Very pleased to introduce from BridgeBio, Neil Kumar, Chief Executive Officer. We only got thirty minutes to cover three hours' worth of content. So maybe start with a very quick snapshot of the company and what we have to look forward to in the months and quarters ahead from BridgeBio.
Sure. First of all, thank you so much for the invitation here, and it's been great partnering with Cantor Fitzgerald. You know, at a high level, BridgeBio is a company that seeks to discover, develop, and ultimately commercialize new therapies for Mendelian diseases. This year, our focus has been primarily the commercial preparation around acoramidis, which is our drug for ATTR cardiomyopathy, and the continued execution of our late-stage phase III pipeline, which includes achondroplasia, ADH1, and LGMD2I.
All right. That was a very quick snapshot. Let's dig in first on acoramidis. We've had now a couple of weeks to digest the vutrisiran data. You know, what's the feedback that you're hearing as you're preparing for commercial launch into TTR cardiomyopathy?
You know, I think, ESC was an exciting moment, for the patient community. Lots of different therapies are gonna be available. I mean, when we started in the field, ATTR was just about to read out, and, you know, effectively, ATTR cardiomyopathy was driving 42% mortality rates over 30 months, and now we've seen with some of our data that, at least in the real-world setting and in our Japan phase III, you can get 100% survival rates over 30 months, so that's a remarkable advance, across the industry, and I'd say, as, as I've said to others, you know, the multiplicity of sponsors suggests to me that the biggest problem in this space, which is a lack of diagnosis of patients, is gonna be tackled.
So, you know, coming out of ESC, I think, you know, we were proud of the data that we were able to continue to publish. One was really tying that knot together between serum TTR, ever-increasing levels of serum TTR and ever-better levels of survival. And then the second was an analysis of patients in our clinical trial, where they come from tafamidis and on to acoramidis, looking at serum TTR levels and seeing what happens. And you saw almost 50% increase in serum TTR, or three mg per dL increase in terms of serum TTR. And recall, we had already presented data suggesting that for every one mg per dL increase at 28 days, you actually see a reduction in mortality of about 5%.
Where are specialists, to your sense in really appreciating the emphasis on monomers as disease driver, as opposed to just TTR in general?
You know, I think it's a mixed bag. Obviously, you know, our understanding of the path and mechanism of this disease is pretty tightly correlated with every time you do better in limiting the amount of amyloidotic precursor or toxic monomer, you do better for patients. I think we've seen that now across three data sets. You know, although there are cross-trial comparisons, I think the 42% relative risk reduction that our drug has and the three-month separation is the best, and I think that is consistent with the fact that we are limiting the amount of toxic monomer more than a partial knockdown or a partial stabilizer.
You know, where specialists are on that, I think some people are deep experts on the biophysics and biochemistry of tetramer and ultimately monomer deposition, and others are coming up to speed on it. So it's a bit of a mixed bag, and it's up to us to educate.
Maybe you can tell us where you think you are in that education process. Do you think there are gonna be early adopters? What might they look like? Who are the late adopters, and what do you need to do to convince them?
I'd say we're in the very early innings of our education process. I just remind everyone that we're in a very sensitive pre-promotion stage right now. We don't have our label. We're not approved, and we're gonna abide by those rules. So, you know, education really first and foremost has to start once we get the label and once we're out there. I just came from our national sales meeting. We have very, very competent and experienced team that's ready to go, you know, at the right moment, and so I think we've got to get out there and start that.
In terms of early adopters, I think it starts with the clinical trial sites, and the folks that have experience with acoramidis, obviously across the phase II and the phase III, and we'll build from there. Yeah.
One thing that we've heard from docs is a belief that a lot of patients are doing just fine on tafamidis. I'm not sure how they even draw that conclusion, but in theory, if you've got a better product, every patient could benefit. What part of the tafamidis market do you think is up for grabs, or how much of it could you put into play with education?
