Blueprint Medicines Corp

NASDAQ:BPMC

Earnings Call Transcript 2019-Q3

[Jeffrey Albers, executive]

Okay, I think we'll get started here. I'm Jeff Albers. I am the CEO of Blueprint Medicines. And on behalf of all of our employees, I want to welcome those of you in the room here in New York City with us as well as those participating on the webcast.

Today marks an exceptional moment in time for us at Blueprint Medicines as we sit on the cusp of bringing our 2 lead programs, avapritinib and pralsetinib, directly to patients and with pending and planned regulatory filings in the near term. But with our long term strategy, it's truly grounded in transformational science and the discovery and development of new targets. And that's going to be our focus of our time together today.

And in that spirit, we have a lot to share. You're going to hear about 4 newly disclosed programs out of our pipeline. We're going to introduce you to our latest thinking on the number of patients with systemic mastocytosis, a number that could be 3 to 4x higher than what we've talked about or estimated previously. And then we're going to focus on our ongoing efforts around novel kinase discovery, and we're going to highlight one of the programs from our cancer immunotherapy collaboration with Roche. It's going to be a busy morning.

So obviously with that type of agenda, we'll be making forward-looking statements throughout, and I'll refer you to our website or our security filings with the SEC. And we fully disclaim any obligations to update those forward-looking statements.

So the Blueprint Medicines vision has been clear and consistent since our founding. And that's to bring forward the promise of precision medicine to patients with cancer and other rare diseases, and that is grounded in great science. And that always starts with the focus of developing a transformational therapy and a selective and potent kinase inhibitor. It's really the marriage of deep and novel biological insights combined with our proprietary library, chemical library that allows us to bring these programs forward quickly.

And I'll highlight that notion of selectivity because that's core to everything we do, and we think it's incredibly important for a variety of reasons. First, it allows you to get the full inhibition of a specific target. Secondly, it allows you to focus in on avoiding certain off targets and unwanted side effects. And third, if you do those 2 things well, you can then bring in the potential of combination therapies as well as optimized sequencing of therapies to change the course of disease.

And similarly, with that focus on selective kinase investigational medicine, you can focus in on the right patients. And it's a commonly used line, but it's something that is core to everything we do, it's developing the right therapy for the right patient at the right time. We're also humble enough to recognize that cancer in particular is an intractable foe and will evolve through resistance. And so it's imperative that we focus on keeping pace and ahead of that developed resistance and constantly evolving our thinking and thinking about how do we stay one step ahead of disease.

And so underlying that long-term vision is the how we work, and so I've highlighted that central focus on transformational discovery efforts. It's also how we work internally and with that sense of urgency and efficiency that we hold true with everything we do. The urgency comes from the notion that we know we need to go fast because we know patients are waiting.

But increasingly, the efficiency comes into play, with the diversified portfolio and pipeline that we have and the depth of our pipeline, that we constantly have to remain critics of our own programs and make trade-offs in terms of what we're accelerating, what we're slowing, how we're reaching the greatest number of patients and having the most profound impacts.

And so when you take that vision and that approach, 2 terrific proof points are our 2 lead programs, avapritinib, which is a selective KIT and PDGFR-alpha inhibitor that we're studying in gastrointestinal stromal tumors, or GIST, and in systemic mastocytosis, which is a blood disorder of the mast cells; and then pralsetinib, our selective RET inhibitor that we're studying in subtypes of lung cancer, thyroid cancer, and then looking for RET fusions that occur at a low instance across a broad range of other solid tumors.

And in both of those programs, we saw clear and compelling evidence of activity in our first-in-human trials as shown or depicted by these 2 waterfall plots that have previously been disclosed. And for these 2 molecules, we were then granted 4 breakthrough therapy designations; 1 for avapritinib in PDGFR-alpha driven GIST, another for avapritinib in advanced systemic mastocytosis, 1 in pralsetinib in second line non-small cell lung cancer, and another for pralsetinib in second line medullary thyroid cancer.

And in both these programs, we went from the idea generation to first-in-human trials to regulatory filings or soon our planned regulatory filings in a very short period of time. And these highlight how we think about probability of success when we start a program and how we can change that paradigm by continuing to invest in new programs and moving those forward with that same urgency.

And interestingly, it also positions us to do something that no other company's ever done, which is to discover, develop and bring directly to patients 2 novel therapies within the first 10 years of our company's existence. And so as we sit here and reflect on where we are as a company at Blueprint Medicines, we both have to look back and look forward.

And so on the left-hand side of this slide, you see a kinome tree. Each branch represents a kinase. A red dot is where you have inhibition of a target. Really the first couple years of our existence, we're focused on developing this proprietary chemical library such that we would have starting points that were both selective and potent for virtually every kinase, and that would enable us to move quickly in a reproducible manner over and over again as targets emerge.

And over the last 4 years, that's evolved to a stage where we've brought 4 programs into the clinic. And then obviously as we look forward, critical to that will be our focus on bringing our most advanced programs directly to patients and our commercial plans that we'll have, I suspect, plenty of time to talk with all of you about in the coming months and years. But what we want to focus on today are the other aspects of that longer-term vision. So one is indication expansion, a second is therapeutic area leadership, and the third is this continued focus on innovative kinase biology.

And so I'll start with indication expansion. And so this image you see here depicts a process that we go through with every program within Blueprint Medicines. And we start with a target product profile that is set to interrogate a specific target for preclinical development such that we can get to clinical proof of concept as quickly as possible. And there we focus on a clear genetic driver, and so examples would be D816V in advanced systemic mastocytosis or RET-driven cancers with pralsetinib.

And once we establish that clinical proof of concept, we then think about how do we expand the opportunities, how do we reach the greatest number of patients. And so that can be, in the classical sense, of moving into earlier lines of therapy, as we're doing with avapritinib in GIST or with pralsetinib in lung cancer or thyroid cancer. It could be identifying other diseases that have similar genetic alterations such as what we're doing with pralsetinib in identifying those other solid tumors where RET fusions or mutations occur at a low frequency, or it can be better characterizing a specific disease.

And that's where we're going to focus this first part of our day together, is on systemic mastocytosis and unlocking that full potential from indolent systemic mastocytosis all the way through to advanced systemic mastocytosis, but also broadening that reach into mast cell disease more generally.

And to that end, we'll also introduce our next generation KIT inhibitor, BLU-263, that we think position us incredibly well to capture the greatest number of patients within that indolent framework where you see patients that have a very high symptom and burden, others that have episodic type symptom burden. So as we take the avapritinib forward and optimize that program, BLU-263 will allow us to reach even a broader potential swath of patients and move beyond just indolent SM into mast cell diseases more generally.

The next area of focus this morning will be on therapeutic area leadership. And simplistically, what we mean by this is any program that gets started within Blueprint Medicines based on learnings from other programs. And so that can be, just as I talked about, a next generation molecule that comes from understanding or specific insights we garner around efficacy, safety or resistance with a specific profile and allows us to move very quickly.

It can be around combination strategies, so with fisogatinib or BLU-554, our FGFR4 inhibitor. We're now working with our partner CStone in China to move forward with a combination study with fisogatinib and a PD-L 1 inhibitor for patients with hepatocellular carcinoma where we think we can deepen the degree of response for those patients. Or it can be around the idea of enhanced patient selection.

And so here we're going to introduce 2 programs, our resistant first-in-class EGFR inhibitors. And these are interesting programs because they came out of conversations from the investigators with whom we work, lung cancer experts with pralsetinib. And given the rapidly evolving EGFR treatment landscape, they were focused on the evolving on-target resistance profiles that would emerge, and we were able to pair that up with our predictive resistance modeling as well as a diverse set of chemical matter that convinced us that we could move very quickly to develop selective inhibitors for these challenging target profiles.

And then third and perhaps most exciting, our efforts around novel kinase discovery. And so that includes wholly owned programs that are going to remain confidential today due in large part to the proprietary nature of those programs, where we think we are clearly differentiated or well out ahead of others in a specific area. But really when you think about novel kinase discovery, our collaboration in cancer immunotherapy with Roche, that's at the core and central to that collaboration.

And the combined Roche/Blueprint Medicines team continues to make very nice progress on 4 different targets or programs within that collaboration. And so we're going to introduce one of those programs, the MAP4K1 program, that we think has the potential to both deepen the response for patients with a cancer immunotherapy treatment regimen, but also broaden the potential number of patients that could benefit from a cancer immunotherapy either through optimized sequencing or likely in a combination setting.

So with all of those new programs disclosed, this is our updated pipeline. And here, I like to pause with the fact that, for a company of our size and our age, this truly differentiates us as a precision medicine therapy. Our ability to continuously identify new targets of interest and move those forward and really change the paradigm in terms of how we think about probability of success, how we make trade-offs on programs is highlighted here.

And I'm going to highlight 2 line items that we won't be digging into in more detail in all likelihood today. The first if BLU-782, our ALK2 inhibitor. So ALK2 is the driver of mutation for an ultra rare, devastating genetic disease called fibrodysplasia ossificans progressiva. And we recently moved that study into first-in-human studies, and we announced a few weeks ago that we've partnered that with Ipsen and we've out-licensed the program.

And so while it's central to our long-term vision to retain meaningful rights, we've also never shied away from the notion that we will look to partners if we think they can either accelerate or expand the reach within a specific disease area. And that's exactly what Ipsen brought to the table in this regard. So given their natural history datasets that they hold as well as the learnings from their program that they acquired through Clementia in FOP with a different mechanism of action, we thought out-licensing this program was best for Blueprint Medicines but, more importantly, it was best for patients over the long term with this severe disease.

And then the second line item I'll note is that we have 2 undisclosed targets, which indicates that we've nominated another program internally. And I highlight that just to point out the fact that we continue to operate in an environment where our scientists are generating more targets of interest than we're able to move forward and prosecute. And that puts us in a very enviable position, that we can maintain a high bar on what it means to become a Blueprint Medicines program.

So before I bring up various presenters, I do want to just update you on our more advanced programs and specifically dial in on the timing of regulatory filings, of which there are several coming over, over the next 15 months.

So first off, as you know, we have a pending application in GIST for PDGFR alpha and fourth-line GIST. And then we have a planned filing in the second half of next year for third-line GIST off of our VOYAGER dataset. FDA recently informed us that they plan to split those pending application into 2 separate filings. So PDGFR-alpha-driven GISTs will remain with that February 14th PDUFA date. And then the split, which was I think a point of confusion with some investors, is that the FDA has the potential to extend that filing by up to 3 months. So it pushed the PDUFA potentially into later Q1 or into the middle of Q2. So we continue to be under review within those filings and have the ongoing dialogue. I asked our head of regulatory yesterday when was the last time we get questioned. He looked at his phone and he said one hour ago. So it continues to be an active and very productive review period.

Similarly, we remain on track for advanced systemic mastocytosis filing in the first quarter of next year. And we remain on track for 2 filings with pralsetinib, one for second-line non-small cell lung cancer in the first quarter of next year and one for second-line medullary thyroid cancer in the first half of next year. So notwithstanding everything that we'll focus on today, we continue to have a lot going on with our most advanced programs.

So for today's agenda, I'm going to turn it over to Andy and Christie, who are joined by Dr. Akin, who's a world expert in systemic mastocytosis from the University of Michigan. We're going to have a short Q&A for about 10 to 15 minutes. We'll take a brief break. And given the nature of the schedule, we'll call you back in very quickly. And then Marion, Tim and Klaus will talk about some of our research programs that I just introduced.

And before I have Andy come up, we are going to show a video and really underscore the question I get frequently, which is trying to characterize what is it like to be a patient with indolent systemic mastocytosis, and what is the need for an effective therapy.

[Presentation]

[Jeffrey Albers, executive]

All right. So the line that sticks with me in there is when you talk to a physician and they say that's systemic mastocytosis, we know how to treat that. And with the development of avapritinib, we think we'll be able to offer up that opportunity for clinicians. And so with that, I'm going to have Andy come up and expand on our latest thinking in the field of systemic mastocytosis.

[Andy Boral, executive]

Great. Thanks, Jeff. So I'm Andy Boral. I'm the Chief Medical Officer at Blueprint Medicines. And wow, that's quite a story.

Well, we say that Melanie has indolent systemic mastocytosis, but I think from the video, you can see that indolent really is a misnomer. Melanie has a severe, devastating disease that has upended her life. And certainly, there is a huge need for effective therapies that treat the underlying cause of disease and can improve her situation.

Mastocytosis or systemic mastocytosis is a single disease. It covers -- it's often talked about as indolent and advanced, but it's really one disease that covers a broad spectrum of severity, manifestations. Again, as we've seen from the indolent form, that can be completely debilitating. But the underlying commonality across this disease is the D816V mutation in the KIT gene that Erica described for us, which is the fundamental genetic driver of mast cell proliferation and hypersensitivities or making them prone to degranulate.

