall expenses will be flat or slightly lower in the second half of the year as we drive towards key data readouts. Finally, our June 30th announcement of a strategic non-dilutive financing agreement with Sixth Street and Royalty Pharma puts Blueprint Medicines in a strong financial position to drive rapid growth while ensuring our path to profitability in the coming years.

As of June 30th, we had $947 million in cash on our balance sheet. This balance includes $175 million upfront payment received under the Royalty Pharma agreement. In addition, in July, we received an additional $400 million in gross proceeds related to our agreement with Sixth Street, which will be recorded in our financial statements in the third quarter.

This quarter was marked by executional excellence across our commercial, clinical and research organizations. We continue to allocate resources towards R&D and core programs that are rapidly advancing towards value-driving milestones.

The combination of our strong cash position with well over $1 billion on the balance sheet as of today, multiple drivers of top line revenue and diversity of important pipeline programs uniquely positions us to continue building a leading precision therapy company, bringing transformative medicines to patients worldwide and delivering value to our shareholders.

I'll now turn the call over to the operator for questions. Operator?

(Operator Instructions) Our first question comes from Marc Frahm of Cowen and Company.

This is Ernie Rodriquez for Marc. Congrats on a great quarter. I have asked 2 questions. If I may, Becker, you mentioned reporting the safety results for PIONEER. And I was wondering if you could tell us what level of granularity should we accept for the safety portion? And why would you see an acceptable number of interstitial hemorrhage or placebo adjusted neurocognitive AE? what level do you think these AEs could significantly affect adoption? And a second question, if I may, for 263, what should we expect for the initial data disclosure what level of details and how should we think about the data when comparing it to pioneering.

So Becker, I think maybe you can start off with both. And then if (inaudible) ()add to the 263 comment, that would be great.

Yes. So for the top line data, we plan to present adverse events and serious adverse events, comparing the 2 arms. As we typically do with top line data when we first see the readout of these trials. With respect to expected rates of adverse events, I hesitate to speculate on what we would see in the trial, I think it's important to remember, though, that these are patients receiving standard of care medications, some of which have adverse events that overlap with the disease or even some that might overlap with some of the AYVAKIT-adverse events.

However, at 25 milligrams in Part 1, we saw an extraordinarily good safety profile with very low rates of even Grade 1 adverse events and really no Grade 3 adverse events. And we would expect the safety profile in Part 2 to be very similar to what we saw in Part 1. And then with respect to 263, we have Part 1 of our study ongoing. The first part is blinded and placebo-controlled as was the case with PIONEER Part 1.

We also have some patients that are in an open-label portion of that study where we can look in an ongoing manner at adverse events and a reduction in TSS score. And we expect to present some preliminary data about that trial during the quarter, before the end of the year. And then we're looking at various opportunities to present the randomized Part 1 data.

Do you want to...

Sure. Maybe just to add a couple of additional comments there. One, just on the safety hurdle for AYVAKIT. One thing that I think is really important for us to all keep in mind is that we have not actually seen a fully placebo-controlled safety data set for AYVAKIT yet.

So we are very much looking forward to having that data and really understanding and contextualizing what safety looks like in benefit risk in the context of a randomized study where we haven't seen that data before. With regards to 263, as Becker said, we will have initial data prior to the end of the year, similar to what we saw from Part 1 of PIONEER.

And I think we're going to be looking at the data coming out of PIONEER Part 2 as well as this data to really understand how best to bring 263 for to patients. We know that the bar there is going to be incredibly high, and it's going to be set by what we anticipate will be really transformational data that AYVAKIT will be demonstrating in this disease. So we really look forward to kind of putting those pieces together and then sharing more about how we see moving our best-in-class franchise forward from there.

Our next question comes from Dane Leone of Raymond James.

Congratulations on the quarter and all the progress. I guess 2 really questions for me, just to clarify some of the commentary from your presentation that sparked some interest, I guess, from the investors on the call. The first one would be, in your slide around Advance SM, your update on the market penetration of AYVAKIT, seems to imply that you have about 50% share in the U.S. now.

And I guess maybe that's a bit below where we and others would think you would be at right now, given the revenue run rate. So if you could clarify, I guess, what your U.S. expectations are for the opportunity in ASM, that would be helpful. And then secondly, could you just clarify in terms of the pricing strategy.