It's a good question. I mean, the market research that we've done, as, you know, sort of recently as two months ago, so post HELIOS-B but prior to ESC, suggests a pretty broad range, somewhere between 15% and 40% of patients, depending on the practitioner, to be understood as effectively progressors with tafamidis. And how people define that, you know, first and foremost, NT-proBNP is probably the most common way that they define it. But it could be quality-of-life deterioration, it could be observations that they have in around, you know, how the patient's feeling. It could be serum TTR, but that's a minority of physicians.
We'd like to see it be a more used indicator of response, but I think it's in that 15%-40% range, where physicians would say, "Yes, they are responding. The drug is obviously active, but there's more we could do for this patient." And I think in the real-world evidence studies that were presented out of the Mora lab and out of Dr. Masri's lab, you see that the rates of survival on tafamidis, somewhere in that, you know, mid-seventies percent range, versus what those same sites are experiencing with acoramidis, which is from the 90%-100% range of survival, suggests that we can actually, you know, get patients to a higher level of survival and certainly from the hospitalization standpoint, lower levels of frequency of hospitalization.
Where do you think you'll have the fastest inroads into the market? Is it gonna come from taking patients perhaps not doing well enough on tafamidis and converting them to acoramidis, or is it gonna be more from identifying new patients where there's not a switch consideration?
You know, I think it's gonna be new patients to start. That's certainly our focus, is the naive population. There's really kind of three populations out there. There's the undiagnosed right now, that's the vast majority of patients, and we're excited to play a role, as I mentioned earlier, in finding those patients. Then there are the diagnosed but not on drug, and my hope is, that things we do and also the IRA can help those patients access important medicines. That's actually quite a few patients. There's 47,000 patients or so, 50,000 patients diagnosed. Today, only about 20,000 on drug, so that's a large chunk there.
Those two chunks are our primary focus, and then the switchers would be, you know, the next piece if physicians feel like their patients aren't adequately managed on tafamidis.
So we can talk about the efforts to find those new patients. Like, where do you go that maybe Pfizer hasn't been? I think you have a new cardiology lab partnership to help with diagnosis. Maybe you can give us a sense of what we might expect on that, for that effort.
Yeah. So, you know, on that partnership, we're applying a new technology called AI, artificial... Have you heard of this?
I don't know.
It's, uh-
Vaguely familiar.
Yeah. So basically, you can, from echoes and other lab data, effectively start to identify individuals that it may not be otherwise identified through technetium scans or you may not have thought of using the technetium scan, so you can pre-identify them and move them into the diagnostic criteria. It's also going after the high-volume heart failure practices that haven't been quite as educated on ATTR cardiomyopathy. If you look at the call point, you know, I think a year ago, we were talking about a call point of maybe 80 centers of excellence that accounted for almost 80% of the scripts, and now it's something like 180. So it's actually for 80% of the scripts.
So it's actually enlarging, and I think we can play a material role in trying to find patients. The other thing I should say is there's a massively underserved community in the African American community that has, obviously, the V122I variant at higher frequency than the overall population. We all collectively have to do a better job of getting out and educating and getting medicines to that community. I think that is an opportunity for us to have our medicine more broadly used as well.
With an intense, intensifying commercial competitive dynamic, you know. First foray really for Bridge into commercialization efforts, and what should give investors the confidence that you can get this right?
Yeah, I mean, you know, first and foremost, I understand if people have questions about it. To your point, it is our first commercial foray, and we've never done it before, so it's right for people to ask the questions. You know, I start with the data. I think the data are wonderful and present a great opportunity for physicians to get you know, their patients on a great therapy and an alternative to what's out there right now, and tafamidis. I think secondly, this is still a rare disease. You know, it's a you know, field force. We're not gonna comment on specific numbers, but we're not talking about a field force of several hundred people. It's a rare disease.