And over the coming I guess hour or so, we'll hear how avapritinib, a highly potent and selective inhibitor of this D816V mutation in KIT, has the potential to be a transformative medicine for patients with systemic mastocytosis, indolent through advanced.

And I'm actually pleased to introduce now Dr. Cem Akin, who will also teach us a lot more about systemic mastocytosis. Dr. Akin is a professor of internal medicine, allergy and immunology at the University of Michigan. He did his fellowship at the NIH, where he first got interested in mast cell disorders. He created the first multidisciplinary clinic for mastocytosis at Brigham and Women's Hospital in Boston.

And he's one of the leading principal investigators on our PIONEER study of avapritinib in indolent mastocytosis and has been a critical advisor to us throughout the evolution of our program. I greatly appreciate having a great world renowned expert in this disease spend his time with us today to teach us more about this disease.

[Cem Akin;University of Michigan;Professor of Medicine]

Thank you, Andy. So welcome, everybody. So I'm going to share with you just a few important highlights about what is important on patients with systemic mastocytosis, what affects their quality of life and why they need new therapies.

I've been seeing patients with mastocytosis for over 20 years now since my fellowship at NIH, and it's been probably close to 1,000 patients. And I hear stories like Melanie's in my mastocytosis day, patient after patient, and each one of them has a different sadness to it, having a chronic disease that is not curable and having to live with those symptoms. And it doesn't really get any easier, but you've seen these patients for 20 years, to tell the patient that, yes, you have mastocytosis, but you don't have any agent to get rid of this disease. All we have is antihistamines and symptomatic treatment. But hopefully, this will change soon.

So these are my disclosures. I am an investigator, as Andy mentioned, in Blueprint Medicines' ongoing phase 2 PIONEER trial. I am also a consultant with Blueprint Medicines and also with Novartis. And of course avapritinib is an investigational agent.

So let me talk about a couple of other patients similar to Melanie's story about what these patients go through. The first one, a 45-year-old female, she had onset of skin lesions at age 7. And usually, we see these skin lesions, which I will show you a picture of later on, they start early in early adulthood, like in their 20s, 30s, and they keep these skin lesions through the rest of their life. They are not like hives or urticaria, eczema. They don't come and go. They are fixed. They are there all the time, and they are a big reminder of the disease that they have and that we don't have any good methods to cure it.

In this patient, it started at age 7, a little earlier than what we see. And it wasn't diagnosed until age 14. And this is another common issue with patients with mastocytosis. There is a big diagnostic delay because when somebody presents with these symptoms, either a skin rash or abdominal pain or low blood pressure, mastocytosis is usually not the first thing -- first diagnosis the doctors think about, so it takes a while.

And she was finally diagnosed at age 14. And initially, the only symptoms were skin and exercise-induced wheezing. And about 15 years later, she developed more symptoms with nausea, diarrhea, increased itching, flushing and bone pain. Why she was stable for 15 years and then developed these symptoms at age 29, we don't know. And that's the unpredictability aspect of the disease.

And then she started passing out and then blood pressure was undetectable. Why do they pass out? Because mast cells, when they degranulate, they release these chemicals including histamine. They act on blood vessels. They dilate the blood vessels. Then the blood vessels dilate, the blood pressure drops, and they have to pass out or lay down so they get enough blood flow to their brain.

And she had a bone marrow biopsy, which is the procedure that we do to diagnose systemic mastocytosis. Now we knew that she already had skin mastocytosis, now we are looking for systemic mastocytosis in the bone marrow. And sure enough, it showed 20% infiltration with mast cells. Almost all patients -- adult patients with mastocytosis will have systemic mastocytosis. By the time you see the skin lesions, they have already started in their bone marrow and then migrated into the skin. So they will always have systemic mastocytosis.

And her tryptase was 76. Now what is tryptase? Tryptase is a surrogate marker of mast cell burden. Normal tryptase is about 5 nanograms per milliliter. We all have mast cells, of course. We all have a certain tryptase value. But these patients have tenfold, hundredfold, thousandfold more mast cells than we need. And tryptase is a measure of how much more mast cells that they have. So in this patient, the tryptase was fifteenfold higher than the normal median level.

And her symptoms progressed over the next 10 years. Then she started reacting to scents, developed flushing, lightheadedness, fatigue. She went through an ultraviolet light treatment to alleviate those skin lesions because they're unsightly. They can be embarrassing to some patients. But it didn't work. It sometimes works for a few months and then it starts to come back. And then she started saline infusions; had a port placed. So she had this progressive loss of quality of her life. And she's only in her late 30s, and she has a long life to live.

And this is her medication list. So there are 12 different items here and some of these are taken multiple times a day. So I have some patients who walked into my office with a backpack, and I said, "What is this backpack? Are you going camping?" And they said, "No, I'm bringing my medication to show you because this is where -- this is how I travel. Wherever I go, I take this backpack with me."

So this is polypharmacy, right? And imagine all of these side effects that you might get from these medications; anticholinergic side effects from the antihistamines, the mood side effects from anti-leukotriene, osteoporosis potentially from proton pump inhibitors and so on and so forth. So it will be important to come up with an alternative that would reduce this polypharmacy for our patients.

So let's take a look at another patient. It's a 51-year-old male. He also had skin lesions as a teenager and diagnosed at age 31 by skin biopsy. And his tryptase was also elevated but not as high as the first patient. At age 47, he started developing these episodes of abdominal cramping, flushing, shortness of breath, chest pain and decreased state of consciousness. He came close to passing out. Then he sat down and he didn't.

So of course, he saw his primary care doctor. He's having chest pains and lightheadedness. Well, let's do a cardiac cath and look -- make sure that your heart is okay. And he did not have significant blockage. At age 49, he started developing these episodes daily. And finally, he had bone marrow biopsy, which confirmed the presence of systemic mastocytosis.

And he was initiated on, again, another polypharmacy with a couple of antihistamines, leukotriene inhibitors, cromolyn, which is supposed to be a mast cell stabilizer, but you know this does not work that great, and a prescribed EpiPen for self-injection in case these episodes come unpredictably and he can administer this himself.

And when I saw him, I was concerned about these episodes, especially him having chest pains, so I started prednisone on him, that also has a calming effect on the mast cells, and applied for initiation of an anti-RGE drug called omalizumab, which is also known by its brand name, Xolair. And it has, again, a calming effect on the mast cell activation. It does not reduce the mast cell burden, but it does reduce the mast cell activation episodes in some patients, but it is not approved for mastocytosis. It is approved for chronic urticaria and asthma, not for mastocytosis. So it's a struggle within the insurance companies to get these medications approved. And sure enough, they declined the coverage of omalizumab.

And 3 days later, as I was boarding a plane to go to Europe, I get this phone call from an emergency room in Michigan saying that the patient was there and he had a myocardial infarction. So I said please check his tryptase level, and it was checked and it was 178. Remember his baseline was 15 and it went up to 178. So this tells us that the myocardial infarction he suffered was not because of the coronary artery disease, but because of the profound hypotension that interfered with the coronary perfusion that killed the [ myocardium ]. And he had a cardiac arrest and was resuscitated. He had 5 rib fractures during the resuscitation, but then he's still alive. And of course, the insurance company approved omalizumab after this event, and he was also started on midostaurin, which is approved for the treatment of advanced mastocytosis, brand name Rydapt by Novartis. And I think that was a [ concession of use ] because the variety that he had was not what we called advanced or the leukemic form. It was the indolent form. And they did take care of his anaphylactic episodes. He was fine for a couple of years.

Then I saw him last year. And he came to me and said, "Doc, I'm happy that I'm not having these anaphylactic episodes, but I just cannot take Rydapt anymore because it is causing me to throw up every day. It is causing me so much nausea and I don't have any quality of life left anymore." So he made a conscious decision to stop the midostaurin because he could not live with these side effects.

Again, when you are dealing with a patient with indolent disease, the tolerability of the drug becomes important, the side effect profile and the tolerability, and this patient could not tolerate Rydapt. So luckily, he's been doing okay since he stopped Rydapt, just on omalizumab, but it's a ticking time bomb, right? We don't know when the next anaphylactic episode will happen.

So this is the typical skin lesion that we see in mastocytosis. Again, these are fixed lesions. They are a cosmetic issue for most patients. They can also be uncomfortable when the patient exercises or expose the feet or something is rubbed or add to friction, they can form into hives. But unlike the hives, which will come and go, these lesions are there all the time. And this patient has an extensive variant of urticaria pigmentosa. Some patients have less. Some patients have even more of these kind of coalescing into one big single plaque. And these are formed by mast cells migrating from the bone marrow, abnormal mast cells, into the skin and collecting under the skin to form those spots.

So why do we have mast cells? Well, I think we have mast cells to protect us from threats. And that could be an external threat or an internal threat. They are innate cells that were developed very early in the evolution. They are even present in mollusks and various primitive animals.

So this is something very important. There are no [ people ] described without any mast cells. And I think the very important thing is to alert us from danger signals. So it could be, again, an external danger, like a bee sting or something trying to penetrate our skin. They degranulate, make us itch, get rid of that. Or it could be an internal threat, internal danger, a chronic infection, stress. How many times you have seen somebody tell you I've been going through a very stressful time and then I had the most horrible hives in my life while going through this stress? And why is that? Because these mast cells tends to stress hormones, substance C, CRH. They have retesters on their sources. And it's a first alert innate defense mechanism, but the key is that it is transient, and when the threat is eliminated, when the danger goes away, the mast cells come back to their normal state.

Now in mastocytosis, we have a couple of problems. First, the patients have ten to hundredfold more of these mast cells. So when you have a danger signal, they respond in an amplified manner. So a big thing which might cause a local swelling in one patient may cause an anaphylactic episode or even death in somebody with mastocytosis because they're amplifying the signal. Then, we have the KIT D816V gene mutation that we think also reduces the threshold of activation for these mast cells so they can start getting activated with a lower threshold to these stimuli.

And when they get activated, they release their granules, which contain histamine. They create lipid mediators, including prostaglandin, leukotrienes, and then they also secret a lot of cytokine. We only have a few medications to block these mediators. We have antihistamines, anti-leukotrienes. But we can't really do a good job blocking the cytokines, and then we can't block every single mediator released from the mast cells.

And now you see the broad spectrum of symptomatology, including the gastrointestinal tract, bone pain, organ involvement, anxiety, fatigue, and anaphylactic type reaction. And there's not a single organ system that has failed in mastocytosis because mast cells are in pretty much all tissues. These are not in a single organ. If you're a kidney doctor or an pulmonologist, you have a organ, right? You can go in and take a look at it, biopsy it, and look at what is wrong with it. But when you are a mast cell doctor, it could be anywhere. It could be any symptom.

And when we suspect mastocytosis, we do a bone marrow biopsy. And these are the criteria. This is not a trivial diagnosis. It is a pathologic. There are certain pathologic criteria that are recognized by the World Health Organization. They need to have either multifocal dense infiltrates of mast cells in the bone marrow or those mast cells should look abnormal. They have the KIT mutation, and they also express a marker called CD25. And with these criteria, you make the diagnosis of mastocytosis.

About 20% of our whole population have advanced version of the disease. And these patients also have, in addition to mastocytosis, other stem cell disorders because essentially what mastocytosis is is a disorder of the hematopoietic stem cells, which is right in the mast cell. And sometimes that stem cell can acquire other mutations and extend and result in other abnormalities in other cell lines. And those patients then go on to have the advanced varieties associated with leukemias or pre-leukemias or organ dysfunction. And those have a poorer life expectancy.

They die from mastocytosis or related complications, as opposed to indolent patients, which is the 80% of -- the majority of the systemic cases. They don't usually -- they have a normal life expectancy, but they suffer from these symptoms all their life. And I made that point with the case reports average of 6 years from symptom start to the diagnosis and at least 3 specialist visits during this time, and they finally find a referral center like our center. They come to us and then we tell them, yes, you have mastocytosis. Take these medications and then come back in a year, we'll check your blood count and make sure it doesn't progress to leukemia. And that's not a very satisfactory thing to hear.

Now look at the symptom burden in indolent versus advanced. These patients have at least as much symptoms as the advanced patients with the systemic, gastrointestinal, and skin. And my experience is that patients with indolent disease have even more skin and anaphylactic type symptomatology than those with advanced disease.

And these symptoms will impact their quality of life, the way they live, the way they take care of themselves and other people in the family. And these are -- 60% is the survey that we sent out using the Mastocytosis Society membership, and these were the results. 60% or higher, they reported their ability to cope was moderately or extremely affected despite best available therapies.

And why was that? Because of the anaphylactic episodes, because of the fear and anxiety. Imagine living in fear. When is the next anaphylactic episode going to come? If you are allergic to something, you avoid that, and then you can have a semi-predictable lifestyle as long as you avoid that trigger. In mastocytosis, you don't know what will be triggering the next anaphylactic episode, so you have this huge unpredictability, as you see there on the 5th line, a big, big impact on the quality of life.