You did as it relates to ISM mentioned, you thought hereditary angioedema could be comp, but that's obviously incredibly highly priced drug. I guess some of the questions there around use of omalizumab and other interventions, maybe off-label for ISM. Where is the conviction that you can price that high in ISM with AYVAKIT or 25 mg day avapritinib?

Yes. Thanks, Dane. So for maybe take both the first question being the 50% market share feels low relative to the revenue run rate and then talking about the pricing assumptions. Yes. Thanks for the question, Dane. So first, to your question about market share. So just first of all, confirming the way we are defining market share is the proportion of patients who are currently receiving AYVAKIT out of the total portion of patients being treated with TKIs and cytoreductive therapies.

And so we have seen this steadily growing, and we're encouraged by this continued growth. Today, that number is over 50%. And if anything, we are excited about the substantial headroom that this represents for the market, both in terms of the market share of treated patients. But even more broadly, we are continuing to grow the portion of the market that is actively being treated, and that's where we see the greatest amount of continued headroom for the advanced SM patient opportunity.

And to your second question about pricing strategy. So I think that the intent was not to say that we were aiming for consistent or the same pricing as other hereditary angioedema therapies, but mainly to use that as a relevant analog for rare diseases where the underlying pathophysiology is known with high medical need where you have medications that can enable disease modification and truly transformative benefits for patients. That is the type of transformative benefit that we anticipate for AYVAKIT.

You referenced omalizumab, and I think it's really important to understand that it's in spite of these cocktails of symptom directed medications, the vast majority of patients still have substantial medical need. So we've talked before about patient and provider burden of disease studies that indicate the majority of patients still talk about having to avoid leaving their home because of SM.

So that's about 2/3 of patients. 80% of patients, despite taking these polypharmacy regimens are reporting serious limitations in their work or daily activities. And so all of these mass cell-mediated therapies are only symptom-directed at the end of the day, and we are really excited for the potential of AYVAKIT as a true targeted approach that addresses the underlying driver of disease to have disease-modifying impact.

And from what we've seen over the many hundreds of patients that have been treated over the past 7 years on AYVAKIT is truly that ability to decrease measures of mast cell burden, improve symptoms as well as quality of life.

(Operator Instructions) Our next question comes from Salveen Richter of Goldman Sachs.

This is Andrea on for Salveen. Maybe just one on the back of your data disclosures at EHA showing the benefit on overall survival. Just curious the feedback you've received there and how this is being marketed to physicians to drive further uptake?

Yes. Becker, do you want to start with the data from EHA and then others can chime in.

Yes. Just to remind you, at EHA, what we showed was an improved survival compared to standard of care treatment. So we looked at patients that have been treated with cytoreductive therapies with midostaurin, and we looked at their overall survival.

And then compared to that to what we saw in our Explore and Pathfinder studies, we saw a substantial improvement in overall survival. And what this has done is it's really solidified the notion that by driving rapid deep responses in this aggressive malignancy.

We're able to achieve survival rates that have not been seen in this disease before. And this is really, in many ways, woken up the community even further than the response rate has. People think about their patients as being very ill because they are, and they end up the hospital repeatedly.

And they are really quickly moving towards a survival event or potentially dying from the disease. And so the ability for a practitioner to stop this and provide additional life and also to see it in the depth of the response has been one that's been really embraced if we share these data.

Yes. And this is Philina. I'd love to add on to Becker's comment and share some of the sort of KOL and provider responses to this data. And so treating physicians are truly excited about this data. They're talking about it as really first of its kind and practice changing.

As we have these discussions through medical interactions with the provider community, we are hearing feedback such as this illustrates, we now have a treatment that can truly obliterate the SM beyond the surrogate measures of mass albert and we're actually seeing prognostic improvement in overall survival of these patients.

The second piece is, we think this is really important when it comes to that opportunity to increase the proportion of patients who are actively being treated for their SM. The greatest subset being patients with SM-AHN, where some providers had historically been used to prioritizing the AHN. Now seeing the important efficacy and safety data for AYVAKIT, the tolerability profile as well as this emerging overall survival data, it truly shifts the balance towards the urgency to treat the SM.