You're talking about MSL forces of well under 50 and I think you're talking about the type of white glove service that a rare disease company can be good at. Now, obviously, our experience with NULIBRY, which is maybe the rarest drug ever commercialized, I'm not saying that is a direct tie to what we're gonna do with acoramidis, but I think some of the experiences that our commercial team has had will stand us in good stead there. Maybe the final piece is just coming from the national sales meeting. We have built an extraordinary team. I mean, the field force is fully hired, the MSLs are fully hired. Every single one of the market access groups is fully hired, from the FRMs to the PALs, and it's, you know, an experienced team.
Fred Hassan and Jennifer Cook from our board were out there. So I think we've got the right level of experience. We've got folks from Pfizer, folks from AZ, folks from Alnylam. We get a nice mix on the field force of people who know TTR and others who just know cardiovascular disease. I think we will be ready to go.
One nuance that I at least I've noticed in conversations post HELIOS-B is, you know, pre HELIOS-B, it felt like acoramidis versus tafamidis versus vutrisiran. Now, it feels like it's almost acoramidis versus the combination of tafamidis and vutrisiran, so kind of ganging up on acoramidis. How do you think about navigating against that combination and, you know, how you convince specialists to kind of prescribe acoramidis as opposed to that combination?
Yeah, that's a great question. You know, I think first and foremost, the market will evolve as a single-agent market for now, and then I think orals will be, and stabilizers will be frontline. So I continue to focus on tafamidis. Obviously, when we launch, tafamidis will be the only other medicine on market for a brief period of time. In the longer term, I think combinations could be quite interesting. And when I think about it, from a pathomechanistic standpoint, it's like, well, how many of those toxic monomers, to go back to your first question, are still remaining? I think a 95% stabler has, you know, stabilizer has 5% still remaining.
You know, Alnylam has 81% mean max knockdown or so it looks like, and Pfizer is a 60% stabilizer. So I actually think a 95% stabilizer, if you just do the math, does the same job, if not just slightly better, on the toxic monomer population than does the combo. So we'll have to see. I mean, you know, these trials so far have not been powered to compare the combination against a single-agent, more potent stabilizer. But physicians will have to figure that out. In the meantime, obviously, if you can have that degree of potency with a more convenient, cheaper stabilizer, I think people will go that way.
What are your thoughts on investing in a monomer assay to really drive this point home? 'Cause I guess that's one thing that we're missing in really understanding the differences across the approaches.
Yeah, it's a great question. We've definitely invested in it already, which is basically an antibody to try to identify that circulating monomer. It's non-trivial. We and others have not been able to make much progress there. The best we have, honestly, right now, is that serum TTR measure, which is admittedly noisy. But, you know, I don't think physicians across the four different in vitro assays necessarily feel... It's not that they distrust it, they just don't know them. You know, what chaotropic agent did you use on the Western blot? Or, you know, how was the FBE assay designed?
You know, I think there's been a little bit of misinformation that's been put out by one of our competitors in and around how these assays are used, et cetera. But you know, if you look at every single one of those assays, if you look at the biochemistry of acoramidis, it is obviously a more potent stabilizer, seizes more target, has a superior Kd, has the enthalpic binding mode as compared to the entropic binding mode of tafamidis. So I think all of those things stand it in good stead. Whether that convinces physicians, I don't know, right? I think the serum TTR is where we'll have to start on that.
Okay, got it. Hold on. I'd say, like, 99% of investors are convinced that tafamidis is going generic in 2028. I think you don't quite espouse that view. What gives you the confidence that tafamidis will stay branded longer?
I mean, you know, first and foremost, we're not necessarily interested in commenting on their patent estate. You know, my hope is that we continue to see more accessible medicines for patients over a long period of time here. You know, I would just observe that Eliquis was just recently defended by Pfizer, although they were guiding to a certain LOE for five more years. They tend to do this. You know, they've taken price increases in the last three years, and they often will guide physicians and say, "Well, you know, the drugs go generic in 2026," which we already know they've defended against. So there's a little bit of posturing there.
Sure.