And they do have polypharmacy burden, and most of them are on H1 antihistamines and H2 antihistamines to block the histamine and then the rest of the medications you see there. We always prescribe them a self-injectable epinephrine to use with these anaphylactic type episodes if they do occur, and they do occur in about 40% or 50% of our indolent patients at least one time in their lifetime. And 75% of indolent patients have taken at least 4 classes of drugs to manage their disease.

So I hope this highlighted the need for new therapies for our patient population. And the new therapy -- the ideal therapy would target the KIT D816V mutation. It would reduce the mast cell burden and systemic symptoms, and it would reduce the polypharmacy burden.

I have been Melanie's doctor for about 15 years now, and I tell her that I have never been as hopeful as I am now since I started studying this disease. And I'm looking forward to experiencing good things to come and offering new and better treatments for our patients.

Thank you for your attention. With that, I would like to invite Andy back here to the stage.

[Andy Boral, executive]

Thank you so much, Dr. Akin. And thanks for sharing that incredibly informative overview of mastocytosis, but in particular those really incredible personal cases, and appreciate your giving us that level of personal detail.

Now that we've learned quite a lot about systemic mastocytosis from Dr. Akin and from Melanie, I'd like to present some data from our ongoing clinical program with avapritinib in systemic mastocytosis, really showing you that avapritinib has the potential to be a transformative medicine for patients with this disease.

Mastocytosis, as I alluded to before, is a single disease entity with a broad range from indolent through advanced but, again, with this underlying flavor of debilitating and unpredictable symptoms throughout. Our clinical trial program is really focused on supporting global regulatory approval across the breadth of this disease.

We are currently working very closely with the FDA on the plan for our first quarter 2020 filing in advanced systemic mastocytosis that will be based primarily on data from the EXPLORER study, which I'll show you a little bit more of that along with data from the 2 PATHFINDER studies; again, on track there for the first quarter of next year with that NDA filing. And I'll talk a little bit about our PIONEER study in indolent systemic mastocytosis, which are moving along very quickly, and anticipate that will not be far behind.

So I think first I'd like to step back a bit and talk a little bit about avapritinib and why is it such a good potential medicine for this disease. Avapritinib was specifically designed to inhibit D816V and KIT, and also to be highly selective for D816V and KIT. It's really that selectivity and potency that are critical.

So across the top of the slide you see a series of images of the human kinome, kinome trees, and on the left you see avapritinib binding to the human kinome. You can see it's very selective. The primary thing that lights up is the KIT gene -- or the KIT protein, which is shown with the green dot. And this is in contrast to some of the other approved and investigational agents currently being evaluated in systemic mastocytosis.

Avapritinib is also extremely potent on D816V. I should point out that this mutation changes the confirmation of the protein from the inactive to the active form. It's notorious for being highly resistant to all of the available kinase inhibitors by avapritinib. And here you see that avapritinib has very high potency, with an IC50 of .27 nanomolar; again, quite a bit more than -- or quite a bit more potent than you see with other agents that are used, investigational and approved.

But I think really most importantly is this biochemical and selectivity profile that we see with avapritinib is translating into really profound activity for these patients. So here I'm showing you data from our EXPLORER study that was presented at the EHA meeting in the middle of the year just to remind everyone that, with avapritinib in advanced systemic mastocytosis, we see a response rate of 77%. This is using the highly rigorous IWG, or International Working Group, criteria, which is really a very high bar for SONC assessment.

And not only do we have a high response rate, but these responses are durable. So the 1 year duration response rate is 74%. This has come in the setting of good tolerability with only 4% of patients discontinuing avapritinib due to a treatment-related side effect. And again, these data are being -- will form the basis of our ongoing discussion with FDA for our NDA submission in the first quarter. And as I mentioned before, that will be in combination with earlier data from our ongoing PATHFINDER study, the phase 2 study in advanced disease.

Now I'd like to put mastocytosis into the broader context of mast cell disorders. So I think as Dr. Akin mentioned, there is a broad concept of mast cell disorders. Systemic mastocytosis is the most common of this subset. But as you see on the upper right, there are a variety of other subsets, and actually some of these are also driven by D816V mutant KIT. The common theme across them all is that they're mediated by mast cells. They're mediated by mast cell activation and degranulation, results of the interactive factors and systemic hypersensitivity reaction.

Now on the advanced SM side of the disease, these patients have a life-threatening disease with a median survival of 3 to 5 years, and they really require intensive therapy that provides rapid reduction in mast cell burden. But even in indolent disease, we're learning with some new data that these patients can also have reduced survival, and in fact due to things like anaphylaxis and other acute hypersensitivity reactions.

And while the patients that Dr. Akin described to us -- the patient he described to us survived their cardiac arrest, you can easily have imagined that being a fatal event if things hadn't turned out well. But again, the commonality across the indolent and systemic disease are these debilitating, unpredictable systems that really make it difficult for these patients to have a normal, productive life working and socializing.

Our program, we are pursuing a comprehensive program across the range of systemic mastocytosis. The EXPLORER and PATHFINDER studies are our ongoing phase 1 and phase 2 studies in advanced systemic mastocytosis. And in a bit, I'll talk a bit more about the PIONEER study in indolent disease, but now I'd really like to turn the focus to actually a subset of 15 patients with indolent systemic mastocytosis who are enrolled on the EXPLORER study.

So keep in mind that the EXPLORER study is actually a study for patients with advanced systemic mastocytosis, so you might ask why do we have 15 patients with indolent disease. We do a regular ongoing central review of pathology and clinical assessments for all the patients. And in retrospect, 15 of the patients who the pros, the world experts conducting the study, had advanced disease, on central review they turned out to have indolent disease. I think this is pretty important because it makes the point that the diagnostic line between indolent and advanced is quite blurry and it's not always at all clear who's got advanced and who's got indolent.

But now let's look at these 15 patients. You can see that they have had -- that avapritinib has provided profound reductions in mast cell burden in these patients across a broad range of measures on mast cell burden. On the left you see serum tryptase. You've heard a lot about that already. That is a global assessment of mast cell burden. You can see dramatic reductions in all 15 patients.

If you move over to the next set of waterfall plots, you see bone marrow mast cells; again, dramatic reductions. This is the quantitative histopathological measure of the disease. We can also look at spleen volume in patients with enlarged spleens, so splenomegaly is a critical cause of abdominal pain, anorexia, weight loss. You can see a reduction in splenomegaly across all the patients.

And on the far right, we're looking at the D816V mutant KIT allele burden, which you can measure in bone marrow or the blood, actually. And here you see profound decreases in all the patients who had measurable allele burden. And again, this is critical because this is the underlying, or let's say a hallmark of the disease, and shows that we really are eliminating the offending monoclonal mast cell that causes the disease.

Importantly, these profound reductions in mast cell burden have translated into very, very durable responses. Of the 15 patients with indolent SM on the EXPLORER study, 14 remain on treatment, and actually 6 remain on treatment beyond 2 years. And this is over time patients have dose reduced. And most patients, 73% in fact, are now being maintained stable at a dose of 100 milligrams once daily.

So we've talked a lot about mastocytosis as a disease of debilitating systems and how that's really what in a sense causes the patients trouble. And so at Blueprint Medicines, we thought it was critical to develop a quantitative way of measuring symptom burden, and we are developing 2 patient-reported outcome tools specifically for patients with advanced indolent systemic mastocytosis. These'll be the first patient-reported outcome tools developed in this disease following the standard FDA guidances in order to support labeling.

So as you see here, the 2 tools are actually quite similar. There's about 70% overlapping symptoms. And as you've heard from Dr. Akin, the patients have symptoms across a range of organ systems, and so the tool really looks at gastrointestinal symptoms. It includes skin symptoms as a group and other systemic symptoms.

This tool is, as I said, to be validated to support labeling, so particularly important for the PIONEER study in indolent disease, where the indolent systemic mastocytosis symptom assessment form, which is the ISMSAF, actually will serve as the primary endpoint in that study. Importantly, to that end, we're making this tool easy to use by patients. So it's being developed on the electronic tablet. It's taken by a patient daily and can be completed in just a few minutes to ensure a very high degree of compliance.

The preliminary data in the EXPLORER study also shows that it's measuring important things. So on the upper left, you can see that we see steady, durable, and significant reductions in TSS, total symptom score, in patients with advanced systemic mastocytosis. And importantly on the far right, you see the patients with most symptomatic disease actually have the most profound improvements in symptom score. This is nice to see because those, of course, are the patients with the most need of benefit and it shows the consistency between the patients' perception of their disease and the symptom score.

Here I just wanted to show 2 specific cases of patients to give you a sense of how the data looks. So both of these patients have had reductions in their total symptom score, showed by the red line, and you can see importantly in both cases that they have profound and rapid reductions in mast cell burden, in this case measured by serum tryptase shown in the blue line. This is a recurring pattern that we see throughout the study as we release Dr. [inaudible] data that patients typically have a rapid, really profound reduction in mast cell burden, in tryptase, in the bone marrow, which is followed by a slower, more prolonged reduction in mast cell burden, and it really shows us -- excuse me, more prolonged reduction in symptom score, and it shows us 2 important things. One is that the measures obtained by tryptase do predict improvement in symptoms in individual patients.

And I'll pause on that for a minute. If you read the literature, there's really a lot of claims that tryptase does not predict symptoms in that mastocytosis. And so, yes, that's probably true looking at summary data across populations, but we're clearly seeing that in individuals, if an individual's tryptase goes down, that certainly correlates with symptom improvement. And then the other thing is that the evolution of improvement of symptoms can take some time. I think that will be important to us as we think about our analysis of the early data from the PIONEER study that I'll come back to in a few minutes.

Up here, I actually want to make the point that the symptom score reduction correlates with the important clinical measures of benefit. On the left side of the slide, I'm really just focusing on corticosteroid use. The patients, as you heard from Dr. Akin, with mastocytosis frequently have to use steroids. They can also be on chronic steroids, which as I think many of you know, have very severe side effects over time. So it's really gratifying to see that in the EXPLORER study that the 22 patients who were on steroids at baseline, on starting the study, 80% actually were able to reduce their steroid use after starting avapritinib, and 41% completely discontinued steroids. So there's a nice objective measure of benefits correlating with symptom improvements since you normally reduce steroids as symptoms get better.

So I'm going to switch gears now and really focus on a single patient case. Since I left clinical medicine, mostly I get to see the summary graphical data from our studies showing that avapritinib is benefiting patients, whether it be mastocytosis or GIST or pralsetinib in lung cancer. It's really rare that I really get to see the primary data anymore, and so it was incredibly gratifying when this investigator on the EXPLORER study shared this case with us.

This was the case of a 45-year-old woman who actually initially had indolent systemic mastocytosis quite a number of years ago. It evolved to advanced disease, and she's now enrolled in the EXPLORER study. The images here are her baseline images when she started on the study. The image on the left shows you an abdominal MRI just highlighting a massive spleen. It's about 3x normal size and was causing all of the typical symptoms of abdominal pain, anorexia, and that resulting in weight loss.

The middle image shows a bone marrow biopsy. It shows that the mast cells, which are the brown dots shown here are seen for KIT, had completely replaced her bone marrow. And this was resulting in profound anemia as well as just acute [inaudible]. And on the right, you see actually a colon biopsy of this patient. She had chronic severe diarrhea, so her colon is biopsied. That is I think no surprise really to docs treating systemic mastocytosis. You can see that her colon was completely infiltrated with mast cells, again, shown in these brown dots.

So overall, this young woman with advanced disease. She had had a 30-pound weight loss over 6 months. She was anemic with severe fatigue and had chronic severe diarrhea. As I'll show you in a few minutes she also had a very impressive, really horrific whole body rash.

So now I'll actually go back to the summary data that I usually get to see. But I think it's important to show you here that, looking at the top panels on this slide, very quickly after starting avapritinib, the patient had a profound and rapid reduction in multiple measures of mast cell burden and that disease reductions are durable. On the upper left, you see both tryptase and bone marrow mast cell reductions, and on the upper right, you see again the D816V KIT MAP4K1 mutant allele burden.

I want to point out that the patient had a partial response after about 2 months of therapy, and this evolved to a complete response after about 16 months. But again, most importantly really, I want to point you to the bottom of the slide, this is not the clinical data. This is actually what the patient cares about. Over time her weight recovered to normal and remained normal stably, and this you can see on the lower left. On the lower right, you can see that her spleen volume has steadily decreased and has actually now normalized.

But now back to images. So I was just actually totally amazed when I saw these photographs. The top row, again, shows the same images that I showed at the beginning. Those are baseline situations, and on the bottom, we see that after 2 months of avapritinib therapy, at the beginning of cycle three, on the far left looking at her bone marrow, the mast cells, the brown stating dots, are almost completely resolved. It's not quite back to normal, but you can see the resumption of [inaudible]. So that's the B-cells that you should normally see on liver fat globule.