Our next question comes from Peter Lawson of Barclays.

In ASM, just what's the proportion of patients you're seeing that are naive to treatment versus already exposed to prior treatments and then proportion of revenues that you think are potentially off-label in the ISM space?

Do you want to take both of these?

Yes, happy to. Thank you for those questions. So we haven't provided specifics on the breakdown of patients who are treatment naive versus switching from another therapy. However, I'd say we do continue to see adoption across both of these patient populations.

And importantly, we are seeing 70% of new therapy patient starts going to AYVAKIT as well as 70% of switching from pre-existing therapies, such as midostaurin and so we're highly encouraged to see that data and that essentially puts us towards a trajectory towards a market share of 70% or above. Your question about off-label treatment.

So certainly, we don't promote to that. And I'd also say we are seeing a proportion of adoption coming from the non-advanced patient community, which is a reflection of the medical need that we see there.

And maybe just to add on to that, a little bit of additional clarity. So as Philina said, we don't break down specifically, but I will say the majority of our starts are, first of all, coming from what we would consider to be previously diagnosed patients, and we still see a lot of headroom actually on both of those fronts.

So a lot of opportunity to increase penetration of what we would consider to be prevalent patients as well as to continue to see adoption for clinically diagnosed patients. And we have seen that increase, and we expect that to continue to increase. For non-advanced SM, as we've previously shared, and as Philina just shared, we have seen from physician reports, some utilization with those patients, it's very small in terms of the proportion of our overall revenue.

So certainly, the vast majority of AYVAKIT revenue currently is coming from utilization and advanced SM. I do think, though, it's encouraging that we've seen prescriptions go through and be paid for non-advanced patients as well, which I think speaks to some of the earlier questions around access and pricing.

Our next question comes from Reni Benjamin of JMP Securities.

Great. Congrats on the quarter. Just sticking with PIONEER, once you have the results in hand that you've submitted, do you expect a full approval from the FDA? Does this get a standard review or a priority and just as you think about the landscape upon something like a full approval, do fast followers need to run a study against AYVAKIT? Or is this disease indication, one where you can run other placebo-controlled trials? And if so, are there strategies that you have to keep the competitors at bay?

So Becker, maybe take the first part, and I'm happy to weigh in on the second part, and we can then as well.

Yes. So with respect to what we would expect from this randomized placebo-controlled trial is we would expect this to be a full approval. Again, this is a supplemental NDA and we do expect a rapid review of the FDA. With respect to what would be required for follow-on compounds, and we thought about this quite a bit with BLU-263.

We think that the bar is going to be extraordinarily high with the AYVAKIT data, particularly given the clean safety profile and the high efficacy that we saw in Part 1. I hesitate to speculate on what the FDA will require, but we do think that coming behind Avapritinib in indolent and non-advanced SM is going to be a difficult lift for any compound.

And just to add, to Becker's point, I think when you think about care standards as well, we have cases where drugs with a similar mechanism are approved within a few months of each other. That's very different than when there's a multiple year gap, right? And so I think that is another context to consider is just a temporal nature. And what does the fast follow really mean.

Our next question comes from Kyung Yang of Jefferies.

One other question on PIONEER study expectations. So in part 1, you showed the 16.5 point difference with about 60% patients responding. And in Part 2, it's a larger number of patient population. So how do you think about the changes in FX side? Usually, in the larger trial, FX side tends to decrease. So can you talk about in this particular indication whether you expect FX side to shrink significantly? Or do you expect it's going to be kind of similar to the data in Part A?

Yes, Becker, do you want to weigh in on that?

Yes. So thank you for the question, and I appreciate the historical reference to Phase 3 trials, generally having a less therapeutic impact than what you might see in some early trials. However, in this case, I still expect very robust results. And part of the reason is that as investigators have learned about the patients, about the benefit of Avapritinib and about how to identify patients with severe and moderate disease, we would expect the results to be relatively similar between Part 1 and Part 2.

Just another thing to remember about historical references is often people will change their design even slightly between the Phase 2 and then the pivotal study. In this case, we've screened patients the same way. We've applied the same type of statistical analysis. So Part 1 and Part 2 are really quite mirror images of each other with just a broader investigator base and patient base. So we expect the results to be quite robust and similar.

