Blueprint Medicines — Episode Transcript

Chapters
00:00:00  Introduction & Hook
00:03:21  Third Rock Ventures: The Venture Creation Model
00:16:07  Blueprint's Science: Kinase Selectivity & Gleevec
00:23:45  Blueprint Is Born: Founding & Early Challenges
00:27:06  The Platform: Building the Kinase Library
00:34:33  Near-Death & Series B: Running on Fumes
00:42:49  IPO & Clinical Programs: The Platform Pays Off
00:50:19  The Pivot: From Cancer to Mastocytosis
01:00:20  Clinical Wins, Commercial Struggles & Kate Haviland
01:24:31  FDA Approval & Diagnosis Ecosystem
01:35:35  The Sanofi Deal: A $9B Acquisition
01:53:25  Competition: Cogent Biosciences & Bezuclastinib
01:57:45  Post-Acquisition & Curie Bio: The Next Generation
02:15:31  Blueprint vs. Bluebird: A Tale of Two Platforms
02:21:12  Scorecard: Patient, Financial & Academic Impact
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[00:00:00] Introduction & Hook
[00:00:00] Matt: Welcome to Approved, the definitive stories behind the world's most interesting biotech ventures. Each episode, we follow a company from founding through FDA approval and commercialization and cover all the drama that happens in between. I'm Matthew Pech, a cancer biologist and drug hunter based in Oakland.
[00:00:17] Alex: And I'm Alex Kesin, a biotech writer based in San Francisco.
[00:00:21] Alex: Hey, Matt. What if I showed you a dashboard, and every time you wanted to drug a new target, it instantly generated a list of potent selective molecules?
[00:00:30] Matt: Man, that would be amazing. I've worked on so many first-in-class programs where that would have saved us years.
[00:00:36] Matt: Kinda sounds like what a lot of AI native drug discovery startups are chasing right now, things like one-shot antibody generation and hits directly from an AlphaFold generated structure. It's definitely interesting to think about how that would change the sort of life science company that you would build.
[00:00:54] Alex: Something like that would be the Holy Grail, wouldn't it? Here's the good news. We don't have to theorize about how that style of platform plays out. There's one company that built exactly that back in the early twenty tens. It was called Blueprint Medicines. And I mean, they genuinely built this kind of platform, spending what was considered a ludicrous amount of money at the time, ten million dollars, to pre-screen every kinase against its own proprietary inhibitor library.
[00:01:23] Alex: And that bet paid off big time. Two approved drugs within four approved indications, all in ten years' time. That's lightning fast, maybe even a record for a life science company, and that's not even counting the fourteen-odd development candidates they nominated over their history. This platform Blueprint built accelerated going from target hypothesis to early leads by roughly a year's amount of time.
[00:01:48] Alex: Today, we unpack the full scientific and business history of Blueprint Medicines, the platform, the near death, an unexpected therapeutic area, and the massive deal with Sanofi. But that's not all because telling the story of Blueprint doesn't really make sense on its own. It's a bit like explaining the Model T without mentioning the Ford assembly line.
[00:02:08] Alex: To understand Blueprint, you have to understand the venture creation engine that built it, Third Rock Ventures, and a rival firm called Curie Bio, born from the diaspora of Blueprint and TRV that's now building what they call a more founder-friendly way to finance and operationalize therapeutic ideas.
[00:02:24] Alex: We made this episode based on new interviews with the people who built this company, Blueprint's former chairman and CEO, its academic founder, and the chemists, biologists, and clinicians who made the programs possible.
[00:02:38] Alex: By the way, if you haven't subscribed to Approved yet, take a few seconds to do that in Apple or Spotify. It's the single most useful thing you can do to support this channel, and you'll be notified every time a new episode drops.
[00:02:52] Alex: All right, let's get into it.
[00:02:53] Matt: Let's get into it.
[00:03:21] Third Rock Ventures: The Venture Creation Model
[00:03:21] Matt: Picture this. It's two thousand and six, and two guys from a drug company called Millennium are on their annual gambling trip to Las Vegas. You've got Kevin Starr, who's this ex-Hollywood finance guy, rides a motorcycle, wears skull rings, and Mark Levin, a chemical engineer who's been the CEO of Millennium for the last twelve years.
[00:03:41] Matt: They've gotten really close marketing cancer drugs together, and here they are in a casino, a couple of drinks in, just totally venting about the pharmaceutical industry.
[00:03:51] Alex: And Starr's complaint, at least how it gets retold, is pretty blunt. The patients are getting the short end of the stick, and somebody needs to actually do something about it.
[00:04:01] Alex: So they end up just leaving Millennium. They pull in a third colleague, Bob Tepper, and they basically start going on a roadshow through academic labs. And what they find, Starr actually called it jaw-dropping, is this incredible early science with real potential for translation, but zero money to make it happen.
[00:04:21] Alex: The lack of dollars was somewhat sensible. Drug discovery is expensive. The odds are bad and looked particularly bad in the mid-2000s, and a lot of traditional venture capital had just straight up walked away from biotech at this time.
[00:04:35] Matt: Right. So they decide, fine, we'll be the source of money. In 2007, they launch a fund called Third Rock Ventures.
[00:04:43] Matt: And yes, that's Earth, third rock from the sun. We're not talking about the sitcom here.
[00:04:48] Matt: They managed to close a fund of three hundred and seventy-eight million dollars in something like ten weeks, which is massively impressive.
[00:04:55] Alex: Yeah, that's, that's wild in its own right. But the timing here is just totally crazy when you put it into context because they're closing the fund in 2007, and then literally a year later in 2008, Takeda swoops in to buy Millennium, the company they just left, for eight point eight billion dollars.
[00:05:13] Alex: So the Third Rock founders are cashing out on this massive Millennium exit at the exact same moment they're standing up a firm designed to make the next Millennium.
[00:05:23] Alex: But how they do it is what makes them different. Most venture firms sit back and wait. A founder walks in, pitches their idea, and the partners decide if they wanna write a check.
[00:05:33] Alex: Third Rock does not wait. They generate the idea themselves, build the company around it, and handpick most of the leadership team. Bob Tepper actually really put it perfectly to The Boston Globe. He said, "We are a company that builds companies." He viewed Third Rock as the front end of drug discovery, launching three to five startups a year that had all been deeply planned internally prior to launch.
[00:06:00] Alex: And Starr described what getting involved actually looks like on the ground. The partners don't just advise. They step into the real jobs. They act as CEO, the chief scientist, the COO for those early months and years. In the early days of a given Third Rock company, the firm would supply all the scaffolding a startup would normally have to scramble to build itself: lab space, HR, legal templates.
[00:06:25] Alex: That way, the scientists just spend their time on the science.
[00:06:29] Alex: And from the academic side, that intense involvement didn't feel restrictive. It actually felt really freeing. We asked one of Blueprint's scientific co-founders, Charles Sawyers, what it was like to be incubated by Third Rock. And from his perspective, he loved it.
[00:06:45] Charles: I was very impressed with how they think.
[00:06:47] Charles: You didn't have to have a very clear, solid set of project one, project two, project three. They just believed in the idea and the right people, and it would come.
[00:06:59] Matt: Charles is spot on here, but Third Rock obviously isn't just writing a blank check based off of good vibes and bona fides.
[00:07:07] Matt: To actually get greenlit, those ideas have to pass a very specific internal rubric to prove that they can be commercialized. What do they call it, Alex?
[00:07:17] Alex: Third Rock Ultra Killer Kriteria. Spelled with two K's on purpose.
[00:07:21] Matt: That's right. And, uh, that's kind of, kind of amazing. And so for a company idea to clear TRUKK, a project really had to have three things.
[00:07:34] Matt: One, it had to be within three years of hitting the clinic. Two, the preclinical data had to be reproducible. And three, it had to live in a space where big pharma couldn't just roll in and flatten you. This whole model where a firm invents the company, staffs it, runs it, and owns most of it, is called the venture creation model.
[00:07:55] Matt: I think in the tech world, it's more typically called the venture studio model.
[00:07:59] Alex: We should point out, by the way, in the tech world, that model has a historically rather lousy track record. The best tech VCs don't really do this. When you think of the famous massive tech outcomes that came out of venture capital, they're almost always from founders that firms just financially back, not from companies built within the firm itself.
[00:08:21] Matt: I mean, yeah, there's literally a VC whose whole thesis is to find great founders and just leave them alone. That's called Founders Fund, and they have exceptional returns. To be fair, maybe there's one exception, um, AlleyCorp in New York that I think they incubated MongoDB. But they're the exception that proves the rule.
[00:08:42] Matt: And, you know, if anyone in their mind is thinking about Y Combinator right now, that's really a different model, right? It's kind of a prestigious boot camp that funds founders in batches. It's not really a firm that dreams up the company and staffs it. So, you know, generally speaking, the build it yourself studio is still not where the serious tech venture firms tend to operate.
[00:09:04] Matt: In contrast, biotech is where that model has consistently worked, right? If you rank life science venture firms by DPI, distributions to paid in capital, which is a cash on cash return metric that is a really simple and important metric of fund performance, a strikingly high number of the very top funds are these company creation shops.
[00:09:28] Matt: Here, we're talking about Third Rock Ventures, but there's also Flagship, the firm that built Moderna in the exact same way. So the build it yourself model that performs terribly in software is somehow one of the best performing strategies in the life sciences.
[00:09:46] Alex: Yeah. So you may be asking yourself, what's the difference between software and biotech in terms of why biotech venture studios do so much better than software venture studios?
[00:09:56] Alex: It really comes down to mechanics. In tech, starting a company is incredibly cheap. A Founder doesn't really need a VC firm to build the product. That's why bootstrapping exists, that meaning they can hustle and create something in their garage with a laptop and an idea. On the other hand, if the idea doesn't work, you can figure that out pretty quickly and also pivot pretty nimbly.
[00:10:18] Alex: But in the early mid two thousands, era of drug discovery, it's a very different dynamic. You could spend a million dollars and twelve months to figure out that your target is wrong, and then you're shit out of luck. The R&D That goes into drug development requires so much capital, time, and talent that a vertically integrated venture firm ends up being this kind of rational place to start a biotech company.
[00:10:41] Matt: Right. So given that dynamic, the firm can take massive ownership right from the start. For Blueprint Medicines, our data indicates that Third Rock owned seventy-six percent of the company in the first round. And their goal is to retain significant ownership all the way through IPO. For a biotech, that usually happens when a company has an early amount of clinical data but is still years away from an approved product, let alone revenue.
[00:11:08] Alex: This is the pleasure and the pain of the venture creation model. Biotech is a notoriously cyclical business, with the biotech IPO window swinging violently between open and shut. When it's open, twenty twenty-one is a good example of this, all of the companies in a venture firm's portfolio can go public, and the fund vintage will do spectacularly well, making a healthy return for the fund's LPs.
[00:11:34] Matt: And when that IPO window is closed, and we don't have to go too far back to remember that, let's say twenty twenty-two through twenty twenty-four, none of your companies go public. The fund performance is absolutely atrocious, and firms go through this really difficult triaging process trying to figure out what companies to keep alive.
[00:11:58] Matt: All right, so that's how Third Rock operates, and that's their plan to make money. On the company side of the equation, many of the incubated companies have their own specific buzzword.
[00:12:09] Matt: A, quote, product engine. The dream is for the company to have a technology platform that can just churn out a whole series of products across different diseases rather than betting the entire fate of the company on a single drug. And that's exactly the model Blueprint ends up running.
[00:12:25] Matt: The Third Rock Ventures crew came in with scar tissue about the right and wrong way to build one of these.
[00:12:31] Matt: Mark Levin had lived the cautionary version of this at Millennium. Millennium launched as this sweeping genomics platform meant to industrialize target discovery and deliver personalized medicine. And that part basically didn't work. The company only found its feet when it moved downstream to a drug that it actually owned, Velcade, which is the piece that Takeda bought later for eight point eight billion dollars.
[00:12:55] Alex: Totally. And because of that experience, Third Rock develops a very specific view about academic science and how to translate it into new medicines.
[00:13:04] Matt: They aren't shy about saying it out loud. Mark Levin has this great quote where he lays it out. He said, quote, "One academic with one idea will not be successful mostly. We go out and meet the best people in the world, and we develop a discovery plan. We will spend years on that idea.
[00:13:24] Alex: Is he French? He likes saying "we" a lot.
[00:13:28] Matt: But there's also, this corollary behind that way of thinking, right? He also said, "You can hire the best 25 people in the world, but great individual effort will not alone build an outstanding company. You need the genius of the group." And that's certainly gonna be the case for Blueprint.
[00:13:45] Alex: Yeah, and i-if you step back a, a little bit, this is really a theory of value creation and ownership in therapeutic drug discovery.
[00:13:56] Alex: So Third Rock fundamentally believes that the scientist who comes up with the idea is supplying a tiny fraction of what it actually takes to turn that idea into an approved drug. To them, the operating team matters more, the capital matters more, the decade of grueling clinical development matters more.
[00:14:17] Alex: Therefore, the founding scientist should really own only a fraction of the company. You know, this is not something they're embarrassed by. It's literally their core thesis.
[00:14:28] Matt: Yeah. And honestly, back when they started, that view was largely correct. If you were an academic in, say, 2009 with a brilliant idea for a drug, that idea on its own was basically worthless.
[00:14:43] Matt: You didn't have access to the high-throughput screening chemical libraries, the assays, the toxicology experts, the regulatory team, or most importantly, the tens of millions of dollars to do all of that and run trials on top of it. The trope you hear in the tech world all the time is like, "Ideas are cheap.
[00:15:03] Matt: Execution is everything." In the drug discovery world, you absolutely needed the venture firm to bankroll that execution muscle, or you needed a giant pharma partner to get anything done.
[00:15:16] Matt: We're foreshadowing a bit here on purpose, but you know, what's fascinating is how that statement has shifted recently. Many fundamental drug modalities like antibodies and small molecules are starting to commoditize, and in twenty twenty six, a lot of that complex execution has become something you can access via CROs and CDMOs.
[00:15:40] Matt: When the execution side gets cheaper and easier to access, well, suddenly that original idea and the scientist who had it becomes worth a whole lot more.
[00:15:50] Alex: All right. So we covered the venture company creation engine and their thesis around the type of company they like to build, a few years away from the clinic based on rigorous reproducible science with a strategic advantage relative to pharma.
[00:16:05] Alex: So what was the science that Blueprint was doing?
[00:16:07] Blueprint's Science: Kinase Selectivity & Gleevec
[00:16:07] Matt: All right, let's dive in. To understand why Blueprint's initial bet was considered improbable, you need to understand why people thought a truly selective kinase inhibitor couldn't be made. Think of a kinase as a biological switching system. It takes a tiny chemical tag, a phosphate, and attaches it onto another protein, flipping that other protein on or off.
[00:16:31] Matt: Essentially, Kinases are the signaling wiring of the cell. They tell the cell when to grow, divide, move, or survive. There are about five hundred and eighteen of these different switches in the human genome, a number that had been made complete and comprehensive around the time of Blueprint's founding with the genome sequencing revolution.
[00:16:50] Matt: The problem starts when one of those switches gets jammed in the on position, usually because of a genetic mutation. Suddenly, the cell starts endlessly growing and dividing when it shouldn't be. Mechanically speaking, that's exactly what a lot of cancers are. A growth pathway stuck in the on position with absolutely nothing telling it to stop.
[00:17:11] Matt: The Holy Grail, going back decades, was to find a drug that could jam one of those broken switches back off, but still leave the other five hundred and seventeen untouched. But the reason that it's incredibly hard to do that is that kinases share a fundamentally similar shape. The pocket on the kinase that a drug actually grabs onto looks really similar across the whole kinase family.
[00:17:34] Matt: So when you hit one, you tend to hit a bunch of them, causing toxicity in the process. If a company comes out claiming they can be exquisitely selective on purpose and do it over and over again, they've essentially claimed to have solved one of the hardest problems in the entire field.
[00:17:50] Alex: That all changed with the discovery of Gleevec. Developed in the nineties, it showed how it was clinically possible to specifically inhibit the right kind of kinase in the right cancer.
[00:18:00] Alex: Chronic myeloid leukemia is driven by one specific broken kinase, a mutant fusion protein called BCR-ABL that gets created when two chromosomes accidentally swap pieces. Gleevec was built by chemists at Ciba-Geigy, which later became Novartis, with a scientist named Nick Lydon running the program internally and a clinical oncologist Brian Druker working on the outside to prove it actually worked.
[00:18:25] Alex: The drug successfully jams BCR-ABL off, and suddenly, in a ton of patients, the leukemia just recedes.
[00:18:32] Alex: Druker actually has this incredibly grand quote about it, and for once, it's completely earned. He said, quote, "In the war on cancer, there will be before Gleevec and after Gleevec."
[00:18:46] Alex: BG and AG. So Gleevec becomes the ultimate kind of proof of concept that Blueprint will end up chasing.
[00:18:53] Alex: Shut off that one broken switch and leave the five hundred and seventeen other ones alone. And the beautiful part is that they should have a never-ending source of new genetically validated drug targets. The ongoing cancer sequencing revolution of the 2000s was going to hand them fresh broken switches to go prosecute, one mutated kinase at a time.
[00:19:14] Matt: All right, so they've got this really ambitious platform play for the company. How exactly does this fit the TRUKK criteria of being three years from the clinic?
[00:19:25] Matt: For that, we'll need to look back at Gleevec. Gleevec was a pretty selective kinase inhibitor, and that selectivity actually came down to some structural biology.
[00:19:35] Matt: A kinase and proteins in general are not rigid little blocks, right? They, they cycle between an active on shape and a different off shape. Gleevec completely ignores the active shape of BCR-ABL, and instead it really only slips into the kinase when it's in its off shape, locking it in that position. It was really an amazing way to get selectivity.
[00:19:57] Alex: Well, almost perfect selectivity.
[00:20:00] Matt: That's right. It turns out Gleevec doesn't just hit BCR-ABL. The exact same drug inhibited two cousin kinases called PDGFR and KIT. And in fact, Druker was the one who proved that it also inhibited KIT. Through this completely accidental twist of fate, the polypharmacology of this drug was in fact quite useful.
[00:20:20] Matt: Aberrant KIT activation drives a rare type of stomach cancer called GIST. So pretty much entirely by accident, this miracle leukemia drug has suddenly become a useful GIST drug as well.
[00:20:33] Alex: Well, then what was the opportunity for Blueprint here, given that Gleevec's polypharmacology was good for multiple cancers?
[00:20:42] Matt: Good question. As it turns out, Gleevec does have a blind spot, and that blind spot is going to be the opportunity for Blueprint. There are specific types of mutations, like the one in KIT is called D816V. The one in PDGFR alpha is called D842V. And these mutations sit right in the part of the protein called the activation loop. These mutations totally wreck that folded up off shape and essentially physically lock the kinase permanently into that active on pose.
[00:21:15] Alex: Got it. So for those keeping track, Gleevec only binds to the inactive shape. So if a kinase can't fold into that inactive shape anymore, Gleevec physically cannot grab it. So against KIT D816V or against PDGFR alpha D842V, Gleevec does absolutely nothing.
[00:21:34] Alex: If you want to make a better inhibitor, you need one that's deliberately designed to grab the active shape that these mutants are permanently stuck in. In biotech terms, that's called a type one inhibitor.
[00:21:46] Matt: So Blueprint wants to make these new types of kinase inhibitors, starting with an opportunity against the KIT kinase. You know, sounds like pharma should be well aware of the opportunity.
[00:21:56] Matt: So how exactly do they expect to not get flattened by big pharma here?
[00:22:01] Alex: Yeah, it's a great question. So there's actually, a couple of parts to that response. The first thing to think about here is that at the time, pharma thought that the economics wouldn't work for these narrow, genetically defined populations. As in, there were too few patients to bother.
[00:22:17] Alex: Why would you purposely narrow your customer base after all? The second was that pharma thought they'd be able to quickly hop from existing kinase inhibitors that they had already made to evolve into another kind of kinase inhibitor, rather than having to build something that selective for a specific kinase from scratch.
[00:22:36] Alex: Because of that, pharma didn't even think drugging new kinases was going to be a hard problem. That attitude, as Alexis Borisy, one of the first CEOs of Blueprint, described it, was basically this.
[00:22:47] Alexis: Of course, pharma was like, we know how to make kinase inhibitors. Which by the way, they totally didn't because the first kinase inhibitor, Gleevec, is a super selective molecule.
[00:22:57] Alexis: We have what we call the selectivity score in kinase inhibitors, and it's like an S score of zero point zero two. It's a really good selective kinase inhibitor. Everything else is like point one five, point two, point three. They're these dirty multi-kinase inhibitors, totally different animal.
[00:23:11] Alex: So the pharma wisdom of the time was that kinases were going to be a crowded space going after a tiny commercial opportunity, and that a company promising to be exquisitely selective on purpose was either redundant or just wrong.
[00:23:25] Alex: That's why nobody wanted to partner with them. And why, as we'll mention in a bit, early fundraising ends up being such a grind for Blueprint.
[00:23:34] Matt: All right, so we covered now how Blueprint was taking shape in these early days and sort of getting into the sweet spot for a build-out by Third Rock Ventures.
[00:23:43] Matt: Let's talk about the company itself.
[00:23:45] Blueprint Is Born: Founding & Early Challenges
[00:23:45] Matt: The idea of Blueprint Medicines starts as a sketch in Alexis Borisy's notebook in October two thousand and nine while he's running another company. The first filing is a placeholder, Personalized Medicine Oncology NewCo. Then it gets its first name, Hoyle Pharmaceuticals.
[00:24:01] Alex: Hoyle? What's that?
[00:24:02] Matt: As in according to Hoyle. Edmond Hoyle wrote the original rule book for card games, so according to Hoyle means by the rules. The pitch was therapy according to the rules of your specific mutation, the exact card you've been dealt in life. But they ended up killing that name because cards mean chance and gambling, and that's a bad frame for people fighting cancer.
[00:24:23] Matt: So Hoyle became Blueprint, the blueprint of your cancer, the thing you read before you can treat it.
[00:24:29] Alex: Ah, man, these guys really like things with cards. You start Third Rock with a card game and name one of your first venture creations with a card name. I bet they probably have a fun office.
[00:24:40] Matt: Yep. So Blueprint officially launches in two thousand and eleven, and right out of the gate, the academic founders include two of the main Gleevec protagonists, Nick Lydon and Brian Druker, alongside Third Rock's own internal entrepreneurs.
[00:24:54] Alex: Yup. And as we've mentioned before, we should remind you whose company this actually is. This is a Third Rock Ventures company in the absolute fullest sense. It came out of their second fund, TRV led every early funding round, and they ended up being the dominant owner at the time of the IPO. Plus, they were literally running the place.
[00:25:14] Alex: Chris Varma, a Third Rock venture partner, was the founding CEO. And Alexis Borisy, another partner, was the founding chairman. You had some other investors take small slices in the early rounds, but this is about as close to a wholly owned Third Rock baby as they'll ever see.
[00:25:30] Matt: Yep. I think it's worth pointing out, too, that Blueprint wasn't just some isolated project for Third Rock, right?
[00:25:37] Matt: So around the time that they were putting Blueprint together, Third Rock was incubating another Cambridge company called Foundation Medicine, which did genomic profiling of tumors.
[00:25:48] Alex: That's right. In the interviews with the Third Rock guys, we often see that they're paired together as sister companies. That's the term they like to use.
[00:25:56] Alex: Foundation is working on finding those genetic drivers, and Blueprint is making the drugs that hit them. They basically built the diagnostic and the therapeutic sides of precision medicine at the exact same time. In a way, not unlike what Millennium was trying to do a decade earlier. Just split into two different companies.
[00:26:13] Alex: In fact, we were told Blueprint was almost folded into Foundation itself. But Alexis told us exactly how the decision to split them went down during a debate with Mark Levin.
[00:26:23] Alexis: Mark and I had this whiteboard, uh, in a conference room at TRV, and we literally were having this exact debate. Should it be all in one company or not?
[00:26:31] Alexis: And we said, "Look, the scale of what cancer genomics is and the need from a fundamental compelling medical perspective to do this right and how transformative it could be to the field, like, that is an all-in thing. And the diagnostic business is a fundamentally different business." And so we're like, "Let's build that company to do it right."
[00:26:51] Alexis: And so that's why we said these should be separate efforts.
[00:26:53] Alex: Okay, so Blueprint is getting off the ground and the decision is made to be a pure therapeutics company that leaves the diagnostic bit to other players. But how is Blueprint approaching their drugs?
[00:27:06] The Platform: Building the Kinase Library
[00:27:06] Matt: Let's dive into the platform. Historically, most small molecule drug discovery has involved brute force screening through very large, very diverse libraries of compounds.
[00:27:17] Matt: After picking your target, you start screening, and you start throwing millions of random chemical compounds at your target, working through a screening funnel, and then spending years turning those hits into something that resembles a drug candidate. It is slow, it's expensive, and it's full of dead ends.
[00:27:34] Matt: Historically, the best libraries were the carefully guarded secrets of large pharma, a real competitive advantage and moat for them.
[00:27:41] Matt: But Blueprint is going to take a different approach. Their plan is to create a proprietary and focused small molecule library rationally designed to achieve a broad, deep coverage of the entire family of kinases.
[00:27:54] Matt: And they map out the selectivity of their library in advance. So for every compound in this library, they already know exactly which kinases it hits and how cleanly it hits them.
[00:28:05] Matt: To hear about this process from the inside, we talked to Erica Evans. She joined Blueprint in twenty twelve and ultimately led the avapritinib and pralsetinib programs from early discovery through phase one.
[00:28:17] Matt: We asked her how the platform actually worked day to day. She told us.
[00:28:21] Erica: The library and the platform was great. It really enabled all of the programs that came from Blueprint. And the amazing thing, like a biologist and a project leader's perspective, was that all of the material in the library was pre-screened against a big panel of kinases.
[00:28:41] Erica: So biologists coming in could say, you know, "Kinase X is my favorite kinase. What chemical matter do we have that hits this kinase, and how selective is it?" So there was no high-throughput screening. Once a target was chosen, it wasn't like we said, "Okay, now let's go do a DEL screen," or, "Let's go do a high-throughput screen."
[00:29:04] Erica: It was really, uh, "Let's interrogate the dashboard."
[00:29:08] Matt: Let's interrogate the dashboard. Man, that sounds so awesome. I've been involved in so many programs where I wish I had a dashboard like this to, to start the therapeutic campaign.
[00:29:19] Alex: Yeah, and it kind of reminds me of what this new generation of AI-for-bio companies seems to be branding themselves as. I mean—
[00:29:26] Matt: Yeah, this all sounds great in theory. I think it's interesting to learn from Blueprint what sort of time and money acceleration this ultimately led to. For that, we asked Tim Guzi, Blueprint's head of medicinal chemistry at the time, to put some hard numbers on what this platform actually brought to the table.
[00:29:44] Tim: at Blueprint, we turned all that effort to screen into basically a computational exercise. Chemists would walk up, they say, "I like this target." And within ten, 20 minutes, have candidate compounds that you could then start working on. So you could realistically go from a 12 to 18-month process and, and narrow that down to under three to six months at most to get started.
[00:30:08] Matt: 18 months to six months, that's pretty good. That speed ends up being exactly how they generated their RET inhibitor pralsetinib. Tim Guzi also told us the following.
[00:30:19] Tim: Pralsetinib was literally started with an exercise to probe what's in the library on our computers, right? Not making any compounds. We wanted things that hit the primary target, that hit the, the mutants that existed in thyroid cancer, and we wanted to do that very selectively.
[00:30:37] Tim: There's a slide we built to show this. It looked like a heat map, but it was black and green, and there's green globules all over the place, and you could identify strips in there of like, "I like this scaffold," and that's what we pulled out to start working on.
[00:30:51] Alex: If you think about it, the funny part here is that the biology became the bottleneck.
[00:30:56] Alex: This library could hand you selective starting points faster than literally the assay teams could build the tests to profile them. And Erica told us what that actually looked like for the pralsetinib program in particular.
[00:31:10] Erica: The realization that RET fusion kinases were found in one to two percent of non-small cell lung cancers.
[00:31:19] Erica: We knew that the small molecules available for RET inhibition were non-selective, meaning they hit a lot of different kinases, and that was in large measure dose-limiting for those. So one of the things we did was go right to the library and see how many different types of molecules do we have that are active against RET.
[00:31:41] Erica: And then among those that are active against RET, how selective are they? And we really sort of jumpstarted that program from that interrogation.
[00:31:51] Alex: As usual, this platform approach that Blueprint was pioneering ended up working beautifully in the end, but as everything in science, it was messy and tenuous and scary during the actual build-out.
[00:32:04] Alex: Christoph Lengauer, founding CSO of Blueprint, gets into that.
[00:32:09] Christoph: All those chemical series or groups were named after type of wine, you know, they had vineyard names, like, Syrah and, like, whatever, like. And as it turns out, this was a total mess because, like, it was complicated to measure selectivity.
[00:32:22] Christoph: We had no understanding of what selectivity means, tenfold, hundredfold, thousandfold. And we, uh, ended up having all those molecules made with all their kinome tree sort of mapping the selectivity score at what concentration, by the way, right? And we're like, "Oh my God, this is a total mess."
[00:32:42] Alex: All right. Let's move away from the science of Blueprint and move back to the financials.
[00:32:47] Alex: Blueprint's Series A was about forty million dollars. Thirty million was put in by Third Rock. Another ten million was put in by what's now F-Prime. Across the early rounds, Third Rock ends up putting in about forty-two million dollars in total. That makes them the largest shareholder by far.
[00:33:03] Alex: There's a catch, though.
[00:33:04] Alex: That first forty odd million dollars didn't get them a drug. In fact, it barely got them even to the starting line of trying to make a new type of kinase inhibitor. Blueprint's own filings at the time call it a proprietary, highly annotated compound library paired with a target discovery engine. A lot of fancy words, but not yet a single dollar of an approved drug came out of it from that stage.
[00:33:28] Alex: They actually had to raise more money twice before they even put a molecule into a human being. From talking to the Blueprint team, those platform building years were an absolute grind, with the company nearly blowing up. Here's what Alexis said about that time.
[00:33:44] Alexis: All this feedback we were getting from pharma that like, "What you're doing is adding no value.
[00:33:49] Alexis: It's uninteresting. You're totally wrong."
[00:33:52] Matt: Oof, that's rough. Erica Evans, who as a reminder, was one of the leading biologists at Blueprint at that time, joined the company right as that pressure was peaking. She remembers what it felt like on the program side to deliver a drug candidate.
[00:34:06] Erica: There was a lot of pressure to demonstrate that we could come up with a potent selective inhibitor of KIT that was mutant selective, because we knew that inhibiting KIT wild type on its own was going to manifest in some safety issues.
[00:34:24] Erica: You know, we had to present to the board every three months on, how far away from a development candidate we thought we were. Yeah, it was intense.
[00:34:33] Near-Death & Series B: Running on Fumes
[00:34:33] Alex: Around 2013, these dynamics come to a head with Blueprint needing to raise a Series B, but not having met the traditional milestones of a Series B company.
[00:34:42] Alex: No development candidate had been nominated yet, and no pharma partnerships were in place. Alexis doesn't soften it when he describes how close they came to insolvency.
[00:34:53] Alexis: We took it down to fumes. We would not have met the next payroll. I tell this often to CEOs when they're worried about, like, ridiculous amounts of money that they have in the bank that they don't have enough money.
[00:35:02] Alexis: I'm like, "No, no, no. If you're not down to the level where you will not meet the next payroll…" We were, you know, uh, at $100,000 or less cash. Mind you, with lots of payable that we owe out there, not to mention our security deposit for the space. Like, we were on vapor.