Then you can see the abdominal MRI with that huge spleen. Again, after 2 months of treatment, beginning of cycle three, it's about the half the size it was at the baseline. It's actually not quite normal yet here. It does become normal, but already she had dramatic improvement in her symptoms. And on the far right, we show that repeat colon biopsy actually done after 6 months of treatment, not the kind of thing you want to repeat a lot. And after 6 months, most of the mast cells have been eliminated from her colon.

So most of those brown dots are gone, and that effect was that actually after just a few months of therapy, this patient had her diarrhea actually resolved long before the 6 months. She regained her appetite. Her abdominal pain resolved. As you saw from prior slides, she was regaining her weight and was no longer fatigued due to the improvement in her blood counts. So it was really transformative for her.

As I mentioned, she also had a rash, and this is a close up of her foot on the left, showing the classic urticaria pigmentosa rash that you see in patients with systemic mastocytosis in general. After 6 months of therapy, you can see great improvement of this rash. And after 29 months, now we're talking 2.5 years on therapy, the rash had completely resolved. Her skin was back to normal, and also making the point that some of these, especially things like rash can take quite a while to get better, even though actually her pruritus, the itching of the rash, resolved much more quickly.

But this rash wasn't just on her foot. This was a whole-body rash that I can show you that covered her entire trunk, again baseline. You can see at 6 months, much, much better, and at the 29-month mark, completely normal skin again. Well, physicians too often -- well, probably Dr. Akin, but many of us trivialize rash. We think people don't die of their rashes. They are kind of not thought to be a severe symptom. But actually though, as I've talked to more patients now and heard more stories, certainly I would say the rash and the chronic diarrhea are maybe some of the most debilitating things for these patients.

So this woman loved to go to the beach. She'd been very social. And between both the rash and the chronic diarrhea, she really couldn't do that anymore. She had stopped working. She mostly stayed at home. Her life had been completely changed. And just a few weeks ago, I followed up with her hematologist who's taking care of her, and she said that the patient recently told her how thankful she was to be able to be on the avapritinib study because she's gotten her life back. And I think that is what we're trying to do.

Now I'll turn my attention to the PIONEER study and our work in indolent systemic mastocytosis. So again, as I think most of you know, the PIONEER study is our ongoing study in patients with indolent disease. We initially completed enrollment in part 1 of the study, which is the dose-finding part, where we've enrolled with 39 patients. In that part, we're looking at 3 lower doses. That is the avapritinib 25, 50, and 100 milligrams once daily. I'm happy to say that avapritinib has been very well-tolerated in part 1 of the study with no patients discontinuing due to side effects.

And another interesting point we see as we screen patients for the study, that actually 84% of screened patients have met the criteria for moderate-to-advanced disease. So we have some specific criteria for enrollment on the study. And I think that just kind of reinforces our prior suspicion that actually the majority of patients have disease that is not at all well-controlled with the available cocktail of antihistamines and Cromolyn and other -- steroids or other symptomatic agents that each of these patients take.

So now I'm spending some time digging into these data. A big piece of that will be to look carefully at the correlations between tryptase reduction, bone marrow reduction, and the change in the PRO score. So we did really thoughtfully pick the optimal dose to take forward in part 2 of this study. In part 2, we will compare avapritinib at this optimal dose to placebo. And this is a registration-enabling study, and part 2 is the registration-enabling piece. And while we're going to take our time and make sure we make the right decision, we are planning to get part 2 going as quickly as possible.

We look forward to moving PIONEER along. And actually I think that another point that I should make that I forgot is that there's no shortage of patients. So we've enrolled -- we had an excess of patients for part 1 of the study. The physicians participating in the study keep asking us, okay, when is part 2 going to be open, and we expect that we will enroll part 2 very rapidly. So we do see that we can move PIONEER quickly and get to an NDA in indolent systemic mastocytosis in the relatively near future.

And with that, I will invite Christy Rossi, our Chief Commercial Officer, to the stage.

[Christina Rossi, executive]

Thank you, Andy. Good morning, everyone. So we've heard repeatedly this morning about the really devastating impacts that systemic mastocytosis can have on the people who are living with this disease every day. We heard it from Andy. We heard it from Dr. Akin, and we heard it really directly and compellingly from Melanie, who talked about really the havoc that this disease has wreaked upon her life. She talked about having to give up a career that she had trained for. She talked about going to the grocery store and being afraid of dying.

And at Blueprint Medicines, I am thrilled to have the chance today to talk to you about our efforts to address those patient needs, not only is systemic mastocytosis but in mast cell disorders more broadly. These efforts are going to be anchored through the development of avapritinib and then amplified through the development of the BLU-263, our next-generation KIT inhibitor.

So it's clear that the patient need here is great. The opportunity is also significant, and it's larger than we previously estimated. Current epidemiology data suggest that the [inaudible] of systemic mastocytosis is about 1 in 10,000 patients, which would equate to about 75,000 patients across the US, EU5, and Japan. These estimates include adult patients with cutaneous mastocytosis, which public data as well as [inaudible] and pathologist perspectives and as we heard from Dr. Akin earlier suggests would actually have a diagnosis of systemic mastocytosis if they were worked up appropriately.

Now, we know that diagnosis and patient identification is the central challenge with this disease, like with many other rare diseases, but I'm encouraged by an analysis of [inaudible] data in the US that suggests that nearly 20,000 patients are already diagnosed with either systemic mastocytosis or adult cutaneous mastocytosis. And it's data like that that will guide our efforts going forward, which are going to be focused in 3 primary areas.

First, we want to deliver tailored, targeted education to healthcare providers on the signs and symptoms and patient presentations that should trigger them to consider a possible SM diagnosis and work that patient up further. We believe there are practical strategies that we can employ there. For example, the use of tryptase testing [inaudible] patients who ought to be further worked up. Dr. Akin spoke about the diagnostic delay that many patients can face, and our goal is through data strategies, such as machine learning, to effectively target our educational efforts at healthcare providers to reduce that delay.

Second, our precision medicine teams in the US and Europe are focused on education and building relationships with pathologists and reference labs. These are critical stakeholders in the diagnosis of SM patients. Dermatopathologists, in particular, really play a critical role here. They're not just running tests that are ordered by other healthcare providers, but in many cases, they're the ones that are determining what the next diagnostic steps are to get to that right diagnosis. So this is a place we're going to focus.

Third, with SM like with many other rare diseases, patient education and activation are going to be critical. As I had the opportunity to meet with SM patients and caregivers over the year that I've been at Blueprint, the common thread that's been clear to me is the role that education and really their own self-advocacy has played not only in getting to the right diagnosis but ensuring that their ongoing medical care is appropriate. This is something that SM patients can really struggle with.

At Blueprint Medicine, we've been committed to understanding patient needs in systemic mastocytosis for several years and in driving innovation to address those needs, and I am excited about the potential for avapritinib to be a truly transformative option for many of these patients. But our commitment to addressing patient needs does not end with the development of avapritinib in SM. We're expanding our research and development efforts to better address the needs of patients with mast cell disorders more broadly, for we believe the medical need is also very high.

And it's in that context that I'm really excited to be able to be introduce BLU-263, our next-generation KIT inhibitor for mast cell disorders more broadly. Now, I'm sure you will have the opportunity to hear more about BLU-263 from Mary in our research team at appropriate meetings going forward, but I'm thrilled that I got to the be the one to introduce this today.

We talked earlier about the disease spectrum, and Andy introduced us earlier across mast cell disorders. And he talked about how patient needs will vary across the spectrum. The one common thread that I think we've heard repeatedly today is that patients can suffer from really debilitating symptoms across the spectrum of these diseases. We head about advanced SM and the life-threatening impact that that can have on patients.

But we also know and emerging data suggests that patients with ISM can also have potentially life-threatening impacts from anaphylaxis. In other respects though, patient needs across the spectrum will vary. Andy talked about patients with advanced SM and the mast cell burden that they have that can really be acutely threatening to them. And so, the need that they have is for intensive therapy to reduce that.

We also know that patients with advanced SM may have organ damage and dysfunction, which can lead to morbidity as well as mortality. Even with a potentially transformational therapy, such as avapritinib, unfortunately, we know that some of these patients will progress, for example due to other hematological neoplasms that they may suffer from.

In contrast, patients with ISM and other mast cell disorders may be living with their disease for many, many years. At Blueprint Medicines, our efforts are focused on addressing patient needs across this wide spectrum. These efforts are anchored by avapritinib, which has demonstrated compelling efficacy in advanced SM, in which we are actively investigating in ISM. And they will be further expanded and amplified by the development of BLU-263, which we believe has the potential to reach a broader population in ISM and potentially in mast cell disorders more broadly, which will really require a therapy that's been developed specifically for and optimized for use in a chronic setting in a much broader patient population.

The design and development of BLU-263 really reflects the core principles that make Blueprint Medicines the leader in precision therapy. The target product profile for BLU-263 was developed based on insights generated from the avapritinib program. BLU-263 is a highly potent KIT inhibitor. It's highly selective, and it was developed specifically not to cross the blood-brain barrier. We are excited to bring BLU-263 forward to clinic and have plans to file an IND in the first half of next year.

As you can see, BLU-263 is highly potent against PDGFRA D842V, as well as KIT D816V, similar to avapritinib. Like avapritinib, BLU-263 is highly selective, and it's been a further optimized to reduce off-target activity. For example, against the sodium channel. Importantly, BLU-263 is not CNS-penetrant. And we believe that this may play a role in helping to mitigate any potential CNS adverse events.

As we've heard today, Blueprint Medicines is really committed to addressing patient needs across the spectrum of mast cell disorders, and it's pretty clear that patients are in urgent need of new therapeutic options. Our efforts are going to be anchored by avapritinib, which we believe has the potential to really be a transformative new therapeutic option for these patients, first in advanced SM where we plan to file an NDA in the first quarter of next year, then in ISM where we look forward to initial data at ASH this year and more data as we go into 2020. And then our commitment today is expanding with BLU-263, which we believe could be a very important new therapeutic option, not only for patients with ISM, but for mast cell disorders more broadly. And we look forward to bringing this forward to clinic by filing an IND in the first half of next year.

So with that, I would like to invite Jeff, Andy and Dr. Akin to the stage for some Q&A.

[Jeffrey Albers, executive]

[Technical Difficulty] perspective. We'll take about 10 minutes of Q&A. Then we're going to take a short break to make sure we have time for the other program. From a housekeeping perspective, we ask that you each ask one question. We'll try to get to everybody in that timeframe.

[Salveen Richter, analyst]

Salveen Richter, Goldman Sachs. Just a question here. Given the spectrum across this disorder and the fact that you're going to be targeting a range of doctors, including allergists, what is the tolerability profile that you view as acceptable as you look to expanding into indolent SM?

[Jeffrey Albers, executive]

So maybe I'll start with that and then hand it over to Dr. Akin, as well as Andy Boral. So I think within the data that Andy showed, early data from the ongoing trial with the 15-patient indolent systemic mastocytosis, I think we've got that with avapritinib for the vast majority of patients. You saw 14 of 15 patients staying on therapy, and I think are being managed by our ability to push dose down. And we hear that time and time again, that clinicians, they will play around with the dose and figure out how to optimize that for the specific presentation for a specific patient.

What you heard a little bit about today with BLU-263 is that where we sit with D816V as that [technical difficulty] driver, that we want to make sure that we bring forward a therapy for as many SM patients as possible. This is a very large group of patients with a very clear need. And so we want to make sure that we are bringing options to them. And so what we're -- what we've done in the classical sense with avapritinib is start at the highest dose and move down. With BLU-263 we get opportunity to start at the lowest dose and push up. And they are going to meet somewhere in the middle, but we think this is a way to make sure the most patients possible see a Blueprint Medicines therapy. Dr. Akin?

[Cem Akin;University of Michigan;Professor of Medicine]

Yeah, I think when we are dealing with indolent disease, the tolerability should be and the drug should not [technical difficulty] a chronic symptom that they can't deal with like, as you saw in my second patient, that he was not able to continue that kinase inhibitor because he has severe nausea and vomiting. I think some mild side effects are going to be expectable, but that remains to be seen, but I think so far my impression is that the tolerability profile of avapritinib has been very [technical difficulty] at least in [technical difficulty] in indolent disease. And as mentioned before, there's more patients remain on drug, and [technical difficulty].

[Jeffrey Albers, executive]

I guess I'm not calling on people. I was about to [technical difficulty]. I'll leave it to you with the microphone. Yes, Andy Berens from SVB Leerink.

[Andrew Berens, analyst]

Thanks, Jeff. In the malignant setting, so PDGFR-Alpha, GIST, [technical difficulty], as well as in [technical difficulty], is there any reason to want [technical difficulty] penetration of your drugs? Is there any involvement [technical difficulty] in those diseases?

[Jeffrey Albers, executive]

Andy, do you want to take that?