Our next question comes from Brad Canino of Stifel.

And thanks for the refresher on market share versus market penetration. So quickly, I'd just like to ask, do you have an estimate on the U.S. penetration rate of disease-modifying therapies in ASM? And then a follow-up on Eun's question for ISM. Do you expect a degree of benefit in PIONEER from the new endpoint to impact physician utilization? If the difference was 10 points between AYVAKIT and placebo, would you expect uptake to be significantly different than if it was a 15-point difference?

So maybe Philina, you want to take the first part of the question around market penetration, and then Becker here if you want to weigh in on the second piece. And Christy, you can also add some color there.

Yes. Thanks, Brad. So starting off, I think we shared in our last call that one of the things we're highly encouraged by is that the share of patients who are actively being treated for their therapy has grown substantially since the beginning of AYVAKIT launch. It's grown by about 40%. Now, an important point to the heart of your question is, this is still a minority of patients with advanced SM today. And that flips into the opportunity where we see significant headroom to continue to increase the size of the advanced SM opportunity.

And Becker, maybe going to the minimal clinical important difference and how you want to think about that relative to practice-changing impact on patients?

Yes. Let's talk a little bit about the endpoint, the endpoint switch and then how investigators and prescribing physicians are seeing it. So as we mentioned previously, the design of the PIONEER and the ISM-SAF are the product of many years of collaboration with the FDA under the breakthrough therapy designation. And both the FDA and Blueprint committed to measuring clinically meaningful benefit for patients in PIONEER Part 2. And then just a reminder, the FDA requested the change in endpoint, elevating mean change to be to our primary endpoint. Now, just a little bit about the various endpoints. You have to remember that there are many ways to measure clinical meaningfulness in systemic mastocytosis.

For patients, it's a return to a new normal after years of suffering from extensive rashes in diarrhea and pervasive brain fog, often preventing them from going to work. And for providers, it also includes objective evidence that the disease burden is substantially reduced. So as we've spoken to investigators and prescribers about this, they look at the totality of the data. So looking at individual patient responses, the proportion of patients that have different depths of response, the proportion of patients with resolution of each type of symptoms.

So when their patient comes into the office, they can consider all of the benefits of AYVAKIT and consider what's right for their patients. They'll think about the look at the trip base, look at the allele burden, they'll look at the most bothersome or most severe symptoms and they'll though look at the results from PIONEER Part 2 to understand what benefit their patients could have attain.

Yes. And I think just to add too, that as we noted for patients, and it struck me as we've talked to patients widely over the last number of months that we know that a meaningful change for a patient is one that really reduces the symptoms and often the most bothersome symptom that has changed their quality of life or their ability to work or to participate in what we all take for granted as just normal activities of daily living.

And what we saw in part 1 is that AYVAKIT had a profound impact on the ability of patients to restore their quality of life to get back to work to be able to do the things that take vacations, things they hadn't done for years. And so to Becker's point, of course, we know that the 7 to 10 point change as we look at the Part 1 data provides this type of meaningful benefit to patients. We are confident in that. And everything we've heard from both patients and providers reinforce that confidence that this will change the prognosis for these patients and change the practice in non-advanced SM.

Our next question comes from David Nierengarten of Wedbush Securities.

Most of them have been asked. But I was curious, you mentioned the high bar for BLU-263 development, assuming PIONEER is positive. I mean, is there a scenario where you discontinue development? Or would you consider is there a role for something like a molecule like 263 in maybe less severe indolent mastocytosis and the mild to moderate version, I suppose? Or is there not a good way to slot that in?

Yes, Dave, thanks for the question. I'll start and the team can add in. But I mean, we are in an incredibly strong position with 2 best-in-class assets that have slightly different profiles that we believe will both have a position both in SM as well as we think about BLU-263 and other mast cell-driven disorders.

And so the data sets, the AYVAKIT and the clinical profile of AYVAKIT and non-advanced SM as well as what we anticipate coming out of PIONEER non-advanced SM and how we talk about it, that's going to be a very high part for AYVAKIT and we're going to think about how to move BLU-263 forward. But there are going to be patients, whether that be less severely affected patients or patients where the profile of BLU-263 is most appropriate and important.