I would say you don't run 12 clinical trials generally to defend a patent estate that goes out to 2035, and then just let it go away in 2028. More concretely, they obviously won the European litigation. There's two real aspects to this, right? One is Form I, or the low free energy form, actually you know occurring in the Vyndaqel manufacturing, and it certainly is. So then you have to flip over and say: Can we challenge the validity of the 2035 patent estate? And that's where everyone's lost, and I think Dexcel and others are effectively filing around the validity of 2035 because it's almost impossible, thermodynamically improbable, to make you know the Vyndaqel generic without accessing that low free energy form.
Got it. Yeah, quick question.
I agree, Pfizer may push the LOE out to 2035, but they're not gonna roll over. I mean, AF progressors is a big market, and they're gonna counter-detail. What is your strategy to fight the behemoth, like, with your sales force?
Yeah.
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How to fight the Pfizer counter-detail?
Yeah, I think it's a great question. I mean, first and foremost, there, you know, there's no one market that I've ever seen where everyone responds to one drug. You know, I think the strength of our data stands on its own, and I think for certain patients, a more potent stabilizer will be of value. Those patients could include, earlier-stage patients that we identify. For instance, we're running a primary prevention study, where if you can limit or eliminate the amount of toxic monomer that's depositing in the heart over time, you might be able to access the type of survival numbers that we've been able to access, which is, you know, +80% all the way up to 100%.
I think the second thing is thinking about hospitalization, where obviously we had a 50% relative risk reduction, as opposed to numerically they had none, and with the Poisson correction, they had about 28%. That's gonna be important for a lot of payers. It's gonna be a lot of important for a lot of integrated delivery networks. And it's gonna be really important for patients and their physicians. So I think really sticking with the data, and then the second thing is making sure that we have designed all of our programs to maximize access to our drug. You know, Pfizer hasn't had a competitor yet.
So being out there and really making sure that we're taking care of the prescribing physicians, making it as easy as possible for them to get their patients on drug, and then making it very easy for patients to stay on drug, that'll be important. I'm not saying that Pfizer won't also respond with those things, but those are avenues that I can see to better the field.
We can turn to I nfigratinib. Breakthrough designation announced this morning. Congrats on that.
Yeah, thank you.
What do you think the FDA saw in terms of the differentiation versus VOXZOGO that led to them assigning that status?
Yeah, I mean, I can just only comment on when the FDA does ascribe you know breakthrough designation, they see a significant improvement as compared to the standard of care, which is VOXZOGO. They saw the entirety of our data set and made that conclusion. What they responded to specifically, I can't tell, but I have my ideas. Obviously, you know, we've been very pleased with both the point estimates that we've been able to drive in and around change from baseline on average height or growth velocity for these kiddos, but also the early signs of impact on proportionality, I think, is very heartening for the community.
What is your confidence that kind of when we have all the data to compare, that the advantage of Infigratinib will go beyond having an oral option as opposed to a sub-Q, but also have clear clinical differentiation, recognizing that we're comparing across trials?
. Yeah, I mean, that's always the million-dollar question, right? And cross-trial comparisons are difficult, and so I think it's gonna be really up to the physician community. But again, as I've said in the past, when one starts with the fact that we are addressing both of the effector pathways... By the way, I mean, you know, it's an interesting discussion we probably don't have time for today, but you can look into the biology of the disease and try to understand, you know, there is an effector pathway associated, obviously, the JAK/STAT pathway, that the CNPs do not address, that could actually be the reason that an FGFR inhibitor might be able to impact proportionality in a quicker and more and at a greater magnitude than a downstream CMP approach.
So, you know, I think it starts with obviously targeting this well-described condition at its source, and it builds from there. The best point estimates on, I think, everything from change from baseline to responder rate to absolute AHV, and then the oral is really the cherry on top, I think.
When should we be anticipating this data? Is it likely to come 2025 or early 2026?
We have not changed our corporate guidance on that, yeah. End of 2025, I think, is what we've guided to.
Okay. How have you kind of honed in on the optimal dose, and do you feel like there's room to continue to dose escalate, maybe for those patients who need some additional catch-up growth or who, for some reason, may not be as responding as well to the target dose?