[Andy Boral, executive]

So I think the disease we're focusing on currently, there is not much frequency of [technical difficulty]. It occurs occasionally from there, in SM. It's not [technical difficulty]. But certainly, avapritinib also has the potential to look at other [technical difficulty] diseases where [technical difficulty] may be, where it may be beneficial. So for example, we have an ongoing [technical difficulty] program [technical difficulty] where you'll see [technical difficulty] in melanomas. You'll see [technical difficulty] in leukemias. And so I think that actually it's not all just a pure negative. It's probably not an important component for GIST [technical difficulty].

[Andrew Berens, analyst]

I'm sorry. So it's not necessary for CNS penetration in GIST?

[Andy Boral, executive]

In GIST -- GIST CNS [technical difficulty] are very rare. I would say that CNS penetration is not important therapeutically, except for the very rare circumstance.

[Andrew Berens, analyst]

Okay, so I guess the question, the follow-up question is, is there any plans to advance 263 into GIST?

[Andy Boral, executive]

Yeah, so we certainly, as Jeff was saying, we certainly want to focus on indolent SM to start with, and [technical difficulty] more broadly in SM. But over time, I expect we would explore 263 just as well.

[Andrew Berens, analyst]

Thanks.

[Andy Boral, executive]

Yeah, I think broadly the 2 markets give us a lot of flexibility, both from a disease state perspective and looking at what that overall market opportunity is, but that's why I talk about the starting low and moving up. That -- there may be certain patients for whom that's an appropriate approach. I still look at the broader data set. And the number of patients who have discontinued for any type of CNS type adverse event is in the 4% to 5%, and we'll share more data on that at [technical difficulty] this year. So we think we've got a very effective treatment with avapritinib, and we'll look to optimize that with 263.

[Michael Schmidt, analyst]

[technical difficulty] It's Michael Schmidt with Guggenheim. How's it going? Maybe just a question on PIONEER study. Can you just remind us what [technical difficulty] criteria are being used to select the go-forward dose for avapritinib in indolent SM, and then maybe as a follow-up maybe help us a bit more clarify how you see avapritinib and 263 to be positioned relative to each other in indolent SM. I think [technical difficulty] the overlapping parts of the 2 drugs in the indolent setting.

[Jeffrey Albers, executive]

Andy, why don't you take the first piece of that on the dosing for PIONEER for avapritinib?

[Andy Boral, executive]

Yes, well, so as we pull those 2 together we'll look at a broad range of parameters. We will be using the [technical difficulty] tool as the primary endpoint, so we certainly need to look at the improvement and total improvement score by dose. But I think it's very important to also show that that correlates with objective measures of mast cell burden. And we look at tryptase in the study we actually -- we do [technical difficulty] even though normally an [technical difficulty] would not follow the [technical difficulty] burden. And then of course just the broader safety profile.

So it will be a multipart composite assessment. And I think the other piece is, as you saw from the couple of cases I showed you, the timing of reduction can take -- the tryptase reduction predicts the improvement in symptoms, but they are separated in time. And so I think it's also important for us to just look for the [technical difficulty] of the two. And it might be that higher doses could be faster improvements, things like that.

[Jeffrey Albers, executive]

And the second part of the question is around a relative focus of avapritinib and BLU-263. Avapritinib is our program in indolent systemic mastocytosis. What we know and what we're really encouraged by, as Andy highlighted, is that we're seeing a higher percentage of patients qualified with an overall symptom score into the trial that we may have originally estimated. I remember we used to talk about that. In indolent systemic mastocytosis, maybe there's some meaningful minority of patients that would qualify for that criteria. We've seen that number rise significantly, and we'll be moving into the registration trial next year in part 2 of PIONEER. So that is the focus.

263, when I mean coming from the other end, is there's always this subset of patients for whom we're not sure what the appropriate therapy is. And that maybe patients who have episodic flares or for whom we want to be on very low dose over a longer period of time, and 263 will give us that flexibility to figure out how to extend and raise that [technical difficulty] treatment of indolent systemic mastocytosis.

[Unknown Attendee]

Thank you.

[Jeffrey Albers, executive]

We change the microphone each time.

[Unknown Attendee]

Yeah. It's a fun game. So 2 questions for me. One, regarding the ISM [technical difficulty] that you put up there for the patients that have been reclassified, they were all titrated down to 100 mg. Was anyone tried out actually sub 100 mg dose, and just to ask it straightforward, [technical difficulty] at the dose that you think would be a good, effective dose for the PIONEER study given it was the maximal dose [technical difficulty] in those cohorts in part one?

And then the second question would be for Dr. Akin. Fatigue is a very prevalent manifestation and impactful quality of life effect for the ISM patients that we saw up there today and got feedback on. Is that due to polypharmacy, which would be somewhat intuitive? And if you have a drug like avapritinib, reduction polypharmacy, is that going to affect that effect of the disease, or is it going to be something more directly related to the mast cell activation?

[Jeffrey Albers, executive]

Okay, so Andy, I'm going to have you take the first part, which is why is the lowest dose 100 mg. There is a very practical answer to that, but the average dose is 126 mg, so close to that 100.

[Andy Boral, executive]

Yeah, so as Jeff pointed out, the average dose is 126 mg. When we started the study actually be 100 mg was our smallest dosage form. We've actually -- but now there are patients at lower dose [technical difficulty] saw 73% are at 100. Some patients can now go to lower dose [technical difficulty]. We are developing new dosage forms to allow [technical difficulty]. But I don't think those data really tell us -- what they let you know is that persistent treatment at 100 mg is very effective at controlling disease. But I don't think that means that you have to be at 100 mg. [Technical difficulty] key question to answer, and we'll be able to assess that in the PIONEER study.

[Jeffrey Albers, executive]

Can you comment on the [technical difficulty] with indolent systemic mastocytosis?

[Cem Akin;University of Michigan;Professor of Medicine]

Yeah, that's a very good question, and [technical difficulty] difficult to answer because I think it is multi-factorial, meaning that it will have some polypharmacy component. It will have some mast cell component. It will have some fear and anxiety and depression component because those are also a significant comorbidity in these patients. So I think if you -- my expectation and hope is that if you reduce the mast cell burden, you reduce the polypharmacy, you reduce the mast cell mediator, and you reduce the anxiety, it should [technical difficulty]. It remains to be seen, but I think I'm hopeful. I don't know, Andy, if you have any preliminary data you can share from the advanced study [technical difficulty] reduction occurred if you looked at fatigue specifically in that [technical difficulty].

[Andy Boral, executive]

Yeah, so that is something we definitely are -- will be getting at some of the [technical difficulty] outcomes who are all individual components. I think at a high level we see that the total symptom score clearly does improve over time with treatment. And as we have more data from more patients, we can break it up into different components. And fatigue is something we look at.

[Marc Frahm, analyst]

Hi, Marc Frahm from Cowen. Dr. Akin, clearly some of the patients who are able to sneak into EXPLORER are voting with their feet that they like the risk-benefit of the drug. But those are the most severe indolent patients who are able to sneak into EXPLORER. So when you think through your clinic, what percent of patients look like that? And today's profile of avapritinib is certainly very attractive to them. And what's the most meaningful thing to [technical difficulty] for you to think about significantly expanding beyond whatever that percent is?

[Cem Akin;University of Michigan;Professor of Medicine]

Yeah, I think when I look at my own patients, as you saw in the slide, that's a pretty accurate representation, about 60% to 75% are not optimally controlled on what they are, and then about one out of 4 patients are coming with no complaints and are happy with [technical difficulty]. Now we put it at 75%. There will be some patients who won't want to take any medication. And they are against [technical difficulty] they are going to want to just manage their disease and be tough. But then there are some that are still going to be on it. And I think roughly I would estimate [technical difficulty] one in -- one out of 3 of the remaining 75% [technical difficulty] will want to be on drug. And this is just based on my own estimation. But I think we have patients that wanted to enroll in avapritinib trials with very low tryptase levels. And the avapritinib did not [technical difficulty] advanced disease by any means, but they were so symptomatic that they really were happy that the trial was available for them and we could enroll them.

[Arlinda Lee, analyst]

Arlinda Lee from Canaccord. I was more [technical difficulty] about the spectrum of disease. And you guys had talked about identifying for thinking that you might have 75,000 patients. I'm wondering about the [technical difficulty] population that you talked about and how that might fit into the treatment paradigm and the addressable patients. And then also on the patient-related outcomes, wondering what you are looking at in the ISM that's different from the ASM and if that might capture some of those effects that are most impactful to patients.

[Jeffrey Albers, executive]

Dr. Akin, do you want to [technical difficulty] hit on the [technical difficulty] SM to SM [technical difficulty] systemic disease?

[Cem Akin;University of Michigan;Professor of Medicine]

Yeah, I think the question more [technical difficulty] for just to relieve the skin symptoms or --?

[Arlinda Lee, analyst]

Sorry. How severe the patients really have to be. And I think you talked about proportions, but I'm curious are the skin patients enough to get diagnosed? And then if they are to see you then versus maybe the broader physician population what that might look like.

[Cem Akin;University of Michigan;Professor of Medicine]

Yeah, I think, again [technical difficulty] group called cutaneous mastocytosis, it is a broad subcategory. It mainly occurs in children, and it seems they only have skin symptoms and not systemic disease. And those patients I wouldn't see them as candidates for kinase inhibitor, at least at this point before we know more about the patient in the population. And plus children, childhood-onset cutaneous disease usually regresses in about 10 to 15 years on its own. And that's very different than the adult population. When they have the skin disease, by the time you see the skin disease, they already have the systemic disease. So I think it's -- a little bit of a mixed understanding when the patient presents with skin symptoms, they actually are presenting at the time of systemic disease.

[Unknow Executive, executive]

So I think it's a little bit of a misunderstanding when, like the patient presented skin symptoms, they actually are presenting with the sign of a systemic disease.

Now, what if they don't have any other symptom? Then, the skin symptoms they are happy to live with, I think it's fine. But, I think the -- I think there will always be a percentage of the patients who present with only skin lesions and they find it unacceptable, cosmetically and socially, who would want to go on the drug. And -- but, so they're probably lower than the population that have the systemic symptoms, anaphylactic, gastrointestinal.

What percentage, I don't know. The pioneer trial did not enroll those patients with just skin symptoms only and we haven't really discussed the historic patient groups. But, I think it remains to be seen the accurate results from the pioneer trial, I think that would spark the interest in these patients with just [technical difficulty] alone. Of course, it remains to be seen.

[Unknow Executive, executive]

I see one hand up, PRO, and then we'll take one more question. I saw a lot of hands still up, so I think we'll stay up here during the 10 minute break.

[Unknow Executive, executive]

Yes, so there -- as you saw, there's a lot of similarities between the advanced and Indolent PRO. There are a number of [technical difficulty]. One thing that comes to mind is that in Indolent PRO, we have a specific question about brain fog, and that's something that's often underappreciated, that in systemic [technical difficulty] Indolent advanced and at least in our -- when we developed the PRO, it came out more prominently in Indolent, actually, potentially to have brain fog and [technical difficulty] and there's a hope that we can actually improve that with [technical difficulty].

[Unknow Executive, executive]

Last question, but we will stay up here to get -- I see a lot of hands still up.

[Unknown Attendee]

Okay, thank you. Anne [technical difficulty] from Jefferies. Final question for Christina. Andy mentioned that oftentimes it's not a clear line between advanced and indolent systemic mastocytosis based on symptoms. So what percent of Indolent patients have severe enough of symptoms that cannot be differentiated from ASN [sp] so that they could be potentially benefited from [technical difficulty] once it's approved [technical difficulty]? Thank you.

[Christina Rossi, executive]

Yeah, so I'm happy to start and Dr. Akin can probably chime in here as well. So first of all, we've seen that symptoms alone are not necessarily a good delineator between advanced forms of the disease and Indolent. So patients with Indolent SM can actually have quite severe symptoms.

I think the challenge in differentiating a diagnosis between an Indolent and advanced is clear and I think the data that we just saw from our own trial sort of underscores that. I know we used the term patients sneaking into the study, but I think the reality is when those patients came into the study, the local investigator thought those patients had advanced SM. And, so then they were then adjudicated essentially and found not to meet the criteria.

And, to me, that just speaks to the real challenge in differentiating. It's a spectrum. What that will mean in terms of what percent of indolent patients may ultimately require a therapy or seek it when Avapritinib is approved, I think that remains to be seen. But, it's clear that the need there is high. If you want to add to that.

[Cem Akin;University of Michigan;Professor of Medicine]

Yeah, I think I emphasize that we don't diagnose advanced mastocytosis by symptom. We diagnose it by organ involvement or whether or not they have a leukemic component to their disease. So it's the pathology [technical difficulty] and clinical diagnosis and that does not involve the symptom, if they have cytopenia, if they have liver dysfunction, if they have gastrointestinal malabsorption. So those are the criteria that we look at to diagnose advanced disease.

Symptoms could be similar in Indolent versus advanced. That doesn't really differentiate one group from the other. It's the pathology [technical difficulty] organ dysfunction that separates the advanced disease patients apart from the indolent patients and the poor survivor life expectancy.

[Unknow Executive, executive]

All right, I think that pulls together [technical difficulty] even there, it's a bit of a blurred line.

So we are going to take a quick 10 minute break. I think we're going to hustle you back in. To the 4 of us, I'm going to make you 3 stay up here because I saw several hands through the middle here still. It seems that you had to sit on the aisle to get your question. And then we will get started with Marion coming up to kick off the second half of our event. Thank you.

[Marion Dorsch, executive]

So we would like to get started with our second session this morning. Please take your seats.

Good morning, everybody, and welcome back after the break, or not break, whatever you want to call it. Today marks the first time since I joined Blueprint Medicines 3 years ago that we are sharing some of -- some parts of our earlier discovery portfolio. I am very excited to unveil 4 of our 9 undisclosed targets today.

It was a difficult choice, leading up to today, which ones to pick and we had a lot of debate. In the end, we selected a variety of targets that really showcase the breadth and the depth of our portfolio.

This tremendous progress would not have been possible without the hardworking and committed discovery team at Blueprint Medicines. I am truly lucky to be part of a team of such driven and committed scientists, and today, we'll have the opportunity to meet some of them, some of my team members, either in person or via video.

At Blueprint Medicines, we are committed to detecting cancer and the many ways it evades treatment. Cancer is a disease driven by genomic aberrations and in the majority of cases, the genetic makeup leading to the cancer transformation is rather complex. It is rare to have a single driver. Moreover, genetic makeup of cancer is not static, but it was over time, and even so -- even more so in reform to treatment.

Blueprint Medicines is built to tackle the challenges of treating cancer. We have the ability to design highly selective medicines against key cancer drivers that we deeply characterize to understand different formative potential. Our proprietary library, together with our integrated research capability, allows us to rapidly adapt to new targets or evolving insights and to advance programs quickly.

There's a keen sense of urgency in everything we do. We work in a very gated, data-driven approach to advance programs that have the highest probability of success in very efficient ways.

Earlier this morning, we have seen the powerful impact, a transformative investigation in medicine that Ava can have on patients. I'm going to tell you this morning how our platform has enabled us not only to discover our current clinical program, but empowered us to do so again and again and again.

We have built and refined our platform over 8 years. We were founded on the idea that cancer -- or that kinase drug discovery can be done better. Our founders were the drivers behind the development of Gleevec for chronic myeloid leukemia, the poster child of successful kinase inhibitor.

Our proprietary kinase library enabled the very differentiated approach and sets us apart and has resided in the discovery of highly selective and potent kinase inhibitors. This was not -- this would not have been possible without our strong biology and computation biology team that continuously provides deep insight into new targets and into disease mechanisms.

The close collaboration with biology and chemistry really has allowed us to leverage chemical tools to discover novel targets and phenotypic screens. And, you will hear more about this later this morning from Klaus Hoeflich, our VP of Biology.

In order to understand our approach to drug discovery in our platform, it is really important that you understand what is unique about our library. Before joining Blueprint, I was highly skeptical about the value of the library. But, now 3 years into it, I have to say I'm really a believer. I bought into it.

Our chemists have designed a truly unique and diverse collection of kinase inhibitors that is very differentiated from other libraries and other publicly available molecules. They used rational design to balance potency and selectivity with novelty and drug-like properties to achieve broad and deep kinome coverage.

And, this is shown here on the right. The majority of kinase within a kinome are covered by at least one or 2 scaffolds in our library and many more are covered by two, three, or more.

But, what is truly unique about our library is just annotation and what does that mean? That means that every single molecule we make is screened against a panel of 450 kinases, so that gives us potency and selectivity of that molecule against the 450 kinases.

This annotation is incredibly helpful and captured in the database that was [technical difficulty] by our computational scientists at Blueprint, which allows us quick access and mining of the data. The majority of kinases in a kinome are covered by at least 1 or 2 scaffolds in our library, and many more are covered by 2, 3, or more.

But what is truly unique about the library is its annotation. And what does that mean? That means that everything single molecule we make it screened against a panel of 450 kinases, so that gives us potency and selectivity of that molecule against those 450 kinases. This annotation is incredibly helpful and is captured in a database that was built by our computational scientists at Blueprint. This allows us quick access and mining of the data.

The annotated library really has allowed for a differentiated drug discovery approach that is very accelerated compared to the traditional approach. In a traditional approach, a target is selected and then it is required to set up assays and to run high throughput screens or other screens to identify hits. These hits then come with little information, only the information against the target of interest but not necessarily against off-targets that one needs to consider, so additional work is needed. Other assays need to be set up to prioritize those hits and select which ones to take forward.

At Blueprint Medicines, all this information is available to us at the onset and up front. If we pick a target, all we have to do is to look in the database that contains the information of our annotated library and to ask do we have any stating point? Do we have selective inhibitors? Do we have potent inhibitors for that target, and how does the selectivity profile look like against the rest of the kinome? This allows us to quickly prioritize hits and take them forward.

Our approach cuts about 12 to 18 months from the traditional approach. And I am proud to say that the fastest we've ever gone is less than a year from program initiation to development candidate, and compare that to industry norms of 4 years plus.

Our library provides potent and selective starting points, but additional work is required to optimize to a development candidate. And here we heavily leverage structured basic designs and computational chemistry to do so, and that has allowed us to go after challenging target profiles. A prime example of that is BLU-782, the ALK2 inhibitor, the highly potent and selective ALK2 inhibitor that we just licensed to Clementia now, an Ipsen company.

Another example is shown here on the left. Here you're looking at the alignment of 2 very closely related to family members, so-called paralogs, and they're largely identical except for the those green areas. What you can probably appreciate, looking at the ATP binding pocket, is there's no green in that pocket.

So that makes it extremely challenging to achieve selectivity. Here we had to leverage heavily our computational biophysics approaches such as molecular dynamics and to look for solid confirmation all changes in the binding sites between the 2 close paralogs to find a selectivity handle. We successfully did so, and we achieved unprecedented selectivity for one paralog over the other, something nobody else has achieved. I'm looking forward in the future to talk about that in more detail and will reveal what target this is.

Going from a target to a development candidate to clinical proof of concept requires the close collaboration of many different functions. One thing we really excel at Blueprint Medicines is the close integration of those functions and how they work together in a very seamless way to bring forward the most promising experimental medicines to patients. Having worked in the life-sciences for 20 years in big pharma -- in big companies and small companies, I can attest that this is truly unique.

And it works both directions. We can take insights from our ongoing clinical trials and bring them back to the lab in a true bedside to bench manner to act upon and to further optimize surgeon profiles. A prime example for that is BLU-263. That was designed based on insights from avapritinib, and there are several other examples we are not covering today.

In the next few minutes, I want to show you how our past and current efforts really have enabled us to tackle the evolving cancer landscape, and how our programs built on each other and how we have learned to leverage synergies between those programs to really make rapid advancements.

A cancer driven by a single genetic mutation is a prime target for a highly potent and selective inhibitor. And avapritinib, which is targeting the KIT D816V gene mutation, the sole driver in systemic mastocytosis, as well as PD GIST receptor alpha D842V, the sole drive in PD GIST receptor driven GIST, is a prime example of the potential and impact on patients a highly selective and potent molecule can have.

The response rate we have seen and the duration with avapritinib really allowed us to get early clinical proof of concept and focus our efforts. For my job, it's incredibly fun to see when a preclinical hypothesis really pans out in patients and makes a difference for patients. I mean, that's why I do what I do. The data we generated with avapritinib have truly validated D816V as the driver of systemic mastocytosis.

And you have heard this morning from Dr. Akin and from Andy and from Christy about the very promising data we have generated there, and also early evidence we have that avapritinib might be beneficial for patients with more chronic and indolent disease.

So to make sure that we get the best possible benefit for the indolent and chronic diseases, we looked for a molecule that is very similar to avapritinib and has equal potency to avapritinib against KIT D816V, as you can appreciate on the table on the lower right, but that has improved selectivity and has lower or no CNS penetration.

This resulted in the selection of BLU-263. And you have heard about this morning we are planning to submit an IND in the first half of next year to take this forward, a very exciting and a very nice example of how we learn from our own clinical programs.

So we talked about earlier quickly that cancer evolves over time and acquires additional mutations, so this was on the forefront of our mind when we designed pralsetinib, our RET inhibitor for RET driven cancers. Here we wanted to make sure not only to capture the initial activating mutations, but also capture the fusion proteins that lead to transformation in RET cancers and, even more importantly, be prepared should resistance arise. And we wanted to make sure that potential resistance mutation in the gatekeeper RET [inaudible] would be covered with our molecule.

So pralsetinib met this with flying colors. It's sub nanomolar potent against all these variants I just described to you, and it's the only RET inhibitor that is truly equi-potent against those variants. The [inaudible] profile has so far translated very well to create benefit for patients in responses and duration of responses.

I'm highlighting here medullary thyroid cancer with a RET gatekeeper V804M mutation that we treated with pralsetinib. That patient had a partial response that deepened over time, which is really amazing to see, how over months the tumor continued to shrink and has lasted so far more than 19 months. This an example where our biochemical data really translated into what's happening in the patient. That's always very rewarding to see.

The experience we've gained with pralsetinib not only in medullary thyroid cancer but, also importantly, in non-small cell lung cancer really gave us a very good understanding of non-small cell lung cancer. And this knowledge is really beneficial for 2 of the new programs we are announcing today in mutant EGF receptor driven lung cancer.

Mutant EGF receptor is one of the major drivers of lung cancer, and several generations of inhibitors have bestowed great benefit on patients with EGF receptor driven non-small cell lung cancer. Osimertinib is also known as Tagrisso. It's probably the experimental medicine with the best benefit so far in patients in terms of response rates and duration.

Not expectedly, even with such a great medicine as osimertinib, resistance evolves, and it has been -- resistance mutations to osimertinib have been described, on-target resistance mutations as well as off-target. But the on-target ones at the ones we are very interested in, and they fall right in our wheelhouse to target challenging profiles that are not easy to capture.

So we are at the moment developing highly potent selective inhibitors against osimertinib EGF receptor resistance mutation. And most importantly, our goal is that they are highly selective over EGF receptor wild type and to avoid any undesired side effects, and that they are enabled for CNS activities to capture for any metastases. So Tim, our VP of -- Senior VP of Chemistry, Tim Guzi, will take you through those EGF receptor programs in a little bit in the next session.

I just wanted to also highlight some other cancers that are much harder to tackle. The net I've shared with you so far, they always -- they are examples of where targeting a single driver has a profound and lasting impact on the tumor, however, that's not always the case. In the majority of the cases, it is way more complex and one needs to resort to other approaches such as combination therapies or cancer immunotherapy to tackle those complex cancers.

Hepatocellular carcinoma is an example of the latter. It's a very difficult to tackle cancer, and we have developed fisogatinib, our highly potent FGFR receptor inhibitor for FGF19 positive HCCs. We were the first to show -- to develop a biomarker assay to enrich for patients that have FGF19 expression and to show that this selection really recited in response and only in those FGF19 positive cancers, not in others.

We saw a response rate of about 17%, which is really promising and exciting for this patient population. However, it's not on part with what we've seen with avapritinib or pralsetinib. We're a bit spoiled at Blueprint Medicines. So we always try how can we do better, and here we went back to the lab and we asked are there other approaches we can try.

So in elegant preclinical studies, we have shown that treatment with fisogatinib leads to high infiltration with T cells into the tumor, suggesting that the combination with a T cell checkpoint inhibitor could be beneficial. This prompted us to start a combination study of fisogatinib with an anti-PDL1 inhibitor from our biotech partner in China, CStone, with their molecule CS1001. The R&D for this combination study was approved in China, and we are hoping to start a trial very soon in Q4 2019, in this quarter.

Another way to go after complex tumors is to evaluate how far cancer immunotherapy from the get-go can tackle them. And here our collaboration with Roche really enabled us to explore cancer immunotherapy as an approach. In this collaboration, we are targeting kinases to enhance immune response against cancer, and we have made tremendous progress there thanks to this very close collaboration of 2 different sciences -- group and medicine scientists with Roche colleagues.

And today I am really thrilled that for the first time we can share some of the progress on that collaboration by introducing one of the targets we are pursuing in collaboration with Roche. And that's MAP4K1. It is a negative regulator of T cell function that is of incredibly high interest as a target in cancer immunotherapy and has been well validated in preclinical models using genetics.

So in the last session today, Klaus Hoeflich, our VP of Biology, will walk you through more details of this program and share this incredible progress we have made there. We are very excited because this could potentially be a first in class, best in class opportunity and capture a large patient population.