And the position we are in is to be able to strategically develop the clinical evidence in those patient populations as makes the most sense when we see the full set of clinical data out of PIONEER. And so we have a first-in-class and best-in-class franchise in systemic mastocytosis and feel very excited about the opportunity to have a Blueprint solution for all patients with systemic mastocytosis regardless of what form or subtype or clinical presentation they have.

Our next question comes from Michael Ulz of Morgan Stanley.

Maybe a clarifying question first. Just for the PIONEER top line results, should we expect both TSS score and responder analysis? And then secondly, just a follow-up to some of the earlier discussion on sort of what's meaningful with respect to TSS. You mentioned having a reduction in the most sort of severe symptom. Is there a particular reduction in terms of points on TSS that you that physicians would be looking for? For example, is a one point change enough or do you need to have a couple of point change there?

Okay, I'll just start with the first one is an easy question, and I'll let Becker answer the second, but you can expect both the mean change in TSS as well as the responder analysis in TSS at top line. And Becker, do you want to weigh in on any specific domain point change?

Yes. So when you look at a patient with a most severe symptom, it depends on where they're starting. There can be 1 to 2 point changes that are extraordinarily meaningful for patients. And when you think about single-digit changes, a 7-point change in something that's scored on a scale of 1 to 10 can be really substantial or even the disappearance of that symptom.

So if you can imagine a patient whose brain fog has been in an 8, and that goes down by even 3 or 4 points. That could be a substantial change in their ability to function on a daily basis and go to work for a rash, having it go from something that's very itchy and all over their body, which might be 7 or 8 and then dropping a few points on that single score that can really be life-changing for patients. So we'll illustrate a lot of those scenarios as we get deeper into the data of PIONEER Part 2. But I think it's going to be transformative in so many different ways for different patients.

We will look forward to presenting those broader data sets at medical meetings coming up. And I mean, as Becker mentioned in the prepared remarks, the PIONEER study is going to give us just a breadth and depth of data in this population that is unprecedented, and we're going to be able to really start elucidating all the dynamics within that data set over time.

Our next question comes from Michael Schmidt of Guggenheim.

This is Paul on for Michael. Just had a quick follow-up on the ASM market. So for market penetration for new patient starts, you mentioned about 70% share currently. How much further room do you expect for growth at peak and/or treatment duration on 18 months trending towards that direction? Does your current full year guidance for indicate incorporate any range of anticipated longer treatment duration?

Philina, would you take those?

Yes. Thanks for the question, Paul. Actually, would you mind repeating just the first part of your question one more time, please?

Yes. Just on the market penetration for new patients in ASM, you mentioned about 70% share currently.

Yes, thanks for that question. So yes, we do see AYVAKIT selected 70% of the time for new patients. And we do continue to see a significant amount of upside to grow the treatment of these new patients, as Christy alluded to. An important point is when we look at the market of actively treated advanced SM patients today, we can see that over the past few years or so, it's only on the order of about 1,000 patients who have received active treatment with TKIs and cytoreductive therapies.

And so when you combine that with our understanding of the prevalent patient population on the order of about sort of mid-1,600 to 3,000 or so patients prevalent. You can see that substantial upside in the need to grow the proportion of patients who today has not yet been treated. So that new patient share is an important source of growth and ongoing focus for our team. Your second question was around duration of therapy.

And we're highly encouraged as we continue along the launch trajectory of AYVAKIT to continue seeing significant durations of therapies in our patient trends. So as I mentioned, we're trending towards 18 months. And we're seeing this consistently across both the academic and the community setting, which indicates a degree of physician comfort in managing patients across both settings.

I'll chime in a little bit to add some color there as well. So to the first question, as Philina nicely summarized, we're thrilled to see really dominant market share at this point, right? So AYVAKIT is clearly established as the best-in-class therapy amongst treated patients. that can increase above 70%. We know that not every single patient will be a candidate for AYVAKIT, right, certainly, patients with low platelets, et cetera.

So as we look at the opportunity to grow, we see room to grow market share but significant room to grow the size of the overall treated market. And as Philina was saying, some of the new data from EHA, et cetera, we think is going to be really instrumental in driving that growth, and there is a lot of opportunity to continue to grow.

With respect to duration, we're very happy to see where we are. Trends in duration are not going to be as relevant for guidance this year. They're certainly going to be important as we think about the overall opportunity going forward. And so we're really excited because these long treatment durations should enable revenue acceleration as we get into further years of the launch and we start to see new patients sort of stacking on top of patients who've been on therapy for potentially quite significant length of time.

Our next question comes from David Lebowitz from Citi.

Out of curiosity, when you look at the TSS score, I'd assume that from the patient and physician perspective, not all of these symptoms are created equal as far as their impact on their treatment direction. Which of the symptoms are most typically cited as driving the treatment decision for these patients?

Becker, do you want to weigh in there and clean also, if you have any color from the interactions commercially?

Yes, David, that's a good question. And I had the same one when I first looked at the data, and I expected that maybe there would be a specific domain or a specific symptom that was driving a lot of the TSS reduction or maybe even more meaningful to patients, but I really discovered the opposite.

If you are a patient with brain fog and you have been practicing attorney and can't go to work anymore and can't function and then improving that brain log is life-changing and extraordinarily meaningful for you. If you have diarrhea 20 times a day and you can't see your family, your friends, you don't have a social life than improving the diarrhea can be really profound. And I've heard similar stories for each of the domains and each of the symptoms.

The skin rash is one, obviously, that can be disfiguring and extraordinarily (inaudible) pruritic. I think we all had allergic reactions and we understand how life-changing that can be even for a day, much less day after day.

So we'll certainly dive more deeply into the various symptoms and the impact on TSS score in the rich data set that we're going to see from PIONEER, but I've really been extraordinarily convinced that all of these symptoms individually and combined, can be tremendously life-changing and the disappearance there will really return these patients to what I've started to call the new normal. You hear so many stories about people saying, "I've never felt this good before because they've been living with this disease for so long."

Our next question comes from Joel Beatty of Baird.

For the top line PIONEER readout later this month, do you anticipate breaking out results by each of the components of the TSS score? And then also to the last point where it sounds like patients are often able to reengage with daily living and daily activities. Are there measures that you're collecting that you may share at some point?

So I'll start and then Becker, please weigh in on a second. So for top line data, Joel, it will be very much the top line. So the endpoints that we've highlighted as well as that top line safety perspective, we will be planning to present this data at a medical conference in more detail, likely a few medical conferences in more detail in the near term after the top line data. And Becker, do you want to weigh in on the second part of Joel's question?

Yes. So we have multiple measures of quality of life that we will be digging deeply into during the filing and subsequently to show various ways of looking at the benefit, not only the measurable symptoms but also the level of functioning and just the general quality of life that the patients have.

And our final question today comes from Matthew Biegler of Oppenheimer.

Maybe it's a controversial question. But given all the debate about the PRO endpoint, I'm just wondering if there's a scenario where you could leverage the breakthrough therapy designation to file for accelerated approval based just on improvements in objective endpoints. And I'm really thinking back to GBT story here in their development of Oxbryta where they essentially shelved the PRO altogether and just filed based on those objective improvements. So that would be an interesting case, but I'm curious to hear your thoughts.

Yes. Thanks for the question, Matthew. I mean really simply that we don't anticipate that scenario for us at all. I mean, this is a well-designed, registration-directed, global placebo-controlled study. And our belief will be that we have a data set that speaks for itself that is going to be registration directed both here and globally, and then we'll be looking for full approval.

There are no further questions at this time. Ms. Haviland, I'll turn the call back over to you.

Thank you, operator and thanks everybody, for joining us today. As we discussed today, Avaprint medicines, we are building a strong and resilient organization that will continue to drive value and growth, delivering transformative new medicines to patients around the world.

Our ongoing global commercial launch success, the breadth and depth of our upcoming milestones and data catalysts and our fortified cash position has a uniquely and exceptionally strong profile as we head into the second half of the year. We look forward to discussing the PIONEER Part 2 top line data with all of you later this month. So thank you for your time today and for your continued support of Blueprint Medicines.

Ladies and gentlemen, this concludes today's conference call. You may now disconnect your lines.