Yeah, it's a great question. I think for the population, we feel pretty good about the dose. You know, the absolute AHV levels of six to seven are approximating what you know, I might expect for my own children. So it feels like we're in that range. Certainly, you know, we had. I think 91% of children in our phase II exhibited some type of growth, and as we defined responder rate, we were at around 75%. So there are people who are not responding. Whether or not they would benefit from a higher dose or whether they have a genetic modifier or another type of modifier, that's at play, I don't know, and so it could be interesting to dose up in those situations.
But by and large, for a commercial drug, we think this is the right dose, 'cause you don't wanna go too high. You don't wanna drive hypergrowth.
Is the right time to explore potential higher doses post-approval, or is there something sooner to be done there?
Yeah, I mean, there could be. Yeah, and you can see this in, I mean, mostly endocrine settings, where some physicians will experiment with higher doses for non-responding kiddos or other patients in other conditions.
What's the timing for efforts in hypochondroplasia, and have you also thought about even going beyond into perhaps non-FGFR3-driven, growth disorders?
Great question. So, hypochondroplasia, I think we publicly announced that we had a first child in the run-in, so that phase II is ongoing. And in terms of other disorders, I know there's been a lot of talk about that. I think that's very interesting. For us, those start with FGFR2 or 3-driven skeletal dysplasias. Some of them are very, very severe, smaller populations, so maybe Wall Street's not as focused on them. But we certainly will be focused on them and have talked to the agency about even potentially running a basket trial there, which I think could be really neat, just in terms of clinical trial design as well.
Beyond that, you know, things like Noonan syndrome or Turner and others, we'd have to think carefully about whether the you know, I've read some notes that, like, CMPs could uniquely do it, where FGFR inhibitors couldn't. That's obviously rubbish, but whether or not, you know, mechanistically, we'd want to come into what is otherwise a wild-type setting and inhibit it, and how much inhibition would be required to drive a reasonable amount of growth, I think those are open questions. I mean, I'll give you an example. In the childhood oncologic settings that we have dosed this drug in, obviously at much higher doses, we do observe elevated growth.
So it is possible to do it in the context of the wild type, but, but how broadly we want to explore that, I think we wanna be sensitive to the unmet need.
Which drug do you think is gonna be bigger, Infigratinib or acoramidis?
I think-
They're both addressing very large markets, right? Both with-
Agreed
multibillion-dollar revenue potential.
I think that they'll both be extremely important to the patients and kiddos that we're serving, respectively, but I think acoramidis will be larger, to be honest, because it's 13%-15% in HFpEF. It's very underdiagnosed right now, so I think the drug is going to be a material advance for our company and for the patients that we serve.
Maybe you'd talk a little bit about Encaleret.
Yeah.
Where is that program in development for type I autosomal dominant hypocalcemia? Maybe you can frame the unmet need for us a little.
Yeah, sure. So this is a first-in-class program. No competitors, so I think people are less familiar with it, but a broad unmet need, again, some 10-12 thousand carriers in the United States, maybe three to five thousand already identified patients. What happens here is that the calcium-sensing receptor has gain-of-function mutations. We're going in and inhibiting it, so again, targeting a well-described condition at its source. I think we recently announced that we closed screening for the trial, so you know, we anticipate obviously full enrollment right after that, and then a readout next year.
In terms of what we're really focused on here, 'cause we need to build this market de novo, in many ways, sort of what Pfizer did in ATTR cardiomyopathy, the focus here is to look and try to. Again, we're already doing this, partnering with academic institutions to look in the nonsurgical hypopara community, for instance, and try to identify patients that are kind of hiding in plain sight. So 20%-30% of nonsurgical hypopara patients actually have gain-of-function mutations in the CASR. So how do we bring those patients into the fold and get them genotyped so that they can avail of this drug, should it have positive phase III data and get approved? I think that's an important next step for us.
So you'd said three to five thousand patients identified. Are those- have those been identified by BridgeBio? Maybe you can tell us a little bit about the progress you've made, you know, ahead of what presumably will be a commercial launch.
