All right, cool. Good afternoon, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowan. Thanks once again for joining us at TD Cowan's 46th Annual Healthcare Conference. For our next session, it's a privilege to have a fireside chat with BridgeBio, and it's a pleasure to introduce Neil Kumar, the CEO of BridgeBio. Neil, thanks so much for joining me. Appreciate being here. Appreciate being here. You got it. So, look, Neil, the stock is corrected a little bit as of late after the huge run ad in the year prior. Personally, I believe it's a bit of kind of sell the news post-ACON. Maybe some are just shorting it in this kind of near-term window ahead of the TAF IP trial and a lack of clinical data readouts. I don't think anything about the fundamentals of the story has really changed. They've continued to improve, obviously, with the three-phase readouts. But with that said, curious to get your perspective on that. And your thoughts on the TAF IP situation as well, given that the trial is coming up here shortly.
Yeah, sure. Thanks for the question. Obviously, we've noted the pullback and the disconnect between intrinsic value and where the stock is trading now. I'd say, first, we feel very privileged to be sitting on top of the last three phase threes, certainly in ADH1, LGMD2I, and the latest in acontroplasia. They all met or beat our expectations in terms of service to the patient communities, and we can go through the details of any of those, and I think that liberated a reasonable amount of intrinsic value, certainly in our models. So what's weighing on the stock, I think people in this room probably have a better idea than I do, but in large part what we've been hearing has to do with the TAF IP overhang. And I'm not going to make a huge deal out of it here. We tend not to talk publicly about our competitor's IP situation, but I obviously will say that the trial is upcoming in late April, and we believe Pfizer has very, very strong arguments both from the standpoint of infringement and from the standpoint of validity. Obviously form one, lowest free energy form, polymorph, we think it's well protected, and we think that it shows up in all the generic batches, and otherwise Pfizer would not be asserting the claim against every single one of the generic manufacturers. In our view, again, I think they also have a very, very strong set of orthogonal methodologies that allow them to pick up form one, obviously solid state NMR, x-ray diffraction, as well as Raman spectroscopy. So we feel good about that. And then on the validity standpoint, from the validity standpoint, which obviously has been a little bit more controversial given what happened in Europe, we really have to to remember that in America, the bar is extraordinarily high for validity. So, if you're going to make form one, you got to make it every single time that way, and then it's inherently anticipated. But if even one or two times out of 100, you get something else, then it's not inherently anticipated. And because Pfizer did not document the acidification step in the context of Vindemax, we believe, and you can see this from the fact that generics have been able to patent metastable or amorphous forms of the crystal, that you're not always going to get Form 1, and therefore we believe the patent is both non-infringible but also a valid patent. Again, that's our view. We'll leave it to Pfizer and others to sort that out. Our view is also that a Truby is a clinically differentiated molecule, and in any circumstance, we'll be able to continue to grow the brand for many years to come.
Okay. Great. Thanