Ladies and gentlemen, thank you for standing by, and welcome to the Blueprint Medicines Conference Call. At this time, all participants are in a listen-only mode. I would now like to hand the conference over to your speaker today, Ms. Kristin Hodous, with Blueprint Medicines. Thank you. Please go ahead, ma'am..

Kristin Hodous:.

Thanks, Kristin, and good morning, everyone. 2021 is off to a productive start and I'm pleased to provide an update on recent progress across our growing portfolio. As we outlined on our year-end call, our 2021 efforts are centered around three strategic pillars.

First, accelerating the global adoption of AYVAKIT and GAVRETO; second, advancing a next wave of therapeutic candidates to clinical proof of concept; and third, further expanding our precision therapy research pipeline. Just a few months into the year, we've already made significant progress against each of these goals.

As Christy will discuss in a moment, we continue to advance the commercial launches of AYVAKIT and GAVRETO. In parallel, we are preparing for the anticipated approval of AYVAKIT in advanced systemic mastocytosis.

As we near our PDUFA date in the US, and with a Type II variation MAA under review with the EMA, we're moving forward with urgency to provide a therapeutic option for as many patients as possible fighting this disease..

Thanks, Jeff, and good morning, everyone. I'm pleased to share our first quarter results as we continue to progress the launches of AYVAKIT and GAVRETO. In Q1, we generated net product revenue of $9 million, including $7.1 million in sales of AYVAKIT, and $1.8 million in sales of GAVRETO..

Thanks, Christy, and good morning, everyone. As we discussed a couple of weeks ago on our AACR call, we're in the midst of a period of robust research productivity, having nominated five new development candidates in the past 18 months. Two of those programs, BLU-263 and BLU-945 are anticipated to begin clinical development in the next few months.

Let me start with BLU-263 and continuing Christy's discussion of our groundbreaking KIT franchise. BLU-263 is a non-brain penetrant KIT D816V inhibitor with similar potency to AVYAKIT.

We presented Phase 1 data at AACR that showed BLU-263 was well tolerated at all doses tested in healthy volunteers, pharmacokinetics for linear and dose-dependent with the half-life supporting once-daily dosing. Based on these data, we plan to initiate the Phase 2/3 HARBOR trial later this year.

Similar to the ongoing PIONEER trial for AYVAKIT in non-advanced SM, we will evaluate a range of doses, quantifying the impact on disease symptoms and safety. This will include a multiple-dose Part 1 to determine the optimal dose followed by a randomized placebo-controlled Part 2 evaluating reduction in total symptom score as the primary endpoint.

One novel aspect of the HARBOR trial will be enrolling patients with a broader eligibility criteria, including patients with a lower baseline total symptom score. This provides the potential to extend our reach to a broader population of patients with non-advanced systemic mastocytosis, a central goal of the BLU-263 program.

In addition, we plan to include an exploratory cohort in Part 2 of the trial for patients with monoclonal mast cell activation syndrome, also driven by the KIT D816V mutation. Turning now to our EGFR programs.

During our AACR call, we outlined how our EGFR inhibitors are designed to address important unmet medical needs by providing comprehensive coverage of activating and on-target resistance mutations. They have optimized selectivity profiles, enabling combination strategies and high CNS activity, to treat or prevent brain metastases..

Thanks, Becker. Earlier this morning, we reported detailed first quarter financial results in our press release. For today's call, I'll touch on a few highlights from the quarter. Total revenues for the first quarter were $21.6 million.

This included $9 million in net product sales, as Christy mentioned, and $12.6 million in collaboration revenue, primarily from our agreements with Roche and CStone.

Our total operating expenses increased moderately compared to the fourth quarter of 2020, primarily driven by costs associated with advancing our early-stage pipeline towards the clinic, offset by cost-sharing for our agreement with Roche on GAVRETO.

As we expand investment in our promising early-stage programs, as they enter the clinic over the next few quarters, we expect to see continued increases in quarter-over-quarter operating expense growth.

We ended the first quarter with $1.4 billion in cash, ensuring that we have sufficient resources to invest in our growing pipeline of wholly-owned drug candidates.

As we look forward to the second half of 2021, we are uniquely positioned to drive revenue growth through a variety of sources, including direct product sales of AYVAKIT in multiple geographies, royalties on both AYVAKIT and GAVRETO outside the US, profit sharing on GAVRETO sales in the US, and milestone payments from our various collaborations.

Based on our projected growth across these revenue sources, and driven largely by the planned launch of AYVAKIT in advanced SM, global expansion of indications for both AYVAKIT and GAVRETO, and anticipated milestone payments in the third and fourth quarters, we continue to be comfortable with the current total revenue expectations for 2021 of approximately $150 million.

This revenue growth will build on the strong financial position that we are in today and help solidify our path to becoming a self-sustaining biopharmaceutical company. I would now like to turn the call over to the operator for questions.

Operator?.

Thank you. And we will now start the Q&A with Salveen Richter with Goldman Sachs..

Good morning. Thanks for taking my question. And maybe with regard to RET patient identification and diagnostics, you've given us some sense of how that was tracking, I think last quarter.

Could you just talk about the trends in 1Q, and how you're thinking about the cadence moving forward?.

Sure. So as I said, there is really two key levers that we are focused on. So one is our share of the RET market, but then the second, as you mentioned, is increasing the number of patients who are identified and treated.

And I spoke about this in Q4 and said that something like maybe 20% of patients, if you look at testing, as well as then the opportunity to be treated with a selective RET inhibitor, are having that opportunity at this point. So there is still I think substantial room for growth.

I will say, we haven't seen as much growth quarter-over-quarter as I'd like to see. I think that's partially driven by the impact of COVID, which we know has really had an impact on patient identification, testing, et cetera.

But I'm optimistic that as we go into the second half of this year and then go forward from there, we will see that grow, and certainly, we've seen with other targeted therapies that the advent of effective treatment is in itself, a primary catalyst. We saw that with ALK, we saw that with Roche, and I think we'll see it here as well.

So we'll look to see that number grow and clearly, that's in the best interest of patient care, so we're working actively with our partners at Genentech to really make that happen..

Your next question comes from the line of Marc Frahm with Cowen and Company..

Hi. Thanks for taking my question. Speaking with Christy, with the guidance on the patient numbers there and can you give detail the -- as we've seen in the clinical trials, like, the definition of a patient between ISM and ASM is very gray.

And can you detail how strict you're being in your definitions when you're making those splits on your guidance? And then along those lines, would you expect some of those patients that are in your guidance in the ISM population to actually be able to gain access to the drug once you're approved in ASM?.

Yes. So you're right on, we've seen that in our clinical studies. I think we see it in clinical practice. It can be challenging to accurately subtype patients. The world's leading KOLs may struggle to deal at a time and certainly, patient typing can evolve even in any given patient over the course of their disease.

Where I think we see most potential sort of gray or overlap is between patients with aggressive advanced SM or ASM, and patients who may have ISM that's more severe.

And so, you know, the patient that estimates that I gave of 2,000 to 3,000 approximately, those reflect that uncertainty, right? I think that's -- you know, as we get into the market, we'll have a better sense of how healthcare providers are subtyping patients. Fundamentally, I think the diagnosis, codes, et cetera are overlapping in this disease.

And we've seen that it's not a space that payers tend to manage closely. So our assumption is that our initial utilization will be driven by patients for whom the health care provider believes that they have adopt to some.

And we are optimistic that we will have good access for those patients given the really compelling value proposition that AYVAKIT will have in that patient population..

The next question comes from the line of Dane Leone with Raymond James..

Thank you for taking the questions, and congrats on start of the year, and thanks for the guidance. May be two questions for me, one in terms of guidance on the SM launch.

Could you maybe provide more color in terms of how many patients are currently treated with mido? And what the patient population and opportunity would be for other switch therapies beyond mido that you think docs would be willing to crossover to avapritinib once approved? And then second question would be in terms of thinking about the development of BLU-945.

Do you think it would be interesting to perhaps partner with AstraZeneca and add an adaptive arm into the Orchard study? Thank you..

Hi.

So, Christy, why don't you take the advanced SM question, and then Becker take the BLU-945 question around combinations?.

Yes, sure. So as I mentioned in the prepared remarks, we would assume that upon approval, where we would expect to see initial utilization will be on patients who are diagnosed and currently being treated. And we know that those patients can be treated with midostaurin, they may be treated off label with other TKIs.

The utilization of midostaurin, we don't have perfect insight into health care providers who report that maybe 30% of adjusted SM patients are treated with midostaurin. The data would suggest it's probably less than that. And I think a driver of the difference there is that patients have a hard time staying on.

And so what we hear is that duration of therapy in advanced SM with midostaurin is unfortunately sub-optimal, and can be well less than a year in many patients.

And so we are feeling confident certainly amongst the SM, KOLs and people who are very comfortable managing this disease that they understand sort of the value proposition that AYVAKIT will have and would expect to see uptake there quickly.

However, you know, we'll go broader than KOLs and get into the community and would expect to see that patient identification grow over time, and have that be sort of the driver of longer-term growth, along with treatment of newly diagnosed patients, which again would happen over time..

And with respect to the BLU-945 program, our strategy is within our studies to really look at the combinations closely. BLU-945 as you may remember is a compound with an extremely high window over wild types of very little inhibition of wild-type EGFR, which makes it a great combination partner for a number of different agents.

We'll be looking at combinations of drugs like osimertinib and BLU-701. And in the future, even drugs that address different mechanisms of resistance like MET inhibitors, so we're going to take it on within our trials initially to understand the tolerability of the combinations and look for a preliminary activity at this point..

Your next question comes from the line of Michael Schmidt with Guggenheim..

Hey, guys, good morning, thanks for taking my questions. I had one on labeling considerations.

And my first question is will -- would you potentially pursue a different brand or label for avapritinib in SM versus GIST? And then thinking further upon potential approval in advanced or SM with different dosing, I guess how would that potentially affect labeling given that side effects and other factors might potentially differ given the different doses used in those two sub-types of SM?.

Christy, do you want to take that?.

Yes, sure. So we are eagerly and urgently working to make AYVAKIT available first in advanced SM and then and non-advanced forms of the disease and are obviously, working actively to finish enrollment of PIONEER. We are excited about the profile of AYVA in non-advanced forms of the disease. So we don't anticipate making a different brand available.

We know that the benefit-risk of AYVAKIT just like in many other -- with many other therapies that are proved the different doses for different indication is going to look different.

And so for non-advanced SM, the preliminary data we've seen at the 25-milligram dose at a Part 1 of PIONEER makes us feel really confident that we're going to have a very favorable benefit-risk profile and allow us to impact many patients with non-advanced forms of the disease.

Of course, we're also excited about BLU-263, as you know, our next-generation KIT inhibitor. And as Becker said, we anticipate that that could potentially broaden even further the number of non-advanced patients that we can impact.

So in terms of the dosing, again there's plenty of precedent in labeling to be able to differentiate what a benefit-risk profile and safety and efficacy look like, both across different indications as well as different dose profiles..

Your next question comes from the line of David Lebowitz with Morgan Stanley..

It's David. Good morning, two questions from us; the first on GAVRETO. So in the early launch stage, what is the initial feedback from physicians on how the RET inhibitor may be used versus say, Retevmo? Are there specific types of patients lean to one therapy first as the other? And our second question is on AYVAKIT.

So in the review of the registration by the FDA, where have questions been focused? How should we expect the label and to look in regards to the safety given the patient death on the clinical trials? Thanks..

Maybe I'll start with the second question first and then I'll have Christy talk about the differentiation components from the physician perspective with GAVRETO.

So obviously, we're in the middle of our review, and as we highlighted last quarter that given that timing and given the active progress that we're making, we're not going to comment on the back and forth, I mean questions change day-to-day.

And I can tell you we're making nice progress and the agency is very engaged and going through the data and understanding of the disease. But in terms of the specifics, we'll not -- I wouldn't dig into that level of detail..

And then regarding GAVRETO and Retevmo, and how the feedback we're hearing, we certainly hear that there are points of differentiation. Certainly the breadth of efficacy and the consistently deep and durable responses across patient types, I think it's something that's been compelling to physicians about GAVRETO.

And then of course, as I mentioned before, there are differences in safety, as well as administration that can become important, and I think more important, even as you get into the community setting. And certainly, QT prolongation and not having that with GAVRETO has been an important point, as well as once-daily dosing.

The bigger picture though this is that there are some physicians who have used both. What we are seeing is that we are still at the beginning stages of really developing this overall market.

And so we are continuing to really add new prescribers and the majority of the prescribers we're seeing for GAVRETO are new to market prescribers, so they're prescribing a RET inhibitor for the first time. And what that tells me is that the opportunity here really is to go out and educate new prescribers and help them identify new RET patients.

And there's still a ton of potential to do that because we know that the majority of RET patients are not getting the opportunities on either one of these drugs..

Your next question comes from the line of Chris Raymond, Piper Sandler..

Hey, thanks. Just got a question on the EGF molecules. So just going through the preclinical data you guys have published on these, it looks like you're able to reach a therapeutically active dose with BLU-701 at much lower doses than BLU-945.

So obviously, there's differences in underlying mutations, but just kind of curious around how do you think about that translating into the clinic and sort of the efforts here to find a therapeutic index?.

Yes.

Becker, do you want to take that?.

Sure. So taking pre-clinical data as a guide to where we're going to stick to study is really how I look at preclinical data on dosing. There obviously are differences between animals and humans with respect to exposure in metabolism. So we've got a solid dose for BLU-945 and we're already working towards that for BLU-701.

We have some predictions about where we will see activity and get full coverage of the EGFR molecule for the full day, both of them, we expect to be amenable to once-daily dosing. And then as we combine them, we expect them to combine very easily because they both have a huge window over wild-type.

So we'll have to get into the clinic to really get more specifics about that.

The programs are not separated in time substantially, so we do expect BLU-701 to potentially catch up with BLU-945, which is great because then we can look at the combination of the two in real-time as we dose escalate, and really get MTDs for single-agent and combination in about the same timeframe.

And as I mentioned earlier, also combination dosing with other molecules such as osimertinib..

Your next question comes from the line of Reni Benjamin with JMP Securities..

Hey, good morning, guys, thanks for taking the questions. Maybe just on BLU-263. Can you -- I think you mentioned here that there is an exploratory arm in monoclonal mast cell activation.

Can you just remind us what are the various types of non-advanced SM patients that you will be enrolling in the study in the registrational part? And will it be evenly split? And if this already have been discussed with the FDA that it could ultimately lead to registrational purposes? Or is it solely based on the data?.

So the foundation of our program is in patients in the AYVAKIT program is in patients with a higher TSS score or symptom score. And so we have that cohort in Part 1 of our study. We're also going to be looking in Part 1 at the effect on patients with a lower symptom score.

The part of the reason that we have this two-part program is to allow us to optimally set up our registrational study. The plan right now is to look at both groups of patients in that registrational study, the obvious one being those with the higher symptom score.

So there will be an opportunity to refine the registrational portion of the study as we move forward. We have had discussions about the general design of our program with the agency. But we're really going to let the data drive how we ultimately design the registrational part of the study..

Our next question comes from the line of David Nierengarten with Wedbush Securities..

Hey, thanks for taking the question. I just had a quick one on diagnosing mastocytosis patients, you mentioned a blood test.

Can you just remind us currently you require, as I recall, a bone marrow aspect to confirm diagnosis? So this replace that? Or would patients still be buying in for a confirmatory or other testing? Maybe just walk us through how you see testing becoming a little bit more patient-friendly in the future? Thanks..

Sure. So yes, you're right. The diagnosis of SM per criteria does require a bone marrow biopsy, that's recommended for every SM patient. However, we know that for some patients, that is a hurdle, and certainly, for some non-advanced patients that are being treated by allergists, that can be a hurdle.

And you know at times, patients are treated based on suspicion versus actually going through the process of getting a bone marrow biopsy. For advanced SM patients, we would certainly expect that a bone marrow biopsy continues to be a very important part of diagnosis and management over time.

For non-advanced patients, I think that blood-based testing can become a really important way of identifying potential patients in a much easier and simpler way that can be managed by allergists more broadly. And so the key to that is really making highly sensitive blood-based testing available.

So there is KIT D816V testing that's available now, but we know from our own data that you can miss patients if you're not using the right approach in terms of sensitivity and specificity. So that's really our -- one of our very key pillars over the next few years is to increase the number of patients who are tested.

Certainly, once the patient test positive, they may still require a bone marrow work up to further understand their disease and pathology. But I think that blood-based testing will be a very critical lever to enabling more patients to get access to the right diagnosis more quickly..

Your next question comes from the line of Eun Yang with Jefferies..

This is Sarah on for Eun. I just had a couple of questions. First on the EGFR program.

Where do you think that the combination of BLU-945 and BLU-701 would differentiate versus osimertinib? And then, when do you think you would expect to start the first line trial? Is there potential to run that trial in a partnership? And then just a quick one on the mast cell activation syndrome exploratory cohort, how many patients do you think there are with that diagnosis in the US currently? Thank you..

Becker?.

Sarah, I'll start with the question about BLU-701 and BLU-945. Just remembering how patients present and why they treated with osimertinib in the first line, they don't have T790M at the beginning. They have the driver mutation in the anti-T790M activity of osimertinib is important to prevent emergence of that driver.

Osimertinib also has a very high potency over that driver -- dose driver mutations. So the combination of BLU-701 and BLU-945 do those things plus additional activity. So BLU-701 has better penetration of the central nervous system than any compound available or in development that we're aware of.

And so treating patients initially with the driver mutation, both in the periphery and in central nervous system will serve to treat small -- well, existing central nervous system disease and any non-measurable central nervous system disease, but also prevent the disease from going to the central nervous system, which is often less well penetrated than the blood is.

So we get amazing coverage throughout the BLU-701. In that context, BLU-945 would be present to prevent the emergence of T790M. So here we've got an all-oral regimen that would treat the entire body and treat all of the resistant mutations that we know that can emerge.

And so what we would expect there is an enhanced treatment of patients with CNS disease as well as longer progression-free survival.

And respect to a front-line study, clearly, we will look at a number of different patient populations during our first two studies and determine the activity there and then look to develop it in the front line in parallel with the other studies that we're doing to develop in resistant mutations..

Your next question comes from the line of Peter Lawson with Barclays..

Thanks for taking the questions. Just I guess a follow-up around the EGFR.

They just -- when could we see the initial clinical data in EGFR-mutant patients? And then as we kind of think about ways to kind of break into that osimertinib market, are there areas do you think of kind of low-lying fruit essentially? Or is it, you need to be in combination with additional agents, whether it's meets or outs etcetera?.

Sure. Maybe I'll take the first part of that and then Becker can talk about the development plan.

So in terms of when we see data, I mean, as Becker just laid out our design with these trials is similar to what we've done with across AYVAKIT and GAVRETO of starting up getting finding the optimal dose and then expanding through various arm -- exploratory arms to best understand the potential activity of a molecule, both as a single agent and/or in combination.

So we want to get those trials up and running before we guide to when we'd be sharing data. But I think a safe assumption would be similar to the time timeframe how and when we shared data from AYVAKIT or GAVRETO.

And then with respect to showing activity and breaking into as you described the osimertinib market, the way I'd like to think about this is in three different buckets.

The first is, patients who have been through a first-generation inhibitor like Iressa or Tarceva, and then moved on to osimertinib, and will develop either an on-target mutation, which often will be the C797S mutation in combination with the driver and T790M with those triple-mutant patients and then patients who have the driver mutation and will develop another mechanism resistance like MET amplification.

So in both cases, you still need to inhibit EGFR. And so BLU-945 is -- it will look for activity as a single agent in those patients that are -- have their disease driven by a subsequent mutation in EGFR.

And then eventually, in our program, we may need to, as you mentioned, look at other types of combinations with other tyrosine kinase inhibitors or other modalities to address the additional mechanism of resistance in that really third line patient population.

The other bucket; I think that is patients failing or patients whose disease is progressing following osimertinib, in that case, BLU-701 is the molecule that we expect to show activity very early in that resistant population.

Again there may be a rationale to combine with other agents, including osimertinib to continue to keep the pressure on all forms of the mutation, and then to prevent subsequent emerging of point mutations.

And then with respect to breaking into the larger part of the osimertinib treatment landscape, it's really looking at either our own proprietary combinations or adding on our drugs to an existing treatment with an EGFR inhibitor to allow longer progression-free survival and really kind of mirror the way that osimertinib marched from beta lines into the frontline of EGFR-mutant lung cancer.

Your next question comes from the line of Brad Canino with Credit Suisse..

Good morning. Just some clarity on the comments you made about BLU-945 in Phase 1. You mentioned that the dose expansion will be in patients with specific mutations. And I assume that will include T790M and C797S. But are you planning to enroll any other mutations? And if so, could you outline the reason why you're doing that? Thank you..

So with respect to other mutations, if you're asking about other EGFR mutations, we're currently preclinically profiling the -- both of the compounds further to identify the full spectrum of mutations against which they are active. And during escalation, we have the ability to expand while we're escalating.

So we expected that early information about where the compound is active so that we can tailor our expansion cohorts to fit these mutation profiles.

With respect to other mutations like MET amplification, that would be in a later part of the Phase 1 where we would need to determine the optimal compounds to combine with, and then we could look at a combination of EGFR inhibition plus another modality of inhibiting the resistant pathway.

There are no further questions at this time. I will now turn the call back over to Jeff Albers for closing remarks..

Thank you, operator. So I'll wrap up with where we started.

Given the strong position, we find ourselves in at this quarterly call around our strategic imperatives, we spent a lot of time talking about our early research pipeline today, but under the leadership of Fouad Namouni, our President of R&D, we continue to identify new opportunities and new targets to focus on to further expand our portfolio.

Becker walked us through the next wave of therapeutic candidates, really anchored around these five recent development candidates that show exceptional promise.

And then as Christy walked through the acceleration of our commercial efforts with AYVAKIT and GAVRETO, and really our focus on ensuring that we're prepared to bring AYVAKIT the patients in advanced systemic mastocytosis, potentially this quarter with the targeted PDUFA date in mid-June.

And all of that's really underscored by the strong financial position that we're in. And Mike walked us through the financials, really focusing on the GAAP financials.

The way I look at it, it's probably a bit more broadly as I tend to anchor in on end-user sales and thinking about how we bring these medicines to patients, both directly in sales that we book, as well as through our various collaborations in the case of Genentech with a profit share, but then with Genentech, GIST and CStone, you also see royalty potential as well as milestones.

And when we take all of that together, the growth potential as Mike highlighted going into the second half of the year, it's becoming increasingly clear to us and should position us to be even further expand our portfolio over time. And so with that, we know, we have a lot of work to do.

It's nice we're actually doing this call from a room together in our office for the first time in over a year, and so we continue to be optimistic about certainly in the US, the ability for business to accelerate as we come to the backside of this pandemic. And so we look forward to continuing to update all of you in calls again in the near future.

With that, thank you for taking the time. Bye-bye..

Ladies and gentlemen, this concludes today's conference call. We thank you for your participation, and you may now disconnect..