Gavin Clark-Gartner with the Evercore ISI Biotech Research Team, and I'm really happy to be here with Tom Trimarchi, who is the Chief Product Officer of BridgeBio, and Bubba Murarka, if I pronounced that correctly.
Got it.
who is the EVP of Corporate Development. Thanks for joining us, guys. So-
Thanks so much for having us.
Yeah, absolutely.
Yeah.
We have 20 minutes. We're just gonna fly right into it.
Jump in the fire. Love it.
Yeah, exactly. Been a busy, busy year, of course. Why don't you just quickly recap what's happened and where things stand today?
Yeah, so let me just start high level, for those of you that are less familiar with the story. BridgeBio, we’re an engine for genetic diseases. We seek to serve patients with any genetic disease in a scalable and sustainable way. So 2023 was a very exciting year for us, where I think we've proven the engine. The engine is proven today. We had, you know, July, we had top-line data from our lead asset, acoramidis, for ATTR-CM, which exceeded even our highest expectations of what that readout would look like, and as we've continued to share data from that at the conferences, it's only looked better, and I'm sure we'll get into detail there.
But behind that, we've got three exciting, pretty de-risked programs in Phase III, with our achondroplasia program, our FGFR3 inhibitor for skeletal dysplasias, which most on Wall Street are quite familiar with. That's a big market, where we've got a best-in-class agent. And two, I think, less well-followed assets that are very exciting to us, with our encaleret, our calcium-sensing receptor inhibitor for ADH1, and our limb-girdle muscular dystrophy program. So that mix of a product that's near the market in acoramidis, plus a de-risked late-stage pipeline right behind it is really exciting. So on the forward, 2024 is the year where we go from an R&D engine to an actual business, right? Where we'll put acoramidis out on the market.
Hopefully, that revenue grows nicely and starts throwing off cash flow, and then, as the other phase IIIs read out and come to the market, we'll actually have a pretty interesting, diversified top line that can really start accelerating.
Awesome. What are your latest thoughts on partnership and licensing considerations, given that there is so much going on?
Yeah, so I mean, I think our base case is always that we will build and go at it alone commercially. Now I think we are always active in terms of BD discussions and have, you know, various going on at all times, but we feel we're the best owner of these assets by the time they reach the market. And so, you know, we're preparing to launch acoramidis. We're preparing to launch the other assets ourselves.
Yeah. And we've already brought on the commercial leadership team to enable that globally. So I think, this year, quarter before launch, we'll start to fill out the field, but, pretty excited about the opportunity to execute and have a world-class team on the field.
Yeah, so it sounds like you've only brought in a couple senior-level commercial hires and haven't fully flushed out the sales infrastructure quite yet.
I wouldn't go that way. I would-
No, I mean, the leadership is all onboarded. So we've had a... You know, it's been an injection of new energy, of folks, senior folks joining. So I think what Bubba's commenting on is the actual field force that gets hired much tighter to launch. So, leadership is in place, so it's gonna be next year about scaling up the actual reps in the field.
Yeah. All right, that makes sense. There's been a lot of discussion in the last few months about the data, so I don't wanna spend too much time recapping all that. Why don't you just give us kind of the quick highlights there?
Yeah, the highlights are, you know, we're really excited about the differentiated profile that we have in hand today, and so there's three elements of that, really. One is mortality and CVH, so the outcomes are better than we've ever seen in this space, right? We're approaching what life looks like without ATTR-CM for these patients, right? Two, is we've got a significant amount of patients that are not only stable but improving from baseline, so when they start our drug, they do better. They can walk further. Their labs that are good predictors of outcomes here, are improving, so it's almost 50%, depending on which mark you look at. That's really exciting. And third, this is data we just shared at AHA a couple weeks ago.
We're seeing almost immediate impact on the benefit you get on the outcomes. At month three, we're seeing separation, clear separation on the composite CVH and all-cause mortality. That is unlike anything we've ever seen before in the space, so we're pretty excited about this. And the nice thing about all of it is it is all tied to be together by the scientific hypothesis behind this molecule. We knew that we wanted to maximize benefit to patients by creating a maximally potent stabilizer, and so it's really rewarding to see all that line up nicely in the end.
Yeah. That's great. All right, so let's shift over and talk about the commercial side of things for taf-, acoramidis. Do you have a good sense today how many tafamidis patients are suboptimally or under-controlled, and their kind of propensity or willingness to switch?