[00:35:18] Alex: A small additional round finally did come in 2014 with Thilo Schroeder, a young investor at a small firm called Nextech, leading the round with a $2 million check, and a syndicate scraped together $25 million in total.
[00:35:32] Alex: A bridge that ended up buying them enough runway to get their first program off the ground.
[00:35:37] Matt: Wow. The, the Series B lead investor, their, their check was $2 million. I think that tells you everything you need to know about how difficult that round was. Um—
[00:35:47] Alex: Yeah.
[00:35:48] Matt: The syndication sounds like it was ultimately accomplished through the sheer will of the Blueprint folks.
[00:35:55] Alex: Have you ever seen that episode of Silicon Valley about the down round?
[00:35:59] Matt: No, I don't know what you're talking about.
[00:36:00] Alex: Well, there's a bit on the HBO show about this kind of, um, financing fiasco in a startup.
[00:36:07] Matt: Maybe, maybe not. Looking at the math here, it doesn't look like it was a down round or anything, but it was still brutal. Blueprint had a post-money valuation of fifty-two million dollars after the Series A, and three years later at the Series B raise, the post-money valuation was only eighty-eight million.
[00:36:25] Alex: So during this time, the library is just devouring cash. Investors are tapping their watches asking for a pipeline, and they've got nothing. They're in a standard tough spot for a platform build-out, needing to have meat in the pipeline as fast as possible, but not having the luxury of waiting for the platform to be finished to start on that process.
[00:36:47] Alex: So in parallel, Blueprint attempts to take a shortcut, seeing if they can use literature compounds to get exactly what they need. They take an existing wild-type KIT inhibitor, something shaped a bit like Gleevec, and try to modify it to hit the D816V mutant.
[00:37:05] Matt: But that Approach mostly doesn't work. Christoph told us they basically proved to themselves that the conventional route was chemically impossible. The protein's active and inactive shapes were just too dramatically different to bridge.
[00:37:18] Christoph: If you can't get from A to B, and you can't get from B to A, there's nothing that bridges those two because they are, like, fundamentally different. Therefore, we proved ourselves that actually we can't do it conventional. And then we got our first hit.
[00:37:33] Alex: So ironically, unsuccessfully trying a quote-unquote “shortcut” proved that they had to use the library, and the library is what handed them avapritinib, the molecule the shortcut never really could have found on its own. It goes right after the blind spot that Gleevec left behind, specifically active shape KIT and PDGFR alpha mutants.
[00:37:55] Matt: We have to give credit where it's due as well here. We talk like these molecules were just spat out of some magical platform, but at the end of the day, these are molecules and scaffolds that were drawn by actual chemists working at Blueprint in Cambridge.
[00:38:12] Alex: Yeah. When we spoke with the head of medicinal chemistry, Tim Guzi, he told us that avapritinib, their first program, in reality actually came together from two dead ends at once.
[00:38:23] Alex: The team was grinding out one series pulled from the literature because the platform and the first program were being built at the exact same time, and separately, another series that came out of the platform itself. But both were stalled. Here's what he had to say about it.
[00:38:39] Tim: We were stuck in one instance with not enough potency for the one series, and it just wasn't quite selective.
[00:38:45] Tim: And then the series that came out of the library, the, the ADME properties were terrible, right? So it's potent and selective, but they're really insoluble, and you struggle to get bioavailability.
[00:38:56] Alex: The breakthrough really came from a scientist, uh, within the company, Brian Hodous, realizing he could splice the two dead-end series to move forward.
[00:39:04] Tim: Brian was a medicinal chemist on the avapritinib program that really broke it open. Said, "Well, wait a minute. I see what's here and I see what's there. What if I just go like this and hybridize the two?" Combining pieces from each one completely reshaped the compound, and that led to good oral bioavailability, good distribution, and compounds that very quickly showed in vivo activity.
[00:39:25] Alex: It's kind of crazy to think about it that way, they kind of Frankenstein the literature scaffold and the proprietary library scaffold together to get everything they needed for this, drug candidate in avapritinib.
[00:39:37] Matt: Yeah. And it ends up being, um, extremely selective.
[00:39:40] Matt: It shuts down the KIT mutant at a potency in the picomolar range, and then you have to crank the dose up seven hundred times to start inhibiting wild-type cKIT. That's a real scientific accomplishment from the Blueprint team. Here's Christoph affirming that.
[00:39:57] Christoph: You can have selectivity of wild type, the normal form over mutants.
[00:40:02] Christoph: If that's an essential gene, you don't want to inhibit wild type.
[00:40:04] Christoph: The big goal for many years was to kind of stay away from the wild type. And then there is like the different mutations there are and how many of those can you cover while sparing wild type.
[00:40:15] Christoph: We thought maybe we can make this super selective wild type sparing KIT inhibitor that covers all the mutations.
[00:40:21] Alex: By the time they finish building the library and get close to avapritinib, the C-suite looks completely different. You've got the founding CEO, Chris Varma, leaving in twenty thirteen.
[00:40:32] Alex: Chairman Alexis Borisy fills in for a year, helping to ultimately bring in the permanent CEO in twenty fourteen, Jeff Albers.
[00:40:41] Alex: Now, unlike Chris or Alexis, Jeff isn't a scientist by training. He's a commercial guy, law degree, MBA, and he's brought in with one very specific mandate: take this company public before the runway disappears.
[00:40:56] Alex: He brings in a very particular pedigree as well. He comes out of Genzyme, Henri Termeer's legendary rare disease company.
[00:41:04] Alex: For some context here, Sanofi had bought Genzyme back in 2011 and kind of scattered its talent to the wind. People call it the Genzyme diaspora, and Albers was right in the middle of it.
[00:41:16] Alex: Which is funny, you know, because Blueprint's founding chief scientist, Christoph Lengauer, was also part of that diaspora just by a more circuitous route.
[00:41:26] Alex: Christoph was actually the global head of oncology at Sanofi. He was running the old Genzyme site in Cambridge, managing hundreds of people, including over 100 chemists. But in the early 2010s, he was starting to get a bit restless. He told us.
[00:41:41] Christoph: Novartis and at Sanofi, we achieved a lot. We got, while I was there, like five drugs approved.
[00:41:47] Christoph: Therefore it was super successful. But for me, pharma was somehow slow and bureaucratic and conformist. I was satisfied at Sanofi, but I wasn't happy.
[00:42:01] Alex: So out of nowhere, Third Rock cold calls him about this tiny third rock startup that wants to drug new kinases. He gets pitched on the Gleevec lineage, the mutation thesis, the whole platform idea, and Christoph is just sold immediately.
[00:42:16] Alex: He believes in it so completely that when he gave his notice to Sanofi, his leadership team actually guessed where he was going before he could even tell them.
[00:42:25] Christoph: At one point, I said to my leadership team, I, I found my company and like, you know, I'll join on January first. And then they said, "Is it Blueprint?"
[00:42:33] Christoph: And I'm like, "How do you know?" They say, " Because that's what you believe in."
[00:42:37] Matt: That's so funny. They guessed it before he said the name. That's amazing. All right, so let's get back to Jeff. Um, so he comes in and fifteen months later, he nails the exact job he was paid to do.
[00:42:49] IPO & Clinical Programs: The Platform Pays Off
[00:42:49] Alex: In April twenty fifteen, with the platform humming and the development candidate nominated for the Kit program, Blueprint goes public at eighteen bucks a share, raising about a hundred and fifty million dollars, which, you know, in some ways is impressive, right? Because they're, they're, they're a preclinical company at this point.
[00:43:07] Alex: They, they haven't dosed a single drug into a single human yet. Now, to be fair, you know, they didn't stay preclinical for long. A few months later, in the fall of twenty fifteen, they had started their phase one trials for their molecule in two indications. But, um, in many ways, they were lucky. They managed to squeeze through the IPO window at sort of the exact last moment you could as a pure platform zero-patient story.
[00:43:33] Alex: Let's explore that IPO window that they were listing in. So April twenty fifteen is when Blueprint is officially listed publicly as a company. Three months later, the biotech index hits its all-time high and then from there falls off a cliff for the next fifteen months. Looking back today, over ten years later, that twenty fifteen IPO class is basically a graveyard.
[00:43:57] Matt: Yeah, I mean, almost none of the companies that Blueprint went public with are still standing, and Blueprint is sort of the belle of that vintage. It ends up being one of the biggest acquisitions of that cohort. I think one of the reasons that they survived is that their platform engine, like actually worked, right?
[00:44:14] Matt: As you might expect, how it works is sort of, a lot messier than the polished version as we'll come to see. With the company public and capitalized, over the next few years, the fully mapped out library kicks out a whole string of clinical stage drugs.
[00:44:28] Matt: You had avapritinib, obviously, then pralsetinib for RET-driven lung and thyroid cancers.
[00:44:33] Matt: There was also a liver cancer drug hitting FGFR4. And elenestinib, a next-generation KIT inhibitor specifically built to stay out of the brain. We'll get back to that later. Blueprint also made a whole family of EGFR inhibitors for lung cancer, CDK2 inhibitor for breast cancer, plus a bunch of immuno-oncology assets they partnered with Roche.
[00:44:55] Matt: One of those, by the way, was HPK1, an immune brake target that half the biotech world was fighting over at the time.
[00:45:03] Alex: Yeah, I mean, all the signs here are of an extremely productive platform. One of the upsides of having all of these shots on goal is that it gives you the safe space, so to speak, to quietly kill the bad programs.
[00:45:19] Alex: This is something that people often overlook. When you are a one-drug company, uh, killing a program is an existential crisis, right? I- if that asset's gone, the company's gone, and everyone gets fired, and it makes it much more difficult for an organization to make clean, objective decisions to, to kill a program when everyone's survival is really tied to it.
[00:45:43] Matt: Agreed. On the other hand, even if your engine only ever produces one massive winner, that winner is going to carry the whole company, which is good.
[00:45:51] Matt: That means it did its job. Platforms are a way that you can at least on the margin, find a winner out of, a broader pool, preventing hundreds of millions of dollars in sunk costs on unviable programs…
[00:46:03] Alex: on the topic of platform, I, I think it's worth highlighting that term can mean many different things in the industry and ultimately represents a really big spectrum, both in terms of how companies are organized as well as the ultimate financial outcomes.
[00:46:20] Alex: On one end of that spectrum, at the very top of the financial hierarchy, you have the sort of companies that are able to essentially collect a toll on a massive drug while barely spending any of their own money. At the other end of the platform spectrum, what you really have is essentially a single molecule wearing a trench coat, and the whole executive team is pretending like it, it has a platform technology.
[00:46:47] Alex: Blueprint is really in the middle between those two extreme ends of the spectrum. It obviously had a real platform, and they pointed that platform at all sorts of different kinases and pulled out real programs. This wasn't a toll booth, though.
[00:47:02] Matt: Erica framed it pretty similarly to the way you just articulated it.
[00:47:07] Matt: I mean, since she was living it from the bench, she knew it was a phenomenal head start, but not necessarily some unassailable moat. Here's what she told us.
[00:47:17] Erica: It lowered the barrier to starting new programs because you had chemical matter that you could test and build around pretty quickly. Um, so it wasn't as if we had to have a hypothesis and then do a high throughput screen and, you know, nine months later validate the hits that come out of the screen.
[00:47:38] Erica: It was really, you have a hypothesis, you could go to the freezer and get the compounds that were shown to have some binding activity already. So I do think it lowered the barrier to starting new things.
[00:47:53] Alex: Yep, spot on. Their platform lowered the barrier to making their own drugs against the most compelling biologically validated targets, gave them a nice real head start, um, against all of their competitors when new target hypotheses were, uh, dribbling out of the cancer sequencing revolution.
[00:48:09] Alex: But again, we can contrast that headstart with what a true toll booth looks like. I'll remind the listener of episode three of Approved, where we covered Keytruda. There was a company called MRC Technology that was involved with exactly one step of the discovery of Keytruda. They were the ones that humanized the antibody.
[00:48:31] Alex: They didn't run a single clinical trial. They didn't do anything to the molecule before or after, but they ended up getting a royalty from that step, and they ultimately sold that royalty stream for, you know, billions of dollars. And MRC ran that exact playbook on a couple other multi-billion dollar blockbusters.
[00:48:51] Alex: So, like, this is the holy grail platform, again, from a economic perspective. You, you take your percentage cut on the revenues, you didn't pay to develop it, and your royalty stream is attached to that molecule regardless of which corporate entity sort of owns it, right? So Blueprint's engine was never like that.
[00:49:11] Alex: It was, as we mentioned, a headstart.
[00:49:14] Matt: Yeah. You can't help but wonder if this new generation of service companies to biotech and pharma are going to be more like MRC or more like Blueprint. Christoph Lengauer actually has this great rule of thumb for where the real value in a biotech company like this actually sits.
[00:49:32] Matt: He says about three-quarters of the value is tied up in the first drug, maybe ten or fifteen percent in the second, and only five to ten percent of the value is in the cash and platform itself, which really tells you everything you need to know about how a product engine actually works. So far, we've spent this entire episode setting Blueprint up as this great Gleevec two point o oncology story, building the ultimate precision cancer engine, having programs for lung cancer, liver cancer, GIST, et cetera.
[00:50:15] Matt: But as it turns out, that's not really the story at all.
[00:50:19] The Pivot: From Cancer to Mastocytosis
[00:50:19] Alex: Yeah, it's the ultimate irony, right? Um, despite everything we just talked about with targeted cancer therapies and tumor-specific mutations, Blueprint ultimately becomes an immunology company focusing on a very specific type of mast cell disorder that's called mastocytosis.
[00:50:37] Alex: There's a little bit of nuance here, of course. You know, this wasn't a complete accident of biology. Mastocytosis is caused by a mutation in kit, and this combination of target hypothesis and clinical indication were absolutely on Blueprint's very first target list. You know, Alexis told us that it was right there in the notebook from day one.
[00:50:59] Alex: But what they didn't have was any sort of feel for this disease. Christoph, who was running the labs, had never even heard of this indication called mastocytosis. So the real accident wasn't the target per se, it was rather the ability to recognize the size of the opportunities that lay before them.
[00:51:17] Alex: That's what happens when you have a very well-engineered molecule that collides with the messy reality of human biology that's often poorly understood.
[00:51:26] Matt: Well said. To kind of get a, an intuitive feel for how this cancer company started by cancer biologists accidentally stumbled its way into, later, as we'll see, allergy and immunology, we're going to need to work backwards from this inconspicuous indication we just described, mastocytosis.
[00:51:44] Matt: This is a mast cell disease that comes in two completely different flavors. There's, on one hand, the advanced form, which is a rare, aggressive, severe organ damage-causing illness. Patients maybe have six months to live. That is on par with orphan kinds of cancer in its severity, and you have to treat it like one, hitting it with high doses of cancer-killing agents and hitting it fast.
[00:52:08] Matt: But there's also a less advanced form called indolent systemic mastocytosis, or ISM for short. Indolent here means slow burning. And this represents the vast majority of patients with mastocytosis.
[00:52:22] Alex: Right. And with the indolent form of the disease, these are not folks that are dying quickly or really at all.
[00:52:28] Alex: They end up having a normal lifespan, but they are dealing with this absolutely brutal inflammatory allergic disease. I think the important point here is that both forms of the disease share similar pathobiology,.
[00:52:42] Matt: The KIT kinase is a master control switch for this specific type of immune cell. These are the cells that activate and flood your system with a variety of molecules during a normal allergic reaction. But when you have that single genetic typo in the KIT gene, you know, the so-called D816V mutation, these mast cells get jammed permanently on.
[00:53:07] Matt: They proliferate too much, constantly over-activating and dumping their inflammatory cargos all over the body.
[00:53:14] Matt: The most dangerous part is really unpredictable anaphylactic shock. People can just go into these life-threatening allergic reactions with zero warning.
[00:53:24] Alex: And it could be really hard to pin down exactly what the triggers are that cause those allergic reactions. We ended up chatting with Dr. Mariana Castells, clinician researcher and director of the Mastocytosis Center at Brigham Hospital, to tell us more about the disease.
[00:53:41] Alex: She told us a wild story about how extreme these misdiagnoses can get before a patient finally finds the right clinic.
[00:53:49] Mariana: flushing, with itching, with, uh, gastrointestinal symptoms, bloating, diarrhea, maybe also mental fog, you know, fogginess, uh, uh, neurological, uh, symptoms,.
[00:53:59] Mariana: So really unpredictable episodes of what was called mast cell activation, which goes into the definition of anaphylaxis.
[00:54:07] Matt: Geez, that sounds like a horrific disease. It's kind of crazy how blind Blueprint was to the opportunity here at first.
[00:54:15] Matt: They were so laser-focused on cancer that they didn't really grasp what was possible in this indication. Christoph also has a great quote about it.
[00:54:25] Christoph: The platform was a kinase platform with its programs. But of course, if you do rare disease, if you do oncology, if you do GIST, if you do mastocytosis, then it's hard to be also the expert in everything.
[00:54:36] Christoph: That's why we were all a bit nervous about mastocytosis. We knew the mutation, but didn't understand the disease. And this was like, I remember there were only like two or three people in the US who were known for treating those patients. A couple of them were interesting characters.
[00:54:54] Alex: So ironic. The actual breakthrough happens completely by accident at a medical conference in late 2017.
[00:55:02] Alex: Blueprint is running an early dose escalation study of avapritinib for that aggressive advanced form of mastocytosis. And in those trials, you start patients on a tiny dose and slowly step it up, basically hunting for the ceiling of what they can tolerate. At the very lowest dose, they try just thirty milligrams, they end up seeing something completely unexpected.
[00:55:24] Alex: The drug is already moving the disease markers, pushing down the blood levels doctors use to track the disease, and it's doing it with a rather clean safety profile. Super low dose, a tangible biological effect, and few side effects is certainly a triple threat in a good way for this program.
[00:55:42] Matt: Yeah. And this is usually not what you see in a clinical trial and is definitely not what you saw in the original Gleevec trials where a lot of dose escalation had to happen before activity was seen.
[00:55:55] Alex: Yeah. I think in, in the Gleevec trials, they had to go up to eight hundred milligrams to get partial responses in CML.
[00:56:01] Matt: Yeah, not surprising. You know, this is the beauty of building a really potent and clean molecule. Your aperture of opportunity opens up. The initial biomarker movement they were seeing at the thirty-milligram dose suggested that they had a target product profile here where the drug could work for the more indolent forms of the disease.
[00:56:22] Matt: And again, that's the bigger patient population. Without this big platform investment, if they had ended up with a messier, less selective drug, they would have had tremendously less room to maneuver. It's really that dosing flexibility and good medicinal chemistry that opened up the larger disease market.
[00:56:42] Alex: And that ended up being life-changing for these indolent mastocytosis patients. When you talk to the Blueprint people, they describe this patient experience as basically living in a bubble. These are people who cannot walk into a hotel because they have no idea what cleaning product was used in the lobby and whether it could trigger anaphylaxis.
[00:57:03] Alex: They can't be in crowds. There was literally a patient in a Blueprint trial who had to use ninety-nine EpiPens in a single year.
[00:57:10] Matt: That's crazy. Many of these people were just isolated at home, completely unable to do the normal things that make up life. It's so easy for a life science company to develop a molecule and then, like, treat the molecule as a hammer and everything looks like a nail. I think in this specific case, it was a situation where the hammer actually did fit the nail perfectly.
[00:57:36] Matt: You have a targeted cancer drug, you drop it to a very low dose, you put it into a genetically defined population, and you do end up with a treatment for a, a chronic immune system disease. I would highlight, too, this is an era where Blueprint was not the only company migrating from oncology land to immunology land.
[00:57:59] Alex: Yep, and it's kind of the opposite scenario from our last episode. Over and over in this era, you see companies built to poison tumors suddenly realize that their most valuable asset actually is somehow tweaking the immune system, like pivoting CAR T from cancers more recently to immunology. Partly because there's A, less competition, and B, because the patients end up staying on the medication for so much longer, given that these immunological diseases aren't fatal.
[00:58:28] Alex: And here's kind of the thing that stings in hindsight with that in mind. Blueprint was not just late to immunology, but kind of knowingly walked past this now we know goldmine of targets that went on to be blockbusters in immunology and instead had tunnel vision on making drugs for cancer. We, uh, have this great bit from Tim running through the list of all of the targets they ended up talking themselves out of.
[00:58:52] Tim: We had TYK2 JH2 domain compounds. We had potent selective inhibitors. We chose not to work on them because it was a non-oncology program, and it was gonna be a long road for us to go. We had BTK scaffolds that were there. We said, "Well, it's gonna be crowded." Um, and, and so if you transition to open up and say, "We'll accommodate more things in immunology," there's huge value in that space, right?
[00:59:15] Tim: Obviously, Nimbus, a follow-on, uh, compound, they're getting sold for $4 billion just on the basis of their phase 2 data. If we'd made that transition five years earlier, they probably would've been a very different company.
[00:59:28] Matt: Yeah. I can totally sympathize with the situation. You have this remarkably productive chemical platform, but ultimately building a non-oncology company is, is just a very different animal than building an oncology company.
[00:59:44] Matt: But it's also a clean illustration of some of the limits that you start to hit when you have a productive platform. You ultimately surface way more, uh, good starting points than an asset centric company has either the focus, capital, human capital, or the appetite to actually prosecute.
[01:00:05] Alex: Yeah, and in all fairness, as we learned from last episode, Keytruda, it's not easy even in a big pharma, maybe even harder in a big pharma, to pivot indications, especially when the biology is still catching up.
[01:00:19] Matt: Yep.
[01:00:20] Clinical Wins, Commercial Struggles & Kate Haviland
[01:00:20] Alex: Let's do a quick recap here before Blueprint goes all in on being a mast cell company and really focus in on Blueprint's trials and tribulations in clinical trials. Back in the late 2010s, Blueprint is still strictly a targeted cancer company, and they have to prove to Wall Street that their platform is a repeatable engine, not just an expensive way to find one good drug.
[01:00:44] Alex: They double down with this incredibly ambitious corporate strategy that they call the expansion fan. You start with one genetic driver and then fan out to new patient populations and tumor agnostic treatments.
[01:00:57] Alex: Their chief medical officer at the time, Andy Boral, directed Blueprint to make a bet that if you find a precise driver in one disease, it's going to keep popping up in others.
[01:01:08] Alex: He basically said, "Look, there's a lot of redundancy in biology. It's incredibly unlikely to find a target that's very active in some disease that isn't relevant somewhere else."
[01:01:19] Matt: I mean, honestly, that's a claim that I have a certain amount of skepticism towards. We are talking about ultra-rare, hyper-specific driver mutations here, and I agree that it's perhaps not surprising that specific kinase mutations end up being implicated in more than one disease.
[01:01:42] Matt: After all, there's only so many different ways to drive aberrant cell proliferation, and so not surprising that certain pathways keep getting reused. But I think importantly, what would be surprising is that you see the same clinical impact of inhibiting a pathway across many different diseases. And, you know, that's the real bugaboo here.
[01:02:05] Alex: By twenty-twenty, the idea of this expansion fan gets to really be battle tested in the clinic. And, you know, first we'll talk about the battles that Blueprint initially wins. January ninth, twenty-twenty, FDA approves avapritinib, brand name Ayvakit, for a specific form of GI stromal tumors, specifically GI stromal tumors that are driven by a mutation in PDGFR alpha that Gleevec couldn't touch.
[01:02:34] Alex: This is Blueprint's first approval.
[01:02:36] Matt: Just to clock the calendar on that, they dosed the first patient in October of twenty-fifteen, file an NDA in June twenty-nineteen, just four years later, and then get approved in January twenty-twenty. That's roughly, like, five years from first in human to FDA approval.
[01:02:54] Matt: And in this industry, that's blazingly fast.
[01:02:57] Alex: That spring, though, things start to turn on Blueprint. On April twenty-eighth, a phase three trial called VOYAGER, which was testing avapritinib in a much broader, more commercially attractive GIST population, outright fails to beat the existing standard of care arm.
[01:03:14] Alex: Within two weeks, all of those broader GIST plans for avapritinib are completely wiped off the pipeline page. Then in May, the FDA sends them a complete response letter, essentially a rejection for avapritinib in late line GI stromal tumors. As a reminder, this is all for the exact same drug. They got a clean approval in January in one indication and a flat no in May for a different use.
[01:03:42] Matt: We should take a moment to understand the sad kind of irony here from the selling point of avapritinib. It is an exquisitely selective drug for this one mutation, PDGFR alpha D842V and KIT D816V. And that is what boxes it in for this specific line of treatment and this specific indication.
[01:04:08] Matt: This is a tiny bespoke slice of GIST. And when you try to move to a much larger relapsed and refractory patient population, you end up finding out that their tumors carry a messy widespread of KIT mutations. So this drug tuned precisely to one specific target within a target in a way just isn't the right tool for the GIST family of cancers.
[01:04:36] Matt: And these trials proved it. It works beautifully in the narrow space it was built for and absolutely nowhere wider.
[01:04:44] Alex: Going back to earlier in the episode, I think this is what pharma feared was developing drugs that get boxed into a tiny economically non-viable patient population. So they need to pivot and to pivot fast.
[01:04:59] Matt: And where else does Blueprint have to look in their portfolio to save the company, Alex?
[01:05:03] Alex: Platform drug number two, pralsetinib.
[01:05:06] Matt: Exactly. In July twenty twenty, Blueprint signs a massive seven hundred and seventy-five million dollar partnership deal with Roche for pralsetinib, brand name Gavreto. That's mostly cash, a little bit of stock, as well as the standard billion dollars of milestone payments.
[01:05:24] Alex: That cash infusion funds the shared launch of Gavreto without Blueprint having to dilute their shareholders by issuing a ton of new stock. Pralsetinib ultimately gets approved in lung cancer that September and in thyroid cancer in December. This kind of deal-making becomes Blueprint's signature survival strategy from here on out.
[01:05:44] Alex: Using big pharma partnerships to pay for its own internal pipeline and commercialization. Every deal is basically a giant check that funds the company without selling new stock. By Blueprint's twenty twenty-two R&D day, you can even see in their presentation they managed to pull on the order of a billion dollars of outside capital across a whole range of different assets and partners at various stages of development.
[01:06:10] Matt: Yeah, and to Blueprint's credit, again, this is what a real big boy platform looks like from the outside. A steady stream of distinct transactions on distinct molecules with distinct partners that have upfront cash payments and that enable the company to maintain ownership of the crown jewels and continue their development.
[01:06:33] Matt: And for Blueprint, the crown jewels were really the RET inhibitor and the KIT inhibitor programs.
[01:06:39] Alex: That's right. I think - with this directional pivot in company strategy, you have to look at who is leading the company at the time, and a lot of credit has to be given to the chief operating officer, Kate Haviland.
[01:06:53] Alex: She would, as we'll talk about later, become CEO of the company, but even in this era of Blueprint, her leadership philosophy of the company at the time was really pragmatic. Figure out what you do best, keep that, and then find partners to pay for the rest.
[01:07:09] Alex: But she also has this bigger commercial strategy about timing these launches. She realized that if you have two drugs hit the market close together, you can justify building one really solid specialist sales force instead of stretching a thin one across the map.
[01:07:25] Matt: Yeah, exactly. So even though the KIT program and the RET program are really targeting very different forms of c- cancer, at the end of the day, they share the exact same oncology prescriber base.
[01:07:41] Matt: And so you can have a single sales team service both programs and frankly rationalize building out the commercial arm of the company internally.
[01:07:53] Alex: Now, you might be wondering where in the timeline of the company are we at, at this point? You have a bunch of clinical failures and a handful of clinical successes hit, new people taking senior leadership.
[01:08:05] Alex: That brings us to June 2021, which is where the company's kind of at this really important inflection point. You have a bunch of clinical failures, a handful of clinical successes, some partnerships and, and deal-making going on. Um, and then there's this kind of middle stepchild program that ends up s- surprisingly taking on a, a major role in the company.
[01:08:26] Alex: Do you wanna take a guess on what that program was, Matt?
[01:08:29] Matt: I guess, uh, mastocytosis, I would imagine.
[01:08:32] Alex: That's right. Avapritinib, also at this point called Ayvakit, gets approved in advanced systemic mastocytosis, that very severe form of mast cell-driven disease caused by that mutation in KIT D816V.
[01:08:48] Alex: All right, so let's take a moment here to unpack everything that's happening.
[01:08:50] Alex: They've got four newly approved indications for their programs in only two years. First, Ayvakit on that narrow GIST subtype back in twenty twenty, then Gavreto with dual approvals in lung and thyroid cancer in twenty twenty, and now a second approval for Ayvakit in mastocytosis in twenty twenty-one as well.
[01:09:10] Alex: Here's the thing, though. These are clinical approvals, not commercial validation. Ayvakit is boxed in by a very small label in GIST, which is already a small indication. And for Gavreto, they were trying to grab market share in RET just as sophisticated competitors were entering. Lilly had a competing RET drug called selpercatinib, which launched in May twenty twenty.
[01:09:35] Alex: Blueprint's launch was four months later. Basically, in oncology, that can be a pretty devastating blow. A four-month head start of locking in prescribers and patients on medication that's otherwise relatively similar in profile is ultimately a massive commercial advantage. Erica Evans ran the pralsetinib program that became Gavreto.
[01:09:55] Alex: From her perspective, why Blueprint lost is less about the molecule and more about the clock.
[01:10:01] Erica: If you compare the two molecules pre-clinically, they're fairly similar. Execution-wise, Loxo filed their IND maybe six months before Blueprint, and, you know, they were off to the races and executed really amazingly, and we were just never able to catch up despite a lot of efforts.
[01:10:20] Erica: Like I said, though, I think pre-clinically and clinically, the molecules are pretty similar in terms of what they're able to do. The mutants they're able to cover and sort of the patient benefit they're able to provide.
[01:10:34] Matt: Well, I think reasonable people can disagree about whether this was purely a, a timing issue versus differences in the safety profile and efficacy between the two molecules.
[01:10:44] Alex: But I think regardless of that, the commercial scoreboard makes it clear that there's a big gulf between the two drugs. By twenty twenty-two, Lilly's drug is pulling in roughly two hundred million dollars a year, while Blueprint is barely doing thirty. Um, in fact, Blueprint's drug sales are so tiny that it doesn't even get its own line item in Roche's investor calls or, or presentations.
[01:11:09] Alex: It's just lumped into the other category.
[01:11:12] Alex: So now it's February of twenty twenty-three. Roche sees that this drug wasn't performing nearly as well as they had hoped, so they end up giving it back to Blueprint. After sinking something like a billion dollars of total value into this partnership with Blueprint, Roche realized that there wasn't much there and wrote the whole asset down walking away.
[01:11:33] Alex: Blueprint ends up passing this leftover drug, though, to a smaller company called Rigel for some token amount of upfront payment. This was supposed to be the undeniable proof that their platform could churn out more than one commercially viable drug. But instead, it seemed to be that there's this kind of brutal lesson about what happens when you're second to market in oncology up against Eli Lilly of all companies.
[01:11:58] Alex: So here's Blueprint. Four approvals, but the company is starting to contract towards a single drug and a single disease, and that disease isn't really even cancer. This is the state of the company that Kate Haviland ends up inheriting as CEO.
[01:12:12] Matt: That's right. And it's a tough situation. In April of twenty twenty-two, right as these struggles with Gavreto are starting to be picked up on, Jeff Albers steps away from CEO and Kate takes over.
[01:12:26] Matt: Let's build some more background around Kate so we get to better understand how she's going to steer the company from here. First to know is that she's yet another product of Genzyme and the diaspora that came from it. She, similar to Jeff, came up through the corporate and deals side, and in between Genzyme and Blueprint bounced through a string of biotechs.
[01:12:46] Alex: Yep, and another thing to know about her is that she has a lot of clarity about what she's good at and what she isn't. She'll tell you flat out, quote, "Although I love science, I am a terrible bench scientist. It's not what I'm good at. As I thought about where I could contribute, it felt more on the business side."
[01:13:04] Alex: So her entire career is built on corporate development, and even though she can jokingly call herself a, quote-unquote, "terrible bench scientist," she's actually staking a claim to a very particular kind of authority. She is the capital O operator, someone who can connect the pieces, structure the deals, and make those hard calls that Blueprint desperately needs in the state that it's in at this time.
[01:13:29] Alex: So let's pivot back to where the real value of this company was hiding all along, mastocytosis. Because honestly here, the most underappreciated part of this entire story is, of all things, diagnosis.
[01:13:42] Matt: Dun, dun, dun. I mean, this is obvious, but before you can sell a drug for mastocytosis, the patients actually have to know that they have that indication.
[01:13:54] Alex: The numbers on this are just totally out of whack. There were these surveys published in 2022 showing that patients with systemic mastocytosis reporting that it took an average of about six years from their first symptom to get an actual diagnosis, and they were seeing more than five different doctors along the way.
[01:14:14] Matt: In many ways, a six-year diagnostic journey makes a lot of sense, right? The symptoms are scattered all over the body, flushing, gut distress, bone pain, brain fog. Those mimic a lot of other conditions, right? So yeah, I'm not surprised it took so long to diagnose folks.
[01:14:35] Alex: Things of, of that milieu, yes.
[01:14:37] Alex: And to really give a sense of how invisible this disease was in being characterized, Christoph Lengauer told us about his experience exploring the field in the early days of the avapritinib program's pivot to SM. He was flying all over Europe trying to find anyone who even treated it. When he would ask for a, quote-unquote, "mastocytosis unit," people didn't know how to spell it, and if one did exist, it was usually in a basement somewhere.
[01:15:04] Alex: He also told us this kind of too bizarre to be true story about going to the worldwide mastocytosis meeting early on, expecting this huge gathering of experts. But instead.
[01:15:18] Christoph: There was a talk by this lady, an Italian lady, and she reported out, like, how many patients had this bee sting allergy and, like, what that correlated with.
[01:15:27] Christoph: And the next speaker was a Swiss lady, and she reported out that her numbers were totally different. And then there was this debate about why those numbers are different. The only way they could settle that argument was the bees in Italy are different from the bees in Switzerland. I'm like, "Okay, good.
[01:15:45] Christoph: Next. Mastocytosis." I'm like, "What are we doing?"
[01:15:50] Matt: Yeah, that's, uh, that's the gathering of the entire global expert community, right? And so in this context, the patient population looked absolutely tiny. This is not an unusual situation in rare disease. Often, for there to be a real impetus to find and diagnose patients, you need to have an effective treatment in hand to really get people across the finish line of a diagnostic journey.
[01:16:18] Matt: I mean, take for example how insanely complicated the diagnostic process was before Blueprint came along. Mechanically, you needed to do a bone marrow biopsy, a tryptase blood test, and specific molecular testing for that KIT D816V mutation. Like, what standard allergist is ever going to order a bone marrow biopsy for their patient?
[01:16:41] Matt: And that creates this catch 22. The only patients who get diagnosed are the ones sick enough to force the system to keep digging for SM. And eventually, aggressive SM kills you, so those patients do end up getting biopsies. The median delay for them getting diagnosed, by the way, is around three years.
[01:16:59] Matt: Still rather long, even for this serious disease.
[01:17:02] Alex: I think it's also important to highlight that in the case of indolent systemic mastocytosis, it's not killing you. It's sort of wrecking your quality of life. And as a non-fatal disease, there was often the situation where clinicians were hesitant to really treat it super aggressively.
[01:17:20] Alex: In talking with mastocytosis clinician Dr. Castells, she really explained this beautifully.
[01:17:26] Mariana: Mayo Clinic and, uh, and MD Anderson have shown that those patients have a normal lifespan. They have complications. They break their bones. Potentially, they have anaphylaxis. They have some things. But patients with indolent systemic mastocytosis have a normal lifespan.
[01:17:39] Mariana: So why would we want to do more than that? Why would we want to actually put patients maybe at risk for complications if we have more aggressive drugs? The reason for that was that even on all those medications, the quality of life of the patients was not totally perfect. The doses that they had to use of antihistamines and mast cell blockers and so on was high.
[01:18:00] Mariana: That in itself had potential side effects. So for example, fatigue. Is fatigue coming from mastocytosis or because I take four antihistamines a day?
[01:18:08] Alex: So you're exhausted twenty-four seven, drowning in antihistamines. And because there was no urgency to treat it, the median delay for these indolent patients wasn't three years, but it was even closer to nine years.
[01:18:21] Matt: Oof. Yeah, that's no good. And during that nine-year period, Dr. Castells told us about the patients she was seeing in the pre-avapritinib era.
[01:18:31] Mariana: Those patients had been seen by, you know, no less than three or four providers. They had seen a gastroenterologist, a dermatologist, sometimes even a psychiatrist, a endocrinologist, an allergist.
[01:18:42] Mariana: Nobody was able to put together all those symptoms because the symptoms were kind of disparate. They were in, in at least two organ systems or three organ systems. So it has been an evolution since, you know, the early '80s to the present time in terms of those patients being seen, but then not having enough tools to make a diagnosis.
[01:19:01] Alex: Ugh, I, I can't even imagine it. Severe physical allergic reactions, bone pain, getting sent to a psychiatrist. It sounds like one of these, these diseases from the 1800s, right? Uh, hysteria or something.
[01:19:14] Matt: A humoral imbalance. Ugh. Yeah. Yeah, it's, it's devastating. And from the corporate side, this is the exact moment Blueprint is kind of cornered.
[01:19:24] Matt: The cancer expansion fan strategy isn't really working. The lung cancer drug is getting crushed by Lilly. The GIST drug is really super niche, and so they need to figure out how to find and diagnose these invisible mastocytosis patients to keep the company going.
[01:19:45] Alex: Yeah, they didn't really have a choice.
[01:19:46] Alex: If there's no diagnosable indolent mastocytosis patients, there's no market. They're forced basically to make this massive, aggressive push to build the diagnostic ecosystem for this disease from scratch. They launch a patient registry, partner with advocacy groups, and run a targeted awareness campaign called It's SMthing.
[01:20:08] Matt: Ba-dum-tss. They hope to get six hundred patients to opt in over nine months in a clinical trial, and they ended up hitting that goal in just twenty-two days.
[01:20:18] Alex: Yeah, this was the first indication that the patient demand was really there. But again, for a disease that involves unpredictable anaphylactic shock, the reality of treating these patients was super intense.
[01:20:32] Alex: Christoph told a story about meeting with advocacy groups and having to clean all of the rooms that the meetings were happening in to, to make sure that there wasn't, uh, someone having an anaphylactic event. And even something as benign as sort of what color pills should be used in the clinical trials ended up being a point of concern.
[01:20:53] Christoph: We made three pill sizes, and we made them red, white, and blue. And she says, "Oh my God." And I'm like, "What happened?" She says, "Almost all red dyes cause an anaphylactic shock in mastocytosis patients." We called manufacturing, canceled the job, changed the dye. That's why there is no red pill for our KIT inhibitor.
[01:21:20] Christoph: That's what you learn from patients, right? Like, you know, it saved maybe the drug.
[01:21:25] Matt: Uh, totally unbelievable. The color of the dye of the pill could have literally triggered anaphylaxis in, in their patients and maybe even derailed the company for more time spent wandering in the desert. So they were basically tiptoeing between testing the drug and getting a better understanding of this disease, which seems to have been chronically understudied before they entered it, to build out this diagnostic awareness for patients.
[01:21:52] Alex: For reference, by the time they were ready to launch, that diagnosed population was already growing straight into this market. So in a way, they had two sides of the same coin for - this indication — kind of a silver lining to the beginning of this episode where we mentioned Foundation and Blueprint being Third Rock's diagnostic and treatment bets for genetic disorders respectively.
[01:22:14] Matt: Yeah, so it was a very complicated situation where the company had to drive patient awareness, develop a better, easier diagnostic test, again, to help drive the patient population. And in that time, they ultimately do that by developing a newer PCR-based test that can detect the KIT mutation from an ordinary blood draw without needing to do a, a bone marrow biopsy or any, any of that.
[01:22:40] Matt: Very much, uh, removing one of the barriers to adoption, where an allergist can now just order a blood test and get a clean readout and move forward with treatment. But even as these patients are moving out of the shadows, getting this drug approved and across the clinical endpoints was really a whole separate mountain that they had to climb, right?
[01:23:00] Alex: Because the regulatory path for indolent mastocytosis really didn't exist yet, and, and Blueprint had to define it. There was no accepted way to measure success or no validated clinical endpoint, uh, that Blueprint could copy from its competitors.
[01:23:15] Alex: And so they had to construct one from scratch. They built a daily symptom diary that scored patients across all of those scattered domains of symptoms, and they did so by working with the absolute heavyweights in mastocytosis research, one who we've already introduced, Mariana Castells at Brigham and Women's, but also people like Cem Akin at Michigan.
[01:23:38] Matt: Still, yeah, I, I can't imagine the difficulty of defining the clinical endpoints in this disease, mostly because the symptoms vary so wildly. And Christoph told us a great story that sort of captured the heterogeneity so perfectly.
[01:23:55] Christoph: We interviewed all those people and we're like, "What do we put on that thing?"
[01:24:00] Christoph: And one said frequent urination and the other is like "No way." And you know why? Because if you do a patient-reported outcome and it's about frequent urination, the farmer says it's not a problem because he just pees in the field. The bus driver loses his job. Even now we had this big thing that our patient-reported outcome didn't work with severity because, like, all those situations, right?
[01:24:28] Christoph: It was an absolute mess.
[01:24:31] FDA Approval & Diagnosis Ecosystem
[01:24:31] Alex: It's now May of twenty twenty-three. This is a moment the company's been waiting for a long time now. After convincing the FDA to use a diary as the primary endpoint for measuring the effects of these drugs on the patient's quality of life, the FDA officially approves Ayvakit for indolent systemic mastocytosis, the first and only treatment for this much larger group of patients than the aggressive form. Literally the market Blueprint had at this point spent five years methodically building towards.
[01:25:04] Alex: So, uh, an FDA approval, you might think Wall Street absolutely loved that headline, right?
[01:25:09] Matt: Nope. Stock drops twenty-three percent the exact same day.
[01:25:13] Alex: It sounds insane until you look at the data. Because the effect in their pivotal clinical trial, called PIONEER, actually came in kind of soft. On the symptom score, which is the measure Wall Street really cared about, avapritinib beat the placebo by about six point four points.
[01:25:29] Alex: Analysts were looking for something in the seven to ten-point range.
[01:25:33] Matt: To think— I'm, I'm— this is so, this is so classic of Wall Street—
[01:25:37] Alex: I know…
[01:25:37] Matt: —to be this precise yet inaccurate, right?
[01:25:42] Alex: Agreed. This is a first-in-indication approval, a disease-modifying treatment for this—
[01:25:47] Matt: Yeah…
[01:25:47] Alex: —horrible illness. And yet—
[01:25:49] Matt: These are analysts sort of groping around blindly to try to understand what the commercial traction will be, and I think understandably, they, they don't really know what to believe.
[01:26:00] Alex: Right. I guess the, the takeaway from it is something like, "This drug works less well than we've already priced it." How about that?
[01:26:07] Matt: Sure, yeah. Completely unsurprising that there's this sort of commercial debate going on. I think underneath the subjective symptomatic score, I think completely hides the fact what the drug is doing to the disease underneath.
[01:26:20] Matt: If you look at the objective markers, mast cell burden in the body, tryptase levels, variant allele fraction, like all of these sort of molecular markers really show that this drug is doing wonders for these patients, really showing evidence of being a disease-modifying treatment that's killing off these mutant cells and clearing the bone marrow up.
[01:26:42] Matt: Part of me is not surprised that there was this sort of disconnect between the molecular markers, but ultimately only a, a quote-unquote moderate change on the symptom score.
[01:26:53] Alex: Let's be real here, too. The, the actual commercial hurdle isn't Wall Street analysts debating a handful of points, but really getting these doctors that are seeing these patients on board to pre- prescribe it.
[01:27:05] Alex: You'd think that for such a symptomatically serious disease, it would be trivial to get doctors interested in offering this to their patients. But Dr. Castells tells us a different story. Getting community allergists in particular to accept that a new targeted kinase inhibitor could be impactful for their patients ended up being a massive sociological challenge in itself.
[01:27:28] Mariana: If you ask me, for example, a regular allergist like in the community, they're still, quote-unquote, uncomfortable about using something like avapritinib, which they consider to be chemotherapy. We do a lot of YouTubing and a lot of open information about that to tell them, "Well, it's chemo, but it's not chemo.
[01:27:43] Mariana: You know? You don't have to worry. You don't need to do blood counts every week," for example.
[01:27:47] Matt: Yeah, I, I really didn't expect this, but apparently, when allergists hear the word tyrosine kinase inhibitor, they think cancer, and they think of chemotherapy. And getting past that hurdle is really everything because when patients actually take the drug, there does seem to be a pretty profound physical and psychological turnaround.
[01:28:08] Matt: You know, we've been focused most on the life-threatening aspects of this condition like anaphylaxis, but Dr. Castells pointed out that one of the most profound reliefs is simply having their skin look a lot better.
[01:28:21] Mariana: One of the most important things about patients with indolent systemic mastocytosis is they have those dots, and those dots really have a tremendous psychological impact.
[01:28:29] Mariana: And you know, the girls can't really wear anything. You know, they have to be covered up to here. You can't go to the beach without being noticed. You have measles. Now, with TKIs, you can actually unfold. Patients rave about their skin's clearing. "I look almost normal." That's what all the patients tell me.
[01:28:47] Alex: It's really hard to overstate how much something like this matters. Seeing a chronic condition you've spent years bouncing from doctor to doctor trying to identify recede with a pill — I can understand why you'd feel inclined to take that medication. Dr. Castells also told us about another story of a CEO she treated, someone that had been suffering for fifteen years with ISM and literally taking up to thirty-two pills a day just to function.
[01:29:18] Mariana: This CEO was giving talks in his company and then feeling flush and itchy and suddenly passing out in front of, you know, maybe five hundred people. So I talked to him extensively about, uh, avapritinib and said, "You know, you are a great candidate for that." Uh, yesterday, he came like a new man. The guy said, “Doc, you saved my life.
[01:29:35] Mariana: I mean, this is completely gone."
[01:29:38] Alex: When you hear these sorts of outcomes, clear visual and symptomatic evidence of people feeling better, the commercial debate that we talked about starts to evaporate a little bit, right? It becomes a question of whether Blueprint can actually find these patients and get doctors comfortable prescribing the drug.
[01:29:59] Alex: And if they do, avapritinib is no longer some niche product. It will actually be a massive franchise. Ultimately, the numbers do back that up. Ayvakit does a half billion dollars in sales in twenty twenty-four, already up, you know, a hundred and thirty-five percent year over year.
[01:30:16] Matt: Let's understand why. It's, it's because beneath the luck of expanding the diagnosis, there is a very repeatable playbook running underneath all of this.
[01:30:26] Matt: It's the one that Gleevec wrote after all.
[01:30:29] Alex: Bingo. Yeah. Chronic myeloid leukemia wasn't exactly a massive disease by head count either, right? And Charles Sawyers, who helped write the playbook of Gleevec, he explained to us exactly why that specific business model is so undeniably powerful.
[01:30:46] Charles: That's a safe drug that you have to take forever because you're not curing the patient.
[01:30:50] Charles: That's why Gleevec is so successful. You know, no one go-- everyone starts it, and no one stops. That was, to me, the eureka discovery from within Novartis.
[01:31:00] Matt: Couldn't have said it better myself. Oncology pricing multiplied by multi-year dosing is a recipe for a blockbuster drug. And you see this perfectly with avapritinib.