Yeah.
The phase II data didn't seem to leave much doubt from the efficacy profile.
It is the highest probability of technical success, I think, program we have, mostly because of the variance of the endpoint is so tight. You know, the three to five thousand patients is basically the number we get to just looking across EMRs and academic medical centers and integrated delivery networks in the U.S. alone. So those are identified ADH1 patients that I think could meaningfully benefit from the product. Yeah.
And then in terms of going out to find the rest, I guess this seems like a bit of a challenging market because the patients spread out amongst the endocrinology community. You kind of got to go in and I guess genetically test to find the ones that would be suitable candidates. How are you thinking about approaching this unmet need commercially?
The good news is that one, calcium is easy to measure, and you can go in and actually see some of the warning signs of the low serum calcium, high urine calcium pretty quickly, so actually, like, you know, you go to, like, a Marshfield or one of these larger networks that you wouldn't naturally associate as a maybe academic medical center and find a lot of folks that once you start looking, so I think, you know, that's the first piece. Second piece is the non-surgical hyperpara community as well, so there are a couple of places that we can narrow down the search, and then it'll be broader education, which I think will be interesting.
Final thing is, I mean, this, this AI approach, I was joking about it, but it's very powerful. You know, KKC employed that very well in the, you know, FGF23, rickets, market, alongside Ultragenyx. And so, there are probably ways that we could look for signatures of, you know, if you have some brain fog, if you have some tetany, if you have, serum calcium levels that are certain level, these are all things that would be in a record, and then we can identify those as plausible ADH1 patients and go from there.
Are there commercial synergies with infigratinib?
There are. I mean, on paper, yes, these are the same prescribing physicians. In practice, oftentimes, it's... Well, right now, actually, for Infigratinib, the call point is changing as we speak. It's really like medical geneticists and then, you know, pediatric endocrinologists. And so, there should be some overlap, but it's probably not as much as you know, it sounds like because these are hyper-specialized physicians.
Yeah.
Yeah.
Maybe quickly on BBP-418 for limb-girdle. I guess we're looking for the interim data readout next year. What is it that you're really looking to see at that interim to really think about an accelerated approval path?
Yeah, so just as a reminder, limb-girdle muscular dystrophy type 2I is the most common of the limb-girdle muscular dystrophies. It's a little bit more common or prevalent in the United States than are the exon 51-associated Duchenne muscular dystrophy patients, so a sizable unmet need. And this is a first-in-class approach that's targeting the disease at its source, providing substrate to the loss-of-function enzyme, which is FKRP. And like in DMD, I think the pathomechanism is well described, and the causal driver of disease, which is lack of glycosylation of this alpha dystroglycan complex, is also well understood by both the regulators, patient communities, and the physician community. So that's the primary endpoint on accelerated approval, and our hope is we can see what we saw in phase II, which is a meaningful increase in glycosylation of that complex.
And then we'll be looking at the key secondary endpoints, which include a whole battery of functional readouts, everything from FEV to ambulatory measures, to the Modified North Star test as well. And we'll be looking for direction there. But according to the natural history of the disease, I don't think we're going to see a huge amount in that time frame. I think we'll be more looking for that, more looking for the impact on the causal driver of disease.
So then for those secondary endpoints, is there some kind of threshold you need to hit, or not really? It's really going to be driven by showing the benefit in the glycosylated dystroglycan.
Yeah, I mean, that is a primary endpoint. Obviously, these things are always a conversation with the community. I mean, it would be, you know, strange and deserve further discussion if the key secondary endpoints went the wrong way. We didn't see that in our phase II, right? But if they achieve statistical significance, I'd also be very surprised. That's why we're running the longer trial. This is a nested trial design that goes out, almost three years because that's what the natural history suggests. It's a very slow, slowly evolving, disease. So yes, first and foremost, it's still glycosylation, but... and then we'd have to look at the trends.
All right, well, a lot of exciting late-stage moving parts to Bridge, and fortunately, we're out of time, because-