Yeah, so I mean, clearly, tafamidis is, is not the right answer for this disease, right? I mean, you have 75% of patients worsening when they're on tafamidis in the pivotal study. This is also supported by recent real-world evidence, cohorts. So I mean, there's a clear need here for something that is maximally stabilizing tetramer that can deliver better outcomes for patients.
Yeah. And maybe similar question, but less so about the clinical control, more about HCP segmentation?
Mm-hmm
... and whether you have a sense at this point, whether it's % of prescribers or % of tafamidis use, that's, you know, amenable to switching.
So, I mean, our focus in our commercial strategy is really new start, right? I mean, if you think of this market, we think there's 40-50 thousand that have a correct diagnosis of ATTR cardiomyopathy in the U.S. today, of probably hundreds of thousands with the disease. About 10,000 are on tafamidis, so, you know, where, where, where would you focus on, on getting some of those 10,000 off onto your drug or, you know, the kind of white space of, of, of new starts? That's where we're gonna be putting our, our, our efforts. There will be switching, no doubt, but I mean, there's, there's more patient impact to be had in cementing ourselves as the first-line agent of choice here.
Yeah.
Especially by making access even better. I think the opportunity, you know, with Pfizer not having a patient foundation to cover copays alone is just something that we can change access and ultimately be a friend to the community out there.
Yeah, and I mean, building off that point, what are your latest thoughts on both pricing, but then access strategy and how this whole landscape will evolve when some of the IRA changes start to come into effect?
Yeah. So we're not gonna comment on pricing too early for that. And I will just say high level, our approach is gonna be to do everything we can to ensure maximal access to the drug for patients. That is the number one problem in this market today, is that patients that need to be on a stabilizer can't get on one, even though they're trying. They either can't afford it, or there's too much paperwork and, you know, prior auth associated with getting on the currently available stabilizer. So our job is to make sure that patients that need this drug can get it.
What about changes with the out-of-pocket maximum-
Yeah
... as IRA starts to go into it?
Yeah. So that's, I think, an underappreciated upcoming change to this whole market landscape is... So today you're dealing with an out-of-pocket to get on tafamidis, if you're on Medicare Part D, of almost $15,000 a year, which is, you know, may not sound like a lot to some of the people in this room, but for someone that's got this disease, that's, you know, 75 years old, it's a lot of money, and a lot of people get the script and don't fill it because they can't afford it. So what's going to happen with thanks to the IRA, is those out-of-pockets are gonna be capped at $2,000 a year.
The affordability of this whole category is gonna go up in a huge way, and that could be up to, you know, a 50% benefit to the market in the U.S. just, just from, you know, affordability.
Got it. What have you said about number of sales reps, commercial infrastructure needed to target, and maybe also just commercial targeting in general? How many docs do you have to go after?
We haven't given a ton of detail on those kind of tactical things. I think we will get into that more as we get closer to launch, and you guys should expect to be hearing from some of our commercial leaders as we do get closer to that. But what we have said is, this is a very focused call point today in the U.S. and also in Europe, so that makes it very doable for a smaller company like us, right? It's not a tremendous investment to build the field to go launch this thing. Now, that will expand over time, because for this category to get huge, like we think it will, it's going to have to get into kind of like the more community cardiology offices in a way that it's not quite today.
But the good news is the brand will be highly profitable. At that point, we can just reinvest to grow share.
Yeah. And just broad strokes on how, providers and KOLs have been responding to the data since you've kind of rolled it out and been presenting it for a little while now. I mean, it feels to me like there's enough to go on here, where if you believe the mechanism a priori, there's enough to kind of confirm that belief.
Yeah.
Maybe similarly, if you weren't a big believer beforehand, maybe it didn't change your mind, and then a lot of middle ground in between.
Yeah. So I mean, I think the prescribers that are closest to this program, this data set exceeded anything they thought was possible in this trial, just understanding, have a nuanced understanding of the patient population, all that. So you know, that group of physicians, when they knew the result and knew the consistency and the tiny p-values, they knew this was a special data set.
Now, I think there are some people that are more excited about tafamidis, or they have a lot of experience with tafamidis, or don't quite understand the scientific story about why this is just a better drug, that even those people, as I hear Wall Street calls or our own market research, they're all moving closer and closer to, "Yeah, okay, this is a better drug." You know, so, you know, we're not even on the market yet, we're not in the office yet, so we're just getting started here. So we're optimistic about our ability to really change attitudes and increase enthusiasm for acoramidis.
Yeah. Great. And the other swing factor within the whole acoramidis franchise is the potential for the polymorph patent for TAF to be upheld, and there have been some ANDA filers earlier this year. So when do you guys expect to hear some updates from this litigation play out?
So, you know, it's kind of a, an odd position we find ourselves in, having to comment on another company's IP. But I think the short answer is, this, this whole thing matters a lot less than maybe some folks on Wall Street think it does, right? I mean, we have a differentiated agent, and if you look at historical analogs, where there's a second entrant, whether it's differentiated or not, by the way, it rarely loses sales when another... you know, the first in category goes generic. When you have a differentiated product, it's even, it's even more clear that you can not only not lose sales, but keep growing right through it. So we don't think it matters as much as people think it does, but, our understanding of the situation is next update in the U.S. will be in 2026.
And recall, we just had a decision that went in favor of Pfizer, upholding the 2035 patent in Europe. So, you know, our belief is that that brand is gonna be durable at 2035.
Great. All right, so let's switch gears here and go over to infigratinib and achondroplasia. You presented the cohort 5 high-dose six-month data, I think about six months ago. Should we expect a 12-month update anytime soon?
You should expect an update next year from that. We're working with, you know, our first. Our hundred percent of our focus today has been on the regulatory interaction that we just had, which went extremely well in our phase II, and then operationalizing the phase III, getting that enrolled, getting it started up. So, that's been where we're focused. Now, in terms of the scientific and medical communication plan, we've been working on that, on the side with our lead investigators, and so, you know, you'll hear more soon from this study.
All right. Should it be at a medical meeting or-
That's being debated. Do we wanna go for a high-profile publication, high-profile talk at a conference? And what we're focused on there is really just maximizing kind of attention on the readout and building excitement around the product so we can enroll the study quickly, and then have a strong initial launch.
Yeah. I mean, speaking of study enrollment, how is the recruitment for the run-in phase been going?
I'm not gonna get into specific numbers, but we started enrolling that in around the first quarter of this year, and enrollment's never been an issue for this program. I think it just speaks to the size of the opportunity, 'cause there are a lot of these people with this disease around, and the excitement around the molecule. Even before we had phase 2 data, enrollment was never really limiting, just because there was so much excitement over the mechanism and the delivery, and now that we've put up the data we've put up, I mean, it's just the phones are ringing off the hook, people that want to get on it, and physicians, and all that, so.
Got it. And should we expect an update when enrollment for the run-in is finished, or when you kind of start dosing patients in the-
Usually, when we've dosed the first subject in a, especially a pivotal study, we let you know, whether through a press release or comments at a conference like this. So, whether we comment on where enrollment's at in the run-in, we tend not to do that, so I wouldn't expect that. But you know, as we get closer and closer to filling that cohort, the timelines for phase three top line become clearer to us, so you know, you'll kind of know.
Yeah, that makes sense. On hypochondroplasia, maybe just frame for us why this is a de-risk path, status of regulatory discussions, and when this phase 2 could start up?
Yeah. So first of all, I think not everyone appreciates that hypochondroplasia has the potential to basically double the size of the TAM in this category, and it's almost the same disease. So like achondroplasia, it affects probably seven to 10,000 that would be treatable, right? People with open growth plates. Like achondroplasia, it's driven uniformly by a mild gain of function in the FGFR3 receptor. And so we're talking about, you know, what we see achondroplasia, it's like a $2-$3 billion TAM, potentially doubling. So that's pretty exciting to us. So why is it de-risk? So scientifically, it's almost the same disease, so we know hitting FGFR3 there is the right thing to do, and we've shown that with some pretty exciting animal data.
I think an underappreciated de-risking data set is the IIT study that actually BioMarin ran with their molecule, vosoritide, where they showed basically in hypochondroplasia patients that vosoritide, the CNP shows about the same effect there as they did in achondroplasia, which suggests to us that we should expect similar data there as we've seen in achon. And, you know, as in achon, there will be a huge amount of demand and excitement for a safe oral small molecule that hits disease directly at its genetic source.