I am extremely pleased with the progress we have made at Blueprint Medicines to advance experimental medicines to patients in need. This was enabled by our focus on the transformative benefits, by our keen sense of urgency that drives us every day, and by the efficient model of drug discovery that we have established at Blueprint Medicines that allows us to do it over and over and over again. The new programs we are sharing today clearly demonstrate not only the versatility of our platform, but also the depth and the breadth of our portfolio.

I am going to end with our milestones for next year. We are planning to submit an IND for BLU-263 in the first half of next year and we're planning to name 2 development candidates. One is the MAP4K1 inhibitor and the other one is one of the non-small cell lung cancer EGF receptor group inhibitors. And you will hear more detail about that later.

So now we're going to shift our focus to our lung cancer programs, in particular the non-small cell lung cancer program. But before we do so, we would like to start the session with a patient video.

[Presentation]

[Marion Dorsch, executive]

So with this inspiring video, I would like to introduce Tim Guzi, our Senior VP of Chemistry. And he will share how we are planning -- or we are already making and planning to make further impact on non-small cell lung cancer.

[Timothy Guzi;Senior Vice President, Chemistry, executive]

Thank you, Marion. I think these patient stories serve to really remind us why we do what we do and actually serve to motivate us even more to do it more quickly and more efficiently.

So what I'll tell you about today is our effort to address tumor evolution in lung cancer. The goal of targeted therapy is to match the right patient with the right drug at the right time. Since the identification of EGFR, non-small cell lung cancer has become the proving ground for targeted therapy.

This is due to the wide variety of identifiable oncogenic drivers that are found within the disease, many of which are kinases, which people believe make things easier to do from a drug perspective. We'll talk about some profiles later that may challenge that assumption.

Implicit in successful targeted therapy is the ability to identify the appropriate patient. Within non-small cell lung cancer, the testing paradigm has also undergone a significant evolution, with now the majority of patients being tested upon diagnosis for EGFR and ALK aberrations.

Additionally, as we think about mutations in resistance, patients also now are more frequently undergoing biopsies, both core -- both tumor biopsies as well as testing by plasma-based methodologies, to be able to understand what the mutational profile of their tumor looks like. Even with these advancements, lung cancer, specifically non-small cell lung cancer, also remain a leading cause of cancer deaths globally.

The reason for this can be traced back to the molecular heterogeneity that's found within the disease. Following an initial activating event, the tumor rapidly increases in molecular heterogeneity. When treated with a first-line agent, patients undergo -- can undergo a rapid response to treatment. However, over time, resistance does emerge because of the presence of clones that are resistant to the initial therapy. This cuts into the achievement of durable patient benefit.

We see and others see, basically 3 ways to overcome this tumor heterogeneity, control the evolution, and really achieve even greater durable benefit. The first is optimized first-line therapy. Here what we're talking about is what Jeff referred to, is identifying really specific inhibitors that can allow great target inhibition. Coupled with that, we are also looking to inhibit prospective resistance mutation so that we can give a longer period of time before resistance clones build out.

Secondly, once resistance clones do occur, we think we can think about the second generation inhibitors that target very specific mutations. We can use these in sequence with the optimized first-line therapy to even give longer patient benefit.

And lastly, there's combinations. In this effort, we can combine first-line treatment was second generation inhibitors to target complementary mutations. We can also think about first-line treatment coupled with bypass -- inhibitors that target bypass mechanisms to actually expand the reach in the number of patients that we can treat.

What's really key for success in each of these 3 approaches are the inhibitors you use, and potency and selectivity is really the drivers that allows us to achieve optimized first-line therapy, sequential therapy, and then effective combination. We believe at Blueprint, as Marion just told us, that we have a platform that can deliver on each of these approaches to really drive patient benefit across different tumor types.

So our entry into non-small cell lung cancer began with our RET fusion inhibitor program. Since the identification of fusions -- RET fusions in non-small cell lung, there's been really no effective treatment options to give to patients. Chemotherapy showed low response rates and high toxicity. The preliminary evidence around the effectiveness of checkpoint inhibitors has been limited, as it has been in other molecular drivers of non-small cell lung, and the multi-kinase inhibitors that were out there happened to inhibit RET as one of the kinases they hit amongst others. And they showed really minimal activity and high levels of toxicity.

When we initiated this program, we put forth a hypothesis that a very highly potent compound that was selective against the kinome, that had equal potency versus the prospective gatekeeper resistance mutations, as well as potential for brain penetration to control CNS metastases could provide a transformative medicine.

We set about a research program to do this. We've discussed this in past meetings both from the discovery perspective and clinical perspective. And the fruit of that effort was pralsetinib. This compound achieved everything we were trying to do within that inhibitor program. It's highly potent. It's highly selective. As Marion showed us, it has equal potency versus the gatekeeper -- the prospective, predicted gatekeeper resistance mutations that could arise and, well not shown here, showed preclinical evidence of control of CNS metastasis in mouse models.

As we progressed pralsetinib through preclinical development and to clinical development, we were gratified to see that our hypothesis held true. Pralsetinib shows substantial antitumor activity in RET fusion positive patients with advanced in non-small cell lung cancer. Pralsetinib shows evidence of durable CNS activity against intracranial metastases in the clinical setting. It is this case report shows, it shows the potential for combination therapy.

In this report, we highlighted a patient, an EGFR positive patient who progressed on osimertinib. It was found upon re-biopsy that he harbored a RET fusion mutation. Treatment of this patient with a combination of pralsetinib and osimertinib gave, as you can see, a partial response of 78% tumor reduction, all with an acceptable tolerability profile.

With this data and the other milestones that are highlighted on the slide, we believe that pralsetinib has the potential to be a best in class inhibitor for RET fusion positive non-small cell lung cancer patients. Additionally, pralsetinib will form the cornerstone of our strategy in lung cancer as we work to use our effective research platform to extend our reach to other molecular drivers.

The development of pralsetinib actually helped us put forth a roadmap to transform -- to potential transformative benefits. In EGFR mutant cancers, osimertinib followed the same roadmap. This is been a transformative medication both for patients who harbor the T790M mutation as well as, more recently, patients who are treated first-line.

Truly, osimertinib has been a transformative medicine in EGFR driven disease. However, like most kinase inhibitors, resistance does emerge. And that resistance -- the resistance profiles are unique and represent an unmet need in EGFR driven lung cancer.

I'm really excited today to take you through a little bit of our thinking and our research efforts around to first in class EGFR inhibitors for the treatment of osimertinib resistant non-small cell lung cancer. Before we do that, we should back up just a little bit. When we start to talk about all these different mutations, especially in EGFR driven, it can get confusing. We throw around Exon 19. We throw around LR. So what I'm going to do is simplify a little bit just to focus on the mutations we're trying to treat.

When patients present with a mutation in the EGFR, there's actually 2 predominant mutations. There's the deletion in Exon 19 and a point mutation at the L858R position. For simplicity's sake, we'll just call these EGFR positive and not have to walk through and say those every time I talk about the resistance mutations. I can, but it'll take me twice as long to do this talk.

Following first-line treatment with osimertinib, the predominant on-target resistance mutation is a C797S mutation. Osimertinib is an irreversible inhibitor and forms a covalent bond with Cys15, which is the predominant mode by which potent activity is observed. When this mutation arises, osimertinib loses affinity for the protein, and hence this -- patients with this mutation can progress on therapy.

Following second line osimertinib, remember second line patients harbor a T790M gatekeeper mutation, patients also show a similar C797S mutation. We'll call this TMCS. For both of these mutations, there is no approved therapy out there, and they represent an unmet patient need. Additionally, for both of these mutations, they represent a significant medicinal chemistry challenge because the goal is to try to get a highly potent inhibitor that spares wild type. That's a key part of our profile.

We therefore decided to take the strategy, rather than try to blend everything to one molecule, to create 2 very potent, very selective inhibitors that we could use a different stages of disease progression. The first one I'll tell you about today is our effort on the TMCS mutation. This would be used following osimertinib progression in the second line.

Again, the profile -- and you'll probably hear me say this so many times you'll get sick of me saying it. The profile is a highly potent and selective inhibitor that spares wild type and also has the potential to treat CNS metastases. As we typically do, we looked into our library to identify robust starting points that could achieve this profile. What we found is a series of compounds that with some significant optimization led to BLU-4810, which is shown on this slide.

BLU-4810 is representative of this series, and is a selective, reversible EGFR inhibitor of the TM and TMCS mutations population. You can see on the left the biochemical profile of BLU-4810; again, a very potent molecule. And you can see with the blue line the selectivity that this compound has for wild type. This compound also demonstrated similarly, although not shown here, a similar profile in cell experiments, both showing a similar level of potency as well as selectivity.

We wanted to progress this compound in vivo to see how it would behave and understand the PK/PD efficacy relationship that we would need, importantly, for a reversible inhibitor. Treating mice who were implanted with an H1975 xenograft model, which harbors the TM mutation, we found that, upon increasing concentrations, we were able to completely inhibit EGFR signaling.

This is an extremely potent compound, and you can see that the unbound plasma IC50 is 1.3 nanomolar. When treated -- when mice treated at 100 MPK, we were able to actually completely suppress, or get greater than IC90 levels of inhibition, over the course of a 12 hour dosing period.

With this information in hand, we moved BLU-4810 into an efficacy study. And we were able to show that when we suppress the pathway with greater than 90% inhibition, we showed levels of activity that were similar to that of osimertinib. This is important to us because we had not seen this -- it has not been seen with a reversible inhibitor to date.

The other thing that we wanted to really look at, because the patient population is the TMCS mutation, is how this compound would fare against models with that mutation. We were able to identify a PDX model derived from a patient who'd undergone multiple courses of treatment. This model was resistant to erlotinib. It was resistant to osimertinib. It was actually resistant to the combination.

When we treated mice implanted with these tumors with a similar dose that we've previously discussed of BLU-4810, we were pleased to see regression within this model showing that this compound was also effective against the TMCS mutation. This is important not only to qualify this compound, but also to give us further evidence that patients who harbor this mutation even after 7 lines of previous therapy are still sensitive -- still have sensitivity through EGFR for control of their disease. We continue optimization of this program, and we hope to nominate a development candidate in the near future.

The second program that I'd like to talk to you about is our CS mutation program, which will follow off osimertinib in the first line. Again, what we're looking for here is a compound that has a high degree of potency for EGFR, maintains a high level of selectivity versus wild type, and has the potential for treating patients with CNS metastases.

Again, we looked into our library to look for a profile of compounds that would have the potential to achieve this profile, and we were pleased to find several different series of compounds that could do this. On this slide, you can see representatives of those series compared to the first generation erlotinib and gefitinib as well as the third generation osimertinib.

These series show significant -- show equivocal -- equivalent, excuse me, potency to both of these -- to gefitinib, erlotinib, and osimertinib, but importantly show an increased level of selectivity with all 3 previous agents. These series have favorable properties, and we believe we can rapidly optimize them to compounds with best in class potential. And importantly, representatives of each of these series show significant brain penetration, giving us hope, optimism, showing us that there's a potential to be able to CNS derived disease.

With these 2 programs, we're really executing on our vision to be able to provide high-quality EGFR mutation inhibitors regardless of prior therapy. With osimertinib is used in the second line, we will provide a TMCS mutation inhibitor to be able to provide patients who have progressed on osimertinib an option. When osimertinib is used third line, we'll be able to provide a different EGFR inhibitor, again to give patients and providing physicians optionality for how they treat their disease.

Depending on the profile of these agents, one could also envision a rational combination of the 2 to really drive durable benefit in the second line and, again, depending on what we see as these progress, potentially giving patients opportunities or options to osimertinib in the first line.

Based on these efforts, based on our identification of BLU-263 and based on the previous 4 clinical compounds that we have developed, we believe that our platform has the unique ability to create high quality, high potency, effective kinase inhibitors for both these -- for various tumor types and patient populations.

I'll now turn it over to Klaus, who will take you through a different approach in our efforts in cancer immunotherapy.

[Klaus Hoeflich;Vice President, Head of Biology, executive]

Usually in the scientific meetings you get applause. So good morning, everyone. My name is Klaus. I led biology at Blueprint. And so what we've been discussing so far today is the heartland of our R&D activities, which is namely targeting clear genomic drivers in disease. And so now I'd like to turn our attention to something that is very complementary and update you on our recent progress in the field of cancer immunotherapy.

So as we know, there are 2 general categories of immunotherapy, and these are tumor-targeted and non-tumor targeted therapies. And so the tumor-targeted therapies include CAR-T and by specific antibodies, for example, and these show clinical benefit but they can be challenged by both manufacturing and also safety. And non-tumor targeted therapies, these include our checkpoint inhibitors, which are antibodies against CTLA4 and also the PD-1 axis, and these ultimately serve to increase the activity of T cells within the tumor microenvironment.

So when you look at this slide, you see the approved immunotherapies and the tumor types in which they are utilized. And one thing becomes immediately apparent, and it is that these are all biologics. No small molecules have been approved. In fact, investigation of small molecules for intracellular targets has very significantly lagged in this field until very recently.

And that is where Blueprint, our research teams and our discovery engine, come into play. And the reason for that is that a number of the very best intracellular targets are actually immunokinases, and these are right up our alley. And these immunokinases have unique modes of action that are distinct from the approved therapies. And just by the fact that these are small molecule programs, you can imagine different dosing regimens can be applied in the clinic, and this will be helpful both in the context of a single agent treatment but particularly in the context of combinations.

And so I feel that this new area is very complementary to our main focus on precision medicine because those mutations in driver genes that we love to target are the same mutations that increasingly make the tumor more non-self. And non-self is an immunological term that refers to the ability of the immune system to see the tumor as being foreign and thereby begin to mount an anti-cancer response.

And this concept is fundamental to the entire field of immunotherapy. And given our genomic focus, I feel that these 2 areas fit together like a hand in glove. And what makes me motivated as a scientist is that this approach has the potential to help many patients across multiple tumor types.

So we began working with Roche about 3.5 years ago. And Roche has deep experience in the field of immunology, and they have a rich portfolio of various immunotherapy agents. And they partnered with us for interesting reasons. It was our kinase expertise, the speed at which we do drug discovery, and being a precision medicine company, we had ideas on how immunotherapy could eventually become more personalized.

So when we started, there were 2 parts to this collaboration. And the first part was to get going and start on some immediately actionable targets whose validation largely came from genetics. And the second part was to harness our expertise in chemical biology and do cell-based phenotypic screens with our tool compound library to hopefully identify additional novel targets. And I'll talk about that more on the next slide.

I'm very proud today to tell you that we have prioritized 4 programs in the collaboration, and on the bottom right-hand side of the slide you can see the mechanisms that we target. And these mechanisms are interesting and important. And ultimately what we are trying to do is to recruit more immune cells into the tumor and reboot their activity so that the efficacy can be more profound and longer lasting.

So in Marion's introduction, she introduced the tool compound library and one of the key adjectives that we use to describe it, and that is annotated. The vast majority of our compounds are profiled biochemically against every kinase for which an assay exists. That's a lot of data, but what that gives you is a priori information not just on the potency but also the selectivity profile, the profile across the kinome as a whole.

And whenever we find a compound that is uniquely selective against a novel kinase or one that is significantly understudied, we pull that compound out and put it into our toolset. And so our toolset is extremely well characterized, and that is valuable when you go into biological systems that are very nuanced or also complex and not amenable to high throughput.

And that's what we did here with the Roche collaboration. Together we built assays using primary cells and different co-culture systems. And the idea was that, if there is a kinase that's yet to be discovered that is important for specific cell type or a specific cell function, that we would be able to find it.

And those hits were put through an extensive de-convolution and the various follow-up processes, including cross-validation. On the right-hand side I show a CRISPR experiment that supports a result obtained with a compound. Usually this process is challenging. And we all know that screens often do not deliver hits. But I'm glad to say that 2 of the 4 programs in the Roche collaboration have come from these cell [inaudible].

So we talked about the why and also the how, so let's move on to the what and discuss our new target, MAP4K1. So MAP4K1 was originally identified in efforts to understand drivers of a differentiation of blood cells. And MAP4K1 is a negative regulator of T cell responses. In other words, it acts as a brake.

This kinase is very proximal to key transcription factors. And when you inhibit this kinase, you drive the over expression of various cytokines that have been proven to be essential for antitumor activity. Now much of what we know about this kinase actually comes from genetics. Either the gene has been knocked out or the patients that render the gene product inactive have been knocked in.

And this is valuable in 2 ways. Firstly, it helps verify the biological mechanism. And secondly, it helps us set the bar to which our compounds need to achieve. And both of these are very useful for drug discovery.

Now some of you may know that this target has been known since 2004, and our knowledge of this space has steadily increased over 15 years. So maybe you ask the question, why is it that no one yet has brought a MAP4K1 inhibitor to the clinic? And I would like to convey to you that there are significant scientific challenges that need to be overcome, and I'll tell you about one of these.

So the MAP4K family of the kinome consists of more than 20 members, and these family members are very similar to each other and almost identical in the ATP binding pocket. In other words, there are no easy structural handles to exploit for selectivity.

But yet selectivity is a must because some of those family members, if inhibited in an off-target manner, would be predicted to cause deleterious consequences and also adverse events in patients. So that is a significant challenge. And it's a challenge also for Blueprint, but honestly, it feels like the type of challenge we should be working on.

So what did we do? Well, we started with the library, but we supplemented with various computational modeling, design, chemical synthesis, and biological testing, and that process we iterated many, many times. And now we are at the point where our pharmacologic agents thoroughly recapitulate the genetics both in vitro and in vivo.

And so on the right-hand side I show an interleukin 2 response curve that looks very nice, and the level of interleukin 2 induction is concordant with the extent of target inhibition. So what does this look like in the context of tumors?

Well, we've run various syngeneic models, and I show just a few of them here. On the Y-axis is tumor volume. On the X-axis is time. And if you look at the red lines, you can see that inhibition of MAP4K1 blocks the growth of tumors to an extent greater than the inhibition of PD-1 or PDL1.

In the middle, we did a very important controlled experiment. We repeated the exact same sarcoma study in mice that were compromised in their immune system, and gratifyingly we saw no change in tumor volume. This proves that the mechanism of our compound is linked to regulation of the immune system and we're not being confounded in our efficacy readout by other activities. And then we've run, of course, other syngeneic models, and you see a similar result.

Now when we look more closely at these tumors by flow cytometry or by gene expression analysis, what we observe is an increased infiltration of CD4 positive and CD8 positive T cells into the tumor. And this can be seen by the dot plot when you compare the red with the blue.

And importantly, these lymphocytes are active. And we know that because they express elevated amounts of key proteases and poor forming proteins that we know are essential for tumor self-healing. And we've been digging into this approach much more with the hopes of uncovering novel insights into MAP4K1 biology.

And so for example, we've been doing NanoString's platform for a while. It monitors 770 genes at the same time. In the middle, I show a volcano plot. On the Y-axis is an adjusted P value score that represents differential gene expression. And you can see that there's a number of genes that are changing.

And some of these genes are associated with a function of T cells, as we would predict, but other genes point to a role of MAP4K1 in different immune cell subtypes. And that's very intriguing and we're following that up. And we're doing it in an innovative way also by single-cell genomics.

Moreover, we are working to build a bridge from the lab into the human system. This is an example of lymphocytes that are purified from a lung cancer patient, purified from both the tumor as well as the circulation. And in this ex vivo experiment, when we inhibit MAP4K1, we see an induction of interferon gamma and also interleukin 2 exactly as we would predict from the lab models.

We've also established a number of key collaborations to further build the link to human biology, and these experiments will be informing our clinical plan going forward.

So what I've told you today is I've shared some of the data on MAP4K1. It's the flagship program in the Roche collaboration, but the other 3 that follow this project are of equal caliber and equal interest. Our goal is to nominate a development candidate in the next several months.

And I'll just conclude by reiterating kind of some of the principles of our discovery group. Our goal is to identify and accelerate projects with a high probability of technical success, do it in a way that is efficient and also sustainable given our current resourcing levels, and where possible, be clever in evaluating platform expansion opportunities. I definitely look forward to the next time when we can share more data because there is more to come.

Then I'll just show a photo of the team. And this was taken at a recent patient event at the Blueprint offices. And with that, I will stop and say thank you very much for your attention.

[Jeffrey Albers, executive]

Tim is not going to like that Klaus got clapped for. You guys stay up here. Marion and Tim, why don't you come up and we'll do a short Q&A. I know that everyone's got busy schedules so we'll keep that to a few minutes and then I'll wrap up.

I will say personally I always like it when these guys present, and they always work in that the targets are hard. I'm told that constantly. And it's also that piece that I like of stretching out the progress we've made, and it's nice to take an opportunity and celebrate how these programs have moved forward and have an opportunity to share that with you. So questions?

[Michael Schmidt, analyst]

Hey, Michael Schmidt with Guggenheim, just a question on your 2 EGFR inhibitors. Just from a positioning point of view, is that something that you see positioned as an agent that could be used broadly in a second and third line EGFR setting, or is it something that was specifically developed for the CS mutation subpopulation?

[Jeffrey Albers, executive]

Maybe I'll start and you guys can feel free to chime in. So part of the opportunity here is that rapidly evolving landscape. So Tim highlighted how that triple mutation emerged when osimertinib was a second line therapy. As osimertinib, particularly in the U.S., has moved into a frontline treatment opportunity, then that mutational sequence changes a bit.

So where we're focused on a start is when the resistance emerges, so it's a very selective opportunity. In terms of scope, I think about these, given the greater frequency of EGFR, of similar in opportunity to say pralsetinib by the time you think about the percent of patients who get a specific on-target resistance mutation.

So then Tim also highlighted that, with the 2 molecules, there's a potential to think about really fully inhibiting the spectrum of on-target resistance that could emerge, and that would be an opportunity to move into earlier lines. But we'll start with that selective resistance opportunity.

[Timothy Guzi;Senior Vice President, Chemistry, executive]

Can I say one thing?

[Jeffrey Albers, executive]

Of course.

[Timothy Guzi;Senior Vice President, Chemistry, executive]

They're not dependent on the CS mutation.

[Andrew Berens, analyst]

Andy Berens, SVB Leerink. With the MAP4K1 drug, are you expecting to see single agent activity, or do you think it's going to be mostly combination?

[Jeffrey Albers, executive]

Klaus, you want to take that?

[Klaus Hoeflich;Vice President, Head of Biology, executive]

So our preclinical data so far supports that single agent activity may be possible. Those 2 models that I've shown are models that PD-1 was traditionally regarded as active in. So if you translate that forward, it's potentially encouraging. But obviously, the way the IL field works, there are various checkpoints that are part of standard of care, so we're going to build that into our clinical plan.

[Andrew Berens, analyst]

On the BLU-4810, the dose that you're showing there was I think 100 milligrams BID in those animal models versus in traditional EGFR some of them there were 5 or 10 milligrams. I guess is that where you're really continuing to optimize before select it, is trying to get -- is that a more potent molecule you're looking for, or is it better bioavailability? Where is the test going now?

[Timothy Guzi;Senior Vice President, Chemistry, executive]

So there's 2 things that are important there. Yes, there is always continuing optimization to work on the breadth of the profile in terms of anti properties in BM/PK. We tend not to read too much into the dose in mice. It is a mouse. It's not a human. And so as we translate compounds from the preclinical setting to the clinical setting, we do a lot of modeling to understand how profiles will translate clinically. So there is continuing optimization ongoing around those parameters.

[Jeffrey Albers, executive]

Okay. Why don't you guy stay here and I will wrap up with some brief comments.

So first off, we announced our quarterly financial results, and so I'd be remiss not to put the financial slide up here. I would say the takeaway, given everything we've been focused on today, is really that we continue to operate from a strong financial position, with updated cash and cash equivalents of $594.5 million. Those exclude some recent milestones that were also included from Clementia as well as from Roche.

I just wanted to pause here as we think about our lead programs and taking those forward. And so obviously we've focused on systemic mastocytosis as an opportunity broadly today. And that's for good reasons, that we think we have a clear opportunity to be first in class and best in class within systemic mastocytosis and identify an increasingly broad range of patients.

But when I look at and reflect on the breadth of opportunity that we have in the near term, this is really uniquely positioned that we continue to make tremendous progress with our pralsetinib program. And we understand there that speed is of the essence because of the competitive landscape. In GIST, we continue to identify patients who are most likely to benefit from treatment with avapritinib and better understanding and characterizing the specific mutations within each patient's tumor to help create the most durable, long term effects.

And so when I think back of when I joined Blueprint 5 years ago, coming from more of a commercial background, having this type of opportunity is incredibly rewarding and exciting for us, that we understand each program has different risks but also different opportunities, but collectively we can't lose sight of the forest through the trees.

And I know these scientists would make fun of me from that perspective. I often say it's why I like hanging out with all of you as investors because you share that sentiment of what's coming next. But I think what's great about an R&D Day is it allows us to step back and look at that broader picture.

And to that same end, as I think about the pipeline we now have, I'm reminded of when we went public 4 years ago, with 2 development candidates and 1 early -- relatively early stage research program, which is now pralsetinib. And when we talk about the 4 new molecules that we've unveiled today and the opportunities that those program have to create the next wave of therapies that could potentially help patients, it's incredibly rewarding.

And obviously, these types of days take a lot of your time, and we appreciate you spending that and sharing that with us today. But also know that it motivates us to make sure that we continue to drive that research so we can share the next wave of programs and provide updates on the programs that we introduced to you today.

So again, thank you for coming. We'll stick around for a little bit to answer any additional questions. But again, look forward to further updates and hopefully seeing you at ASH in the not so distant future. Thank you.