[01:31:12] Matt: The exact same molecule, a modest business in GIST, and a, a multi-billion dollar franchise in mastocytosis because these indolent patients neither die nor get cured, but still benefit tremendously from the treatment. They just stay on the drug year after year. Blueprint is now providing guidance towards two billion dollars a year in annual revenue by twenty-thirty.
[01:31:35] Matt: This is pretty much exactly what Blueprint's leadership started to realize as these patients' stories were trickling in, and it goes to show the amount of influence that these patient advocacy groups have on these companies that focus on rare diseases. They lean on this single disorder so much that you can literally kind of watch the company's entire repositioning happen in real time.
[01:31:58] Matt: We took a look at the Wayback Machine of the company's pipeline page from twenty-twenty-three onwards. At first, you see their full sprawling inheritance of molecules that they were testing in clinic or got approved, Gavreto, the EGFR lung cancer franchise that they were building.
[01:32:15] Alex: Bunch of other stuff as well, right?
[01:32:17] Matt: Yeah.
[01:32:17] Matt: And they're still pitching this sort of like super expansive pipeline back in twenty-twenty-three.
[01:32:22] Matt: And then you can see between specifically December twenty-twenty-three and April twenty-twenty-four, all of it gets deleted. Gavreto, gone. The entire EGFR franchise, gone. It's all reduced in an investor deck to just a single bullet point about cutting quote unquote "operating expenses."
[01:32:42] Alex: Classic.
[01:32:43] Alex: Yeah. It, it's really fascinating to see the evolution of the original core platform thesis, right? Blueprint started out pitching a world of opportunity around drugging all of the five hundred different human kinases.
[01:32:57] Alex: And by twenty-twenty-four, the pitch is a lot narrower and a lot sharper. It's a world of opportunity inside one target KIT in the mast cell indication.
[01:33:10] Matt: Pipeline in a pill. They basically just line up three shots on goal in that, that single axis from there on out. You've got Avapritinib for mastocytosis.
[01:33:20] Matt: You have a next-gen drug, elenestinib, built to fix avapritinib's brain penetration issues. And then you have a brand new asset, BLU-808, aimed at the much bigger world of mast cell allergy and inflammation. This sprawling kinome platform that it started with kind of ended up collapsing into a highly focused KIT franchise, which means by mid twenty twenty-four, Blueprint is telling one incredibly clean story.
[01:33:49] Matt: We are a rare disease and mast cell company.
[01:33:51] Alex: A quick note about the elenestinib story because it comes together unusually fast. Once Blueprint starts to have a compound that shows activity in mastocytosis, you start to get a sense of where the compound is good and where there's room for improvement. And it became clear that for this opportunity in the indolent patients, you needed a cleaner safety margin than what they were originally thinking about. Here's Tim talking about that program's TPP.
[01:34:24] Tim: We knew that we had a active compound. We knew what to look for clinically. We also knew that to, to expand maybe most productively into the more indolent disease in SM, you wanted a higher safety profile than we had in our heads when we were targeting an oncology indication. And so at that moment, you took, you know, all that learning and what that new TPP might be that would win in that indication actually really informed and accelerated the identification of that backup.
[01:34:52] Tim: And that was a very quick program to be able to do that.
[01:34:56] Matt: And so by twenty twenty-four, platform company number one focused on kinase discovery has really transitioned to platform company number two, driven around their expertise in KIT biology, prosecuting a whole spectrum of diseases driven by mast cell disorders.
[01:35:14] Matt: That shift is happening essentially one year before Sanofi shows up to, to buy them out.
[01:35:35] The Sanofi Deal: A $9B Acquisition
[01:35:35] Alex: Let's move forward to January of twenty twenty-five. You're now looking at two entirely different corporate timelines running straight towards each other at terminal velocity. On one side, you have this nimble, hyper-focused player that has finally decoded its own machine and is watching its revenue curve go vertical.
[01:35:53] Alex: On the other side, you have one of the largest pharmaceutical companies on Earth pulling in billions, but painfully aware of when that revenue stream will drop to zero.
[01:36:03] Alex: This is the collision that defines the multi-billion dollar exit that we've been foreshadowing for this entire episode. To see it coming, you have to look at the stage where the industry's biggest cards are always played, the J.P.
[01:36:16] Alex: Morgan Healthcare Conference in San Francisco.
[01:36:19] Matt: Let me tell you, if, if you haven't been to JPM, uh, conference is really a misnomer here. JPM is really not about any sort of public talks that may happen. It's a one-week event that happens each January in San Francisco, where every single BD person, executive, and investor in the life science industry decides to cram into a couple of blocks of San Francisco.
[01:36:44] Matt: I usually think of it as the industry's annual forcing function for making deals.
[01:36:50] Alex: exactly. It's sort of our version of Sun Valley or in some ways Burning Man a little bit. Which is why Blueprint treats it with that exact level of gravity. For JPM of January twenty twenty-five, they run an incredibly tight ship.
[01:37:08] Alex: They almost never hold lavish standalone investor days and instead save everything up for this exact moment. This January twenty twenty-five presentation deck that they show to investors is the exact document that Sanofi's corporate development teams are almost certainly going to dissect in due diligence, and the numbers inside it are the reason the checkbook comes out.
[01:37:32] Alex: The revenue ramp Blueprint puts up for avapritinib in that deck is fantastic. Fifty-three million dollars in revenue in twenty twenty-one, a hundred and eleven million in twenty twenty-two, two hundred and four million in twenty twenty-three, and almost a half billion in twenty twenty-four. But it's the guidance that shifts the gravity of this sector.
[01:37:52] Alex: They raised their estimated peak revenue for the mastocytosis franchise to four billion dollars a year, up from previous decks where they had pegged the number around one and a half billion dollars. It's a nearly three times upgrade anchored by a hard projection of two billion dollars in annual revenue by twenty thirty.
[01:38:09] Alex: Let's take a moment to remember the entire reason these numbers are climbing. It's A, the diagnosis numbers from the mast cell story we just tracked, and B, the patient benefit that many people with indolent mastocytosis were seeing on Ayvakit. The deck officially reframes the observable US mastocytosis market to about twenty-five thousand patients visible in claims data, up from sixteen thousand just a couple of years earlier.
[01:38:37] Alex: So that peak revenue estimate is as high as it is, because that bigger, newly diagnosed population is now flowing in directly to the financial model. The entire valuation of this company essentially has transformed because the drug made a hidden disease visible.
[01:38:54] Alex: In avapritinib, Blueprint now has a molecule that is historically right in the sweet spot of the sort of drug that pharma wants to purchase.
[01:39:04] Alex: So why does Sanofi, of all companies, want this drug so badly, you know, badly enough to spend almost nine billion dollars? It comes down to a single drug Sanofi doesn't fully own and an absolute wall that they're running towards.
[01:39:18] Alex: That drug is Dupixent, an absolute monster of an immunology and allergy product.
[01:39:24] Alex: It treats asthma, eczema, chronic hives, and a constantly expanding list of indications. In twenty twenty-four alone, Dupixent generated about fourteen billion euros for the company. It is the undisputed economic engine of modern Sanofi, but it has two structural flaws. First, Sanofi shares the economics with Regeneron, and their cost-sharing arrangement which has been a massive tailwind for years, runs out at the end of this year, twenty twenty-six.
[01:39:55] Alex: By Sanofi's own financial disclosures, that transition creates a drag of a few hundred million euros in twenty twenty-six, ballooning to an eight hundred million euro hit next year in twenty twenty-seven. Second, the core US patent expires in twenty thirty-one, followed by Europe in twenty thirty-three. So Sanofi is sitting on a mountain of cash, but that mountain has an expiration date.
[01:40:19] Alex: Paul Hudson, Sanofi's CEO until recently, had been spending the last few years aggressively remaking the company as it hits the loss of exclusivity event. He famously described the old Sanofi as a slow-moving French dinosaur with zero R&D focus. He immediately jacks up the R&D budget from around five billion euros a year to almost eight and a half, pushing every dollar towards what he calls clear winners.
[01:40:45] Alex: His great line about the typical big pharma R&D budget is that the company spreads around resources like Nutella, a super thin layer over absolutely everything, so nothing ever gets enough resources to win. To fix that problem, he ruthlessly spins off Sanofi's consumer health business for around eleven billion euros and immediately recycles that capital into high-conviction immunology and rare disease deals.
[01:41:09] Matt: So Sanofi has this massive budget, but they can't really focus it. It kind of begs the question, why didn't big pharma just build Blueprint's kinase engine entirely in the first place? They certainly had the cash for this, right? If they could just sell off one of their businesses for eleven billion euros, that easily dwarfs the ten million that, that Blueprint put into their platform.
[01:41:32] Alex: Yeah. So we asked the head of the platform, Tim Guzi, that exact same question. B-before Blueprint, Tim actually worked at Schering-Plough and was trying to convince that big pharma to, to do this type of screening approach. And, uh, he had a pretty good explanation for why the pharma giants really can't stomach this style of investment.
[01:41:53] Tim: And so to go and say we're gonna invest $40 million, well, $10 million is probably more accurate than, than, you know, it was a $40 million raise, but if you-- probably $10 million in the library and the screening effort, and then do that, you know, a million dollars a year, year on year on year, that's a hard hurdle.
[01:42:09] Tim: It was surprising there, you think a big pharma-- there's so much revenue, you're like, "How can you not just do this?" But there's always that, well, if I'm doing that, I'm not doing something else, and what's the tangible benefit of this, and how do I rationalize to everyone in the larger company that this is a good idea to have this money towards this, for maybe we don't even have a program?
[01:42:32] Matt: Really illuminating from Tim. Our understanding is, is that pharma's inertia toward high-risk projects ultimately leaves it to venture capitalists and biotech startups to take those ten million dollar swings to build something like Blueprint from scratch. And then, you know, fourteen years later, contingent on success, big pharma will saunter back in with nine billion dollars to buy the finished product.
[01:42:55] Alex: But the cleanest statement of why Sanofi specifically targeted Blueprint doesn't even focus on the science. It comes from Brian Foard, Sanofi's head of specialty care, and what he points to is Blueprint's unique sales force. He said, quote, “Their call points uniquely fit us perfectly. Think about our pipeline being built right now. Amlitelimab, lunsekimig, TL1A. The call points for those assets are going to be dermatologists, allergists, GIs, which is exactly where Blueprint is today.”
[01:43:26] Alex: So yes, when Sanofi is thinking about buying Blueprint, they are getting a growing mast cell drug, but they're also getting a fully mature, ready-made commercial machine pointed at the exact specialty doctors that Sanofi's entire next generation of immunology drugs will desperately need as Dupixent hits its patent cliff.
[01:43:50] Alex: Blueprint is getting rewarded essentially for the years of hard work it has performed to build relationships with those specialists and finding the elusive mastocytosis patients. So from Sanofi's side of the table, this cancer company turned mast cell company is a really valuable distribution channel for immunology assets.
[01:44:13] Matt: Yeah, the actual n- negotiation of the deal, I have to say, is really fascinating. Thanks in part to the tender offer filings that we read up on, we can kind of reconstruct it almost meeting by meeting, starting with something way smaller than you'd expect. So winding back the clock a bit from JPM twenty twenty-five to May of twenty twenty-four, Sanofi ends up signing a confidentiality agreement with Blueprint, but it's only to look at BLU-808, that very early stage allergy asset.
[01:44:45] Matt: The filing notes something really important in plain language. That agreement did not include a standstill provision.
[01:44:52] Alex: Right. And for those who don't know, standstill is a standard clause where the buyer promises not to go buy up the company stock or make a hostile run while they're talking. So when there isn't a standstill provision, it means that Sanofi has deliberately kept the option open from day one to come after the entire company.
[01:45:10] Alex: So yeah, the conversations start with an early stage asset, but as we'll see, they'll end up taking the whole kit and caboodle. Things escalate really quickly from there. In November of 2024, at an industry conference are the first explicit talks of an acquisition, and then we hit January 2025, the JPM conference, and that's the week that Blueprint updates their peak revenue projection models.
[01:45:37] Alex: Kate Haviland and Paul Hudson end up having dinner at the conference. Uh, Jeff Albers, the former CEO, is also part of that conversation as well. No specific terms are discussed, but four days later, on January 17th, Sanofi sends a formal written proposal, 124 bucks a share, all cash. That's about eight and a half billion dollars.
[01:45:58] Alex: Blueprint's board immediately calls it inadequate.
[01:46:02] Alex: But they open the books for priority diligence, form a transaction committee, which includes Albers, Borisy, and a director named Lonnel Coats, and they bring in Centerview and Jefferies as their bankers. The very next day, those bankers reach out to four possible other buyers to see if they can spark a bidding war.
[01:46:20] Alex: One of them, labeled Party A in the filings, expresses some preliminary interest and takes a look. The other three decline immediately. There's never really a bidding war for Blueprint.
[01:46:31] Alex: Doesn't matter for Blueprint because a few days later, Sanofi still comes back with a higher offer. A hundred and twenty-nine dollars of cash now, plus nine dollars in the form of a contingent value right, or a CVR.
[01:46:44] Alex: You can think of a CVR as a sort of IOU kicker that gets bolted onto a deal. It's extra money that only pays out if a specific milestone happens at a later date. This CVR is added, and it's entirely Sanofi's idea, showing up in the term sheet for the first time. Blueprint quickly counters on the twenty-ninth, wanting a hundred and thirty-five dollars a share in cash plus five dollars a share in CVRs.
[01:47:11] Alex: Then on February fifth, Sanofi walks away. They cite, quote-unquote, "other priorities and evaluation gap," and leave the table.
[01:47:21] Alex: Ultimately, this is just a negotiation tactic, and Sanofi comes back to the table. There's another dinner between Haviland and Hudson, this time in Paris. And then finally, in May, Sanofi delivers what it calls its absolute final offer, a hundred and twenty-nine dollars a share in cash and a CVR worth about six dollars.
[01:47:41] Alex: Importantly, the CVR pays out two dollars if an early asset hits a clinical milestone and four dollars if it ever gets to FDA approval. The deal goes stale in four days, so Blueprint has four days to take it or leave it. The board is terrified Sanofi will walk again because they think this time they mean it.
[01:48:01] Alex: So they end up taking it, and ultimately, Blueprint Medicines closes for about nine point one billion dollars in cash up front in an acquisition from Sanofi. But let's pause here for a second because this detail about the CVR is really interesting and would be a shame to let slip away. If you really wanna understand why Blueprint accepted this structure, you have to go and look back who's sitting on the Blueprint side of the table receiving this offer.
[01:48:28] Matt: Yeah, you got essentially a whole bunch of Genzyme folks. Kate Haviland, who came from Genzyme. You have Jeff Albers, who came from Genzyme, and, you know, they're part of that Genzyme diaspora that, that all left after the company was acquired by Sanofi.
[01:48:45] Alex: Let's do a bit of a flashback. Genzyme was acquired in 2011 by Sanofi, and the way that Sanofi managed to do this acquisition was through CVRs, the same exact trick.
[01:48:59] Alex: They bolted a CVR onto the cash price, and here we are more than 10 years later, them trying the exact same playbook on some of the same people who were at the company at the time.
[01:49:11] Matt: Yeah. Well, I mean, we-- I think CVRs are an extremely common thing in the life science industry, and so the fact that we're bringing it up is because, uh, there was a huge amount of controversy related to the Genzyme CVR.
[01:49:28] Matt: Uh, so during that deal back in 2011, the CVR was tied to, uh, the performance of a multiple sclerosis drug called Lemtrada. And so essentially, if certain milestones were met in the sales of that drug, the Genzyme shareholders would get paid out. So as a reminder of, like, who ultimately was responsible for the drugs driving that CVR.
[01:49:56] Matt: It's Jeff Albers. So the exact person who's now on the transaction committee evaluating essentially a second buyout offer and a second CVR from Sanofi. Jeff has lived to know what can go wrong with a CVR. As you could imagine, uh, there's a certain incentive on the counterparty to just barely miss the triggering criteria for a CVR.