Got it. What about the timing of regulatory interactions for this?
Have a discussion come up later this year. Expect we'll start the study next year, and once we've had our FDA interaction, we'll be able to communicate more clearly what exactly the path is. So, you know, is it a phase two, then a phase three, single protocol, et cetera, so but we're working on it.
Got it. All right, let's switch and go over to encaleret in ADH1.
Great.
Just remind us, ADH1, what is it? What are the...
Yeah.
What are the outcomes?
For those of you that know postsurgical hypoparathyroidism, this is essentially a severe and genetic form of hypoparathyroidism, which occurs, of course, when you haven't had any neck surgery, right? So, phenotypically, it looks very similar. You have low blood serum, low PTH, high urinary calcium. It's managed with ineffective standard of care, which is just calcium supplementation. It's caused by a gain-of-function mutation in the calcium-sensing receptor, which throws off all of your, you know, kind of the system that monitors levels and regulates that. So what we have is just a direct inhibitor of that mutation that theoretically was designed just to normalize the condition. If you fix the genetic driver, you should fix the disease. And that's exactly what we've seen in phase 2.
And in terms of the opportunity we're talking about here, you know, this is, this is a little bit unknown because diagnosis is, is a little bit of a... it's, it's underdiagnosed today, but we think there's probably 3,000-4,000 with a correct diagnosis in the U.S., and probably up to 10,000 in the U.S. that carry the genetic mutation. So the question is, how far between, you know, 3,000-4,000 and 10,000 do we get once we're out there in the market?
Yeah, that makes sense. For the phase 3, what exactly is the primary endpoint, and how is that measured in the trial? 'Cause there are some nuances to it.
Yeah, so the primary endpoint, so what we're trying to do here is fix the disease and fix the calcium level regulation. So what that would look like if our drug was working is blood calcium gets into the normal range from a very low range, where these patients are at baseline. Urinary calcium, because they're able to come off their high doses of calcium supplements, should get into the normal range from a sky-high value that they come in the door with, which, by the way, over the long run, is gonna destroy their kidney. And serum PTH levels should go up into the normal range as well. That's exactly what we've seen in phase 2, and the primary endpoint for our phase 3 is the proportion of patients that have both normalization of serum calcium and urinary calcium.
And so in phase two, we've shown that about 70% of the patients, so with that kind of effect. We know from case studies in natural history, that you almost never see this without an intervention like ours. You can't achieve that with standard of care, because when you put calcium in the system to try and get blood levels up, you shoot up the urinary level. So it's, you're like, physically unable to achieve that with supplementation. So, you know, we're powered pretty conservatively there.
What is the timeframe that it's measured over, and do patients need to be within that range for a certain number of measurements?
It's at six months. It's at six months, are you, are you eligible?
Single month.
Yeah. But we're, you know, we've seen a rapid and sustained ability to get patients into that range. So you know, our expectation is that within, honestly, days of initiating therapy, you should get normal and stay normal.
Yeah. All right, maybe in our last minute or so, we can touch on 631 for CAH. You're just framing the bar for this one, what we should expect in terms of expression...
Yeah. So this is our 21-hydroxylase gene therapy for congenital adrenal hyperplasia, another big, very common genetic disease in the endo space. You know, so I think there's three win scenarios, two which are much more likely than the third. First is that we would have a gene therapy which can effectively do the same thing that the CRF1 antagonists do, which is better control of disease with lower doses of steroids, and we're looking at 17-OHP getting... You know, I think what we know there is about 50% of participants got 50% or better benefit there. So that's the kind of like the lowest bar for a win scenario.
Above that would be, if we can do something more profound on those steroid markers, so you get better control of the disease, and by the way, you'd restore endogenous control of the whole system, 'cause you've got the functional gene in there. You know, I think we'd be pretty excited about that. The third, I think, less likely, but, you know, real grand slam scenario would be if you can do all of that with some endogenous cortisol coming in, which I think would be really exciting for the whole community.
Yeah, sounds great. Maybe just any last closing remarks before we wrap up here?
No, it's been a fun and exciting year, despite you know, sometimes challenging market dynamics, but we've had our heads down. We've been, hopefully you agree, we've been executing, and 2024 is really, you know, kind of the first day of the rest of the story here, where we could talk - got really big -