[01:50:22] Matt: So if the payment happens, if there's two hundred million dollars in annual revenue, you can imagine there's a lot of incentive to have the sales number that year be, you know, a hundred and ninety million or something. That's ultimately what happened with the Genzyme CVR. They missed a FDA approval deadline by a couple months, and they missed a sales threshold just barely.
[01:50:48] Matt: And this ultimately triggered a lawsuit between Genzyme shareholders and Sanofi, where they explicitly alleged that Sanofi was sort of deliberately slow walking the rollout of that drug to avoid paying the CVR.
[01:51:02] Matt: As it turns out, Sanofi ended up settling years later for twenty-four cents on the dollar.
[01:51:07] Alex: Not a great deal for Genzyme shareholders, but more than nothing. Now it's 2025. Sanofi slides in with this new six dollar CVR across the table for Blueprint's early-stage allergy drug, BLU-808. The Blueprint team already knows the punchline. They've been on the receiving end, again, of this exact same mechanism from this exact same buyer, and understandably, they're a little bit nervous about accepting CVR money, which in some ways you could compare to monopoly money used to make a headline price look bigger.
[01:51:42] Matt: Yep. And, you know, everyone was wide-eyed here. The, the bankers valued that six dollar CVR at about two bucks, and I think the market was valuing it at maybe thirty-three cents. So Yeah, it was effectively monopoly money, and ultimately, I think the CEO of Sanofi pretty much called it upside optionality, which is a pretty good euphemism for monopoly money.
[01:52:08] Alex: I'm gonna use that every time I wanna cheap out on someone. Upside optionality. Blueprint knew the real deal, of course, was that $129 in hard cash. They took that guaranteed money, let Sanofi staple their little IOU to the press release to save face on the total valuation of the company, and then walked away with that beautiful nine billion dollars in cold hard cash.
[01:52:35] Alex: Let's try to understand today, in 2026, what Sanofi actually got for its nine billion dollars in cash. From our understanding, it's almost exactly what they paid for. Ayvakit has kept ramping. Full year 2025 sales came in at around seven hundred and twenty-five million dollars in revenue, slightly ahead of the projected number Blueprint had set before the deal had even closed.
[01:53:01] Alex: Plus, it's still accelerating. The first quarter of 2026 just did about two hundred and seven million dollars, almost entirely from the US market. That's up nearly forty percent year over year, and it's now sitting at a run rate north of eight hundred million dollars annually, putting the billion dollar blockbuster line firmly within reach.
[01:53:25] Competition: Cogent Biosciences & Bezuclastinib
[01:53:25] Matt: It's twenty twenty six, and avapritinib is doing great, but the life science industry of this era features absolutely brutal levels of competition. There's a direct competitor aggressively chasing the franchise, and it could be the reason Sanofi pulled the trigger exactly when they did. A company called Cogent Biosciences has a drug called bezuclastinib.
[01:53:45] Matt: It goes after the exact same target, that KIT D816V mast cell mutation, but it's engineered specifically to fix the weaknesses in avapritinib.
[01:53:56] Alex: To understand why that matters, we have to talk about brain penetrance. As we've mentioned a couple of times already, avapritinib crosses the blood-brain barrier.
[01:54:07] Alex: Why does that matter, though? Well, as it turns out, when titrated up to the super high doses needed for GIST, that brain penetrance is a source of severe cognitive side effects, memory problems in something like forty percent of all GIST patients, plus a scary warning about bleeding in the brain…
[01:54:26] Matt: Cogent's drug, on the other hand, was designed from the ground up to stay completely out of the brain and to spare the normal healthy KIT kinase even more cleanly.
[01:54:35] Alex: In a way, this proves something we flagged at the very start of this episode. Blueprint's platform was never a truly unassailable moat.
[01:54:43] Alex: Instead, it was a really strong headstart. The moment an opportunity in something like GIST became legible to competitors is the moment everyone realizes the goal is a clean, mutant-selective KIT inhibitor for, say, mast cell disease. Other competent chemists can look at the identical target, see what liabilities still exist in it, and draw their own molecule, .
[01:55:06] Alex: Blueprint and Sanofi were, of course, painfully aware of these competitive dynamics at play as they were chatting about doing an M&A event. Sanofi was announcing the acquisition on June 2nd of twenty twenty-five, and then Cogent's trial in indolent mastocytosis read out hardly a month later.
[01:55:28] Alex: And it ended up hitting cleanly with numbers that are actually stronger than avapritinib's in some ways.
[01:55:34] Matt: Yeah. I mean, you can see the sort of chess match that was playing out there. Um, there were strong factors at play pushing to have a deal happen as fast as possible, as well as other factors that would drive delaying a deal, and ultimately the, the game theory of it pushed for a deal to happen in June of twenty twenty-five.
[01:55:56] Matt: You know, around this time, uh, the competition between Blueprint and Cogent was crossing from the scientific into the personal.
[01:56:04] Matt: At a investor conference right before the big Cogent readout, Cogent's CEO straight up said avapritinib was, quote, "So toxic it was killing patients.".
[01:56:13] Matt: And claimed that, you know, the Blueprint molecule was essentially inferior and required dose de-escalation to really be tolerable.
[01:56:24] Alex: Not very, uh, sportsmanlike. In, in all fairness, Cogent was, was backing up their harsh words. In the later half of last year, they posted another positive phase three, this time in GIST. And now they have their mastocytosis program under FDA review with a decision date at the end of this year.
[01:56:43] Alex: But here's Blueprint's secret advantage in all this. This is a chronic disease, and it's not cancer. Once a mast cell patient is stable on a drug that works, they're gonna be reluctant to switch, even if a rival, say, posts somewhat cleaner numbers. This is not oncology, where a fresh wave of newly diagnosed patients is going to show up every month making a fresh decision of drug A or drug B.
[01:57:08] Alex: Incumbency in chronic disease is sticky in a way that it just isn't in cancer.
[01:57:14] Matt: Yep, it's, it's just, it's so much easier to convince a untreated patient to start taking a drug than it is to convince a patient relatively happy on the drug they're on to switch to a new drug. When Sanofi buys Blueprint, one of the things they're buying is certainty, right?
[01:57:32] Matt: They bought it right ahead of a catalyst readout that could have gone either way, and, you know, by the time Cogent's rival data actually prints in July, Blueprint is part of Sanofi, and, uh, that's the end of the story.
[01:57:44] Alex: Exactly.
[01:57:45] Post-Acquisition & Curie Bio: The Next Generation
[01:57:45] Matt: All right, let's track what happens post the Sanofi acquisition because the story is not lost here, and there's a wonderful symmetry of events at play.
[01:57:55] Matt: Christoph actually texted his old boss, Christopher Viehbacher, the former Sanofi CEO, right after the deal closed.
[01:58:02] Christoph: I have to confess, I immediately sent a text message to Chris Viehbacher because when he was CEO of Sanofi, I got along with him enormously well. Of course, he had left Sanofi also in the meantime, and, and now this was all a new thing, and I'm like, "Chris, here's all the news."
[01:58:20] Christoph: nine and a half billion with a company that I started. And he texted me back, "I think it's better so for everybody. Sanofi, Blueprint, and yourself."
[01:58:32] Matt: Man, that, uh, you can always tell who's been a, a CEO. That's a extremely diplomatic answer. This poetry doesn't stop there because within months of closing the Blueprint deal, Sanofi starts cutting.
[01:58:45] Matt: They lay off about a fifth of Blueprint's staff. They quietly shelve a bunch of their preclinical programs. Kate Haviland, the CEO who engineered the Blueprint sale, she's gone as well. The executives change, the molecules change, but the rhythm of the industry never really changes.
[01:59:01] Alex: Sounds like a Bob Dylan song. I mean, this time the talent that walked out the door didn't just go sketch out another biotech company on a, say, a coffee shop napkin. We're at a very interesting moment in biotech, Matt, and I think a lot of people, even those that have been in the industry for a while, are seeing the writing on the wall for how companies are made in this sector.
[01:59:26] Alex: So some of them have decided to build a competing machine not only to, to Blueprint, but to something like Third Rock Ventures, really running with a modern perspective on how to run drug discovery campaigns.
[01:59:42] Matt: Yep. So just like at the beginning of the story, we had the Millennium diaspora get bought out and start their own venture firm.
[01:59:52] Matt: We now have the Blueprint diaspora getting bought out and start their own venture firm. This time though, this competing machine that they set up really is running with a new sort of logic to meet the reality of modern drug discovery. To get more into the specifics here, we're talking about Alexis Borisy, chairman of Blueprint, Third Rock partner, teaming up with Christoph Lengauer, Blueprint's founding CSO, and Zach Weinberg, among others, to launch Curie Bio.
[02:00:24] Matt: In twenty twenty-three, they launch a brand-new venture fund focused on seed investing. Their entire pitch is a direct structural assault on the exact model that built Blueprint. They literally call it freeing the founders.
[02:00:36] Matt: It sort of raises the provocative question of why exactly do folks like Christoph and Alexis think that the founders need freeing?
[02:00:46] Matt: To understand why the exact guys who built Blueprint are now actively attacking the model that made it successful, you have to look at who actually makes all the money. When Sanofi finally cuts that $9 billion check, who actually makes all the money?
[02:01:17] Matt: We don't actually have to guess. In a buyout like this, the merger filing, it's called a 14D-9, legally has to lay out the biggest payouts person by person, share by share.
[02:01:27] Alex: The insider group, which is the directors and officers, about 19 people total, collectively clears somewhere around $365 million. Sitting right at the top is Kate Haviland.
[02:01:39] Alex: The operator, who assumed leadership of the company long after it started, takes roughly $70 million in equity. The single best paid individual in the entire transaction.
[02:01:50] Matt: One very crude way to think about that payout is kind of like a brokerage commission, right? So picture the job of a CEO in a mid-stage biotech less as an operator and more as a real estate broker whose actual job it is to find a buyer for the company.
[02:02:10] Matt: In that frame, which I acknowledge dramatically simplifies the complex role of, of being a CEO, Kate Haviland gets paid roughly a one percent commission for closing a 9 billion dollar sale. Not very different from what a real estate broker makes for selling a house. Most people do not see that number as particularly scandalous, but for some, the ratio between the CEO's cut and everyone else's is.
[02:02:37] Alex: Right. And Jeff Albers, who is the CEO through the big approvals and then became chairman, he walks away with about $55 million. Alexis Borisy, the founding chairman and Third Rock partner, gets about twelve million, and that's completely separate from his share of carry he receives as a partner in the Third Rock venture fund.
[02:02:56] Matt: And then there's Nick Lydon, co-inventor of Gleevec, Lasker laureate, literally one of the handful of human beings whose foundational work made the entire category of precision medicine even exist. He walks away with about $11 million. So about one-sixth of what the hired operators make. The other two scientific founders, Brian Druker and Charles Sawyers, their stakes are so diluted that the filing doesn't even have to name them.
[02:03:22] Matt: Their names are on the company as founders, of course, but the actual holdings are below the reporting thresholds.
[02:03:28] Alex: And what about the bench chemists, the people who literally drew these molecules up? None of them are executive officers or get executive tier equity. To our estimates, the payouts run in the low to mid-eight figures across the entire group combined.
[02:03:43] Alex: Brian Hodous, who proposed stitching together the two sides of the avapritinib molecule, our best estimate is he had a realized payout likely in the hundreds of thousands to maybe the low millions.
[02:03:56] Matt: It's wild because scientists who've been in the industry for a very long time often start out not really understanding anything about owning equity.
[02:04:05] Matt: Christoph Lengauer tells a story about how green he was coming over from his job at Johns Hopkins. He had no frame of reference for the value of equity at all. As he put it, “I didn't even ask what percentage of the company I was getting. I just thought, a million shares — that sounds great.” He genuinely couldn't tell whether a million shares was a fortune or a rounding error.
[02:04:29] Matt: I get the sense that this is a blind spot that's pretty specific to biotech.
[02:04:34] Alex: Agreed. For one, that scientific founder naivete is, is one tell. In tech, people are fluent in equity because options are half of the comp conversation when they join a new startup. But in biotech, a brilliant academic founder will happily just sign the docs and never really ask what percentage they hold.
[02:04:54] Alex: Uh, I mean, many people prefer this, frankly, because in biotech, the upside is indeterminate and the downside is 0. So a lot of the time you just want to hedge your bets and take cash.
[02:05:04] Matt: All right. So we've talked about some of the individuals and the money they made. Let's get to Third Rock, the folks that ideated and brought this company to life.
[02:05:13] Matt: As a reminder, Third Rock put in roughly forty-two million dollars early on. By our estimates, they realized about three hundred and forty million dollars on Blueprint. You know, as you would expect for a blockbuster portfolio company, this single company ends up coming close to returning the entirety of Fund II.
[02:05:35] Matt: So to recap, the VC firm puts in forty-two million, makes a couple hundred million. The professional CEO makes about seventy-five million for nine years of work. The best paid scientist is in sort of the double-digit million range, low double-digit million range. Chemists who were involved in the final drug embodiment are in the low million range.
[02:05:56] Matt: And you know, this is the venture creation model doing exactly what its core theory says it should do, which is value flows to the people who supply the capital and who run the system, because fundamentally the model believes that is what matters the most.
[02:06:14] Alex: To make that gap really concrete, we have a highly relevant counterfactual to Blueprint.
[02:06:20] Alex: A few years earlier to the purchase of Blueprint by Sanofi, Eli Lilly bought a precision oncology company called Loxo, and the CEO of Loxo, Josh Bilenker, was a physician who was both the founder and the operator all the way through the sale. He ended up walking away with around two hundred and eighty-eight million dollars because he had founder equity stacked directly on top of operator options.
[02:06:44] Matt: Blueprint scientific founders captured none of that math because they were never involved in running the company. They stayed at their academic jobs and let Third Rock do the hard work of building machine around them. The distance between Nick Lydon's eleven million and Josh Bilenker's two hundred and eighty-eight million comes down to who's sitting in the executive chair when the deal closes.
[02:07:06] Matt: And these dynamics are exactly what Borisy, Lengauer, and others at Curie Bio are trying to address.
[02:07:30] Alex: Let's talk about Curie Bio and what's changed in the industry between two thousand and seven, the founding of Third Rock, and Curie Bio in twenty twenty-three. Fundamentally, Curie is making a massive bet that the math of drug discovery has fundamentally changed, and a new type of venture model is necessary.
[02:07:50] Matt: Right. Back in '07, the assumption was that ideas were cheap and execution was everything. An academic with a great idea, but no pharma backing had nothing. Curie is betting that execution has started to commoditize, or at the very least, democratize. Because today, you can rent the chemistry, the toxicology, and get the manufacturing from contract research organizations.
[02:08:15] Matt: A clever drug hunter can cobble together an entirely virtual drug discovery organization, mixing and matching specialized capabilities across a dozen outsourced partners without ever building a wet lab of their own.
[02:08:27] Alex: And Alexis is totally transparent about how much cheaper this outsourced process is today compared to the some forty-five million dollars they burned in those early days of Blueprint.
[02:08:39] Alexis: The cost of one going from inception to development candidate was eight million. The cost of the other was nine million. If we can get development candidates for five to ten million dollars, then if our ideas are the best ideas, if we keep those ideas tight, and if we deliver super high quality development candidates, you know, we're gonna do just fine.
[02:08:59] Matt: So Curie's model is essentially putting this exact thesis into practice. They write small early checks into companies with a very focused sense of what the optimal target product profile looks like for a specific indication, with the goal of getting to a development candidate super efficiently. That cash for equity exchange is all very standard, but Curie's innovation is having a second offering for founders, so-called sweat for equity.
[02:09:26] Matt: Curie employs over a hundred in-house drug hunters as full-time internal employees, with Christoph Lengauer acting as the chief drug hunter. It's a shared pool of veteran drug developers that the founders can draw on ad hoc as the scientific needs of the program change.
[02:09:44] Alex: Yeah, and I gotta say, Matt, veteran drug hunters is really an understatement here.
[02:09:49] Alex: This is like an all-star cast of folks who have contributed so much to the modern drug landscape. Across the drug hunter team at Curie, they're responsible for fifty-six approved medicines and hundreds of clinical stage programs. Take, for example, Greg Carven, who we interviewed in our last episode. He co-invented Keytruda.
[02:10:11] Alex: And of course, Tim Guzi and Erica Evans, who are in the story we highlight today.
[02:10:17] Matt: Yep. It's a very impressive group. So a founder's idea can be handed to that team of hardened professional, quote-unquote, co-pilots so that the founder doesn't have to learn the brutal discipline of drug development on the fly.
[02:10:32] Matt: Through more efficient execution by the most experienced drug hunters in the world, smaller checks are required to fund the earliest phases of company build-out, enabling founders to own more of their company by taking a smaller check. You can understand the logic. If you're a venture firm, why give a hundred dollars to a founder who is immediately going to spend seventy percent of that money at some third-party CRO, a CRO that may not be the best in the world and who may not be giving that founder the best prices?
[02:11:06] Matt: If Curie has internal folks that can execute better and use their scale to get better prices at CROs, less money can ultimately go a lot further and founders can keep more of their company.
[02:11:18] Alex: you see, when execution gets cheaper and more predictable, a couple of important things happen.
[02:11:24] Alex: For one, it makes less sense to fund full platform build-outs. Instead, it's more efficient to tightly focus on the one drug and indication that makes the most sense. For Blueprint, that would be like skipping all the way to mastocytosis with avapritinib. Secondly, the scarce resource shifts back to the idea and to the first person who had it.
[02:11:48] Alex: Look at their showcase company, Forward Therapeutics. After raising a fifty million dollar Series A, the founders still owned close to thirty percent of the company. Lengauer's line on this is pretty apt. Quote, "If Forward gets bought for five hundred million, the founders are gonna walk away with a hundred and fifty million.
[02:12:05] Alex: That's serious."
[02:12:07] Matt: Erica Evans, former VP of biology at Blueprint, now works at Curie and is able to weigh exactly the trade-off between a lean founder led company, and a more resource intensive platform co. Her take is two-sided.
[02:12:22] Erica: In general, I like the focus. You know, it's free of distraction. I think you obviously lose some of the kind of learnings you can gain from when you're in a company with a platform and you're moving from one target to a second target.
[02:12:38] Erica: And I would say, you know, for Blueprint, the third and fourth and fifth programs that we worked on were done much more efficiently than the first one because we learned a lot and optimized both our workflow and our understanding of what was important. And I think with the single asset company, you obviously lose that.
[02:13:00] Erica: You know, you're building it and learning something new every time. You probably also, you know, don't get the benefit of, of serendipity the same way as when you're in a platform company.
[02:13:12] Alex: And the question of whether Curie would fund something like Blueprint today is also something we couldn't resist asking a couple of the ex-Blueprint folks that are now at Curie, including Erica.
[02:13:23] Alex: Here's what she had to say.
[02:13:25] Erica: I doubt at the scale that the library was funded at the beginning of Blueprint. I think if there were some platform element, you would have to have clear description of how you were going to deploy that. What is the target that you're going to use it to enable? So, you know,.
[02:13:43] Erica: I think you'd have to know what that program was and sort of how you're gonna deploy the library to make it faster and better.
[02:13:51] Matt: But does the Curie model actually work? The honest answer is we don't know yet, at least from a financial perspective. Curie launched in twenty twenty-three, and in that short window, it's already seeded almost forty companies. That's the beauty of small checks going a long way. But given its focus on early-stage science, not one has yet produced an approved drug or a billion-dollar exit.
[02:14:14] Matt: Without a DPI scoreboard to point to, Curie highlights the rate at which their portfolio is progressing through early drug development milestones as evidence that their model is working. In contrast, of course, Third Rock has the actual DPI scoreboard across multiple fund vintages, the cash returned to investors.
[02:14:35] Matt: Curie still just has the promise at this point.
[02:14:37] Alex: Exactly. You can kind of see in these years that Blueprint has matured as a company. It's almost become a, a bit of a Rorschach test. If you're someone like Third Rock, for example, Blueprint is your thesis and a case study in why the Third Rock model works.
[02:14:54] Alex: You take academics who stay in their labs, supply a CEO some money, and a decade's worth of grinding away, and you can produce a miracle drug and a nine billion dollar acquisition by Sanofi. Those scientists could not have done that alone. Nobody's denying that.
[02:15:11] Matt: But if you're Curie, Blueprint is kind of an indictment in a way.
[02:15:15] Matt: The people whose science made the whole category of medicine possible walked away with a fraction of one percent of what they created, while the venture firm and the hired operator took the rest. You believe you can build it in a different way now that's more capital efficient and founder-friendly.
[02:15:31] Blueprint vs. Bluebird: A Tale of Two Platforms
[02:15:31] Alex: Before we wrap up this episode with our usual rubric of scientific, financial, and patient impact, we'd also like to philosophize a bit about the nuances of running a platform company and the biotech venture creation model. It's hard to believe that a Third Rock company started in the early twenty tens, which developed drugs leveraging novel biology to treat rare genetic diseases with the stock ticker BLUE, ended up getting sold for only twenty-nine million dollars in the summer of twenty twenty-five.
[02:16:02] Matt: What? Wait, that doesn't sound like Blueprint.
[02:16:05] Alex: And you would be correct, Matt, because I'm not referring to Blueprint here. I'm actually talking about Bluebird Bio, the other Third Rock BLU company. You see, where Blueprint was TRV's steady bet on novel small molecules and mutant kinase disorders, Bluebird was more of a hail mary. a bet on gene therapy, the flashiest science of the twenty tens.
[02:16:28] Matt: And for a while, the company was a star. Bluebird peaked near an eleven billion dollar market cap in twenty eighteen, but soon thereafter it started to unravel. Three approvals, a decade of work, an eleven billion dollar market cap peak ends up selling in twenty twenty-five for the price of a nice apartment in New York City.
[02:16:52] Matt: I think what actually killed them as a platform, and which is a reality that Blueprint never had to face, was that even after Bluebird got three gene therapies into the market, I don't think that their gross margins were positive, let alone net profit.
[02:17:11] Matt: The unit economics of the gene therapy were just atrocious. Each dose was a bespoke product manufactured from an individual patient's own cells. The cost was enormous. The manufacturing process was impossible to scale. The sort of COGS question just ended up eating the company alive. By 2024, loan obligation after loan obligation was starting to really pile up.
[02:17:38] Alex: Agreed. And that makes the contrast with Blueprint, — which technically you could call both product engines — really stark. Their economics were very different. On one hand, you had cheap small molecule chemistry for this expandable market, both of which weren't the case for Bluebird. when the broad pipeline didn't pan out for Blueprint, you could just ruthlessly get rid of most of it. Gavreto?
[02:18:03] Alex: Out-licensed to Rigel. The secondary programs like the EGFR molecules? Put on the shelf. And then refocus on the molecule that actually works. It's really crazy to think that these companies have remarkable, albeit superficial similarities coming out of the same vintage of TRV, but had totally opposite economics.
[02:18:25] Matt: Yep, and it'll be interesting to see whether any company that doesn't have the gross margin structure of a small molecule, whether any of them ever figure out how to survive. It'll be something interesting to watch.
[02:18:40] Alex: Agreed.
[02:18:41] Matt: You know, we're not bringing this out of the blue for, for no reason here, and that's that—
[02:18:46] Alex: No pun intended?
[02:18:46] Matt: No pun intended. Even though the terminal value of Blueprint was nine billion and the terminal value of Bluebird was, like, 25 million, both of them were equally good outcomes for Third Rock Ventures.
[02:19:00] Alex: What? Wait, really?
[02:19:02] Matt: Yeah. So essentially, the way that venture model works is they own a huge slice of the equity at IPO, and then they don't hold on to that equity forever as a public company.
[02:19:17] Matt: They sell it and distribute the shares back to the LPs. And in the case of Bluebird, that means selling near the top of the market and not owning the company when the ugly reality of commercializing a gene therapy reared its ugly head. The downside of that, of course, is for Blueprint, where, you know, some of the value inflection points that happened later on, TRV didn't ultimately financially benefit from.
[02:19:46] Matt: So- Mm-hmm… you can sort of think of it as almost a downside-protected, upside-limited model in a way.
[02:19:54] Alex: This all kind of reminds me of that, uh, Bruce Booth piece on the so-called Hotel California in biotech, if you've ever read it.
[02:20:02] Matt: No, I haven't.
[02:20:03] Alex: So it basically goes like this. In biotech, you get diluted round after round on a 10-year hold.
[02:20:09] Alex: A firm that only owns a sliver at the start ends up owning almost nothing by the exit. So by that logic, the founding scientist owns something like 1%, because that's literally what's left after you build a massive financial structure that gives a drug a real chance to exist in the first place.
[02:20:27] Matt: Yeah, I understand that perspective.
[02:20:29] Matt: I think it's funny that we're recording this episode a week or two after SpaceX went public, and we're talking about a company that was founded in 2002, took two decades and $10 billion of private capital to reach an IPO. And despite that, the founder still owns double-digit percent of the company and pretty much all of the voting shares.
[02:20:58] Matt: There's definitely worlds where that sort of dilution is not an absolute requirement. The rules are different for Elon, right?
[02:21:05] Alex: Yeah. Biotech is a harder mistress than the moon.
[02:21:09] Matt: Yeah, perhaps, or Mars. All right.
[02:21:12] Scorecard: Patient, Financial & Academic Impact
[02:21:15] Matt: So- After that digression, uh, it's time to do playbook and analysis. So like all of our approved episodes to date, let's score this story across three distinct dimensions: patient impact, financial impact, and academic impact.
[02:21:31] Alex: Let's start with patient impact then. You marked this as high, right?
[02:21:35] Matt: I did. I, I think I called it medium-high, like a, a B-plus, an old-school B-plus, right? Before grade inflation. Um, I mean, Blueprint was so impressive. Fourteen plus development candidates, two approved medicines, five approvals. From a patient impact perspective, I see them as really proving that the right sort of KIT inhibitor was incredibly helpful for mastocytosis patients, and, uh, they have the patient uptake and compliance to prove that there was a massive need for new medicines in that space.
[02:22:09] Matt: More broadly, in twenty twenty-six, lots of people are interested in developing drugs for mast cell-driven diseases, and Blueprint deserves a lot of the credit for doing the legwork to educate healthcare professionals around the world around the existence of at least this specific mast cell disease to help it get treated.
[02:22:27] Matt: I think even if avapritinib ends up not being the exact perfect target product profile for this disease, it led the way, and it has spurred efforts from Blueprint and Cogent and others to develop the ideal version of the drug in, uh, in this disease, which will mostly involve peripheral restriction and potentially a new generation of immune modulating drugs as well.
[02:22:52] Alex: Yeah, I'm on board with you about the patient impact, specifically for mastocytosis. But if we're looking at Blueprint holistically as a company, I'd say I'm a little bit more split on patient impact. I mean, the founding mission of this company versus what indication they ultimately scored in is kind of muffled, right?
[02:23:11] Alex: Blueprint was in the right place and the right time to prosecute things like, and this is a long list, EGFR, RET, ROS1, ALK, TYK2, non-covalent BTK, and then they ended up only making their market on KIT in mastocytosis. Don't get me wrong, the work that they did in that space is fantastic, and it's great that these patients now have an effective disease-modifying therapy.
[02:23:36] Alex: It also, on the other hand, makes you wonder how many missed opportunities there were within this company, given the strength of their platform and the programs that they had to shelve in order to keep the company afloat.
[02:23:49] Matt: Yeah. That's a really good point. I think it accentuates how hard it is from an organizational perspective to prosecute all of the good drugs that may come out of a really productive platform.
[02:24:04] Matt: When the chemistry delivers, it doesn't solve all the problems. It just shifts it elsewhere within the organization of how do you prosecute pre-clinically and clinically all of these good agents. I think it also highlights the degree to which getting a drug approved is not the finish line in the world of drug discovery anymore.
[02:24:27] Alex: If this is your first time listening in, that's pretty much the theme of this whole series.
[02:24:34] Matt: Oh, yeah. Yeah. The first four episodes to date. Yeah. Good point. All right, let's move on to financial impact.
[02:24:43] Alex: Here, I think we're, we're fully aligned. This was a huge slam dunk for Third Rock and an equally huge slam dunk for Blueprint.
[02:24:51] Alex: A $10 billion exit, I mean, that's a relatively big terminal exit value for a life sciences company.
[02:24:57] Matt: Yeah. I mean, as we mentioned before, Third Rock could have done even better on this investment, and we discussed some of the structural reasons why it had to get out when it did. And again, going back to this question of platform productivity, you can definitely squint and imagine a world where Blueprint had not only been successful in the world of KIT, that they had managed to out-compete Lilly in the RET world.
[02:25:25] Matt: Maybe they focused a bit on TYK2 and, and BTK, and I think there's a real chance that the counterfactual here is Blueprint is essentially a Regeneron, meaning like an enduring fifty billion dollar plus market cap pharma organization. Yeah, the financial impact is a plus, but in the back of my mind, I still wonder what could have been here.
[02:25:50] Alex: Makes sense. I mean, it's a clear win, but more left to be desired. What about academic impact? You had that one down, I think is pretty minimal, right?
[02:26:00] Matt: Yeah, and to be fair, I feel like I'm a pretty tough grader here. Yeah, I'm really focused on sort of like what new knowledge did they create in the world. I think they really validated systemic mastocytosis as being a hyper KIT-sensitive disease.
[02:26:15] Matt: They established some regulatory criteria there. I guess you could argue that the Blueprint library approach really helped the field understand that it was possible to develop exquisitely selective kinase inhibitors. The screening approach was clever and innovative, but at the same time, that has not proven to be the only way to develop type one kinase inhibitors, nor to develop selective inhibitors more broadly.
[02:26:45] Alex: I think I'm on board with you there. Tim gave us some interesting commentary about how scientifically interesting kinases were as an opportunity to find new drugs via trying this idea as a platform.
[02:26:59] Tim: There's a lot of chemical crosstalk that you can exploit very efficiently within that space. And, you know, the protein doesn't move that much. You're really looking for subtlety in interactions to drive your selectivity. Other targets are much more dynamic, right? There's less crosstalk within one particular structure to get you to the pharmacology that you want.
[02:27:20] Tim: There's many, many, many approved GPCR compounds, but the notion that you could walk from GPCR to GPCR the way you can from kinase to kinase just doesn't hold.
[02:27:32] Matt: Tim makes a really good point there, which is that this approach works in kinases for reasons very specific to how kinases function, and it wasn't a general purpose invention that you could just point at any protein family and get the same results.
[02:27:50] Alex: As the dust settles since the summer of twenty twenty-five, Kate Haviland perfectly summarized the whiplash of Blueprint as a company in a recent interview with Luke Timmerman. Quote, "If you had told me when I joined Blueprint at the end of twenty fifteen that we'd be selling allergy, immunology, and dermatology, I would have said, 'You're crazy.'
[02:28:13] Alex: And that was only ten years ago."
[02:28:15] Matt: Yeah. Let's look at that whole picture. It starts as a kinase company built by cancer scientists and a venture firm born out of the nineties genomics boom. It gets handed over to a CEO from the Genzyme diaspora. It follows the biology completely by accident, uncovers a hidden allergy market, gets bought by Sanofi to plug a patent cliff, and ultimately sparks a discussion over who deserves the spoils of biotech.
[02:28:43] Matt: In the final bookend, we start with a few operators who had just sold Millennium sitting around inventing a new way to build companies, Third Rock. We end with a few operators who come out of Third Rock companies sitting around inventing the next way to build companies, Curie.
[02:29:00] Alex: Two generations with the exact same instinct, arguing about how to build new drugs and who should get the spoils.
[02:29:07] Alex: Blueprint is the company both generations are pointing at.
[02:29:12] Matt: That's our show for today. For Approved, I'm Matt Pech.
[02:29:15] Alex: And I'm Alex Kesin.
[02:29:18] Matt: We'll see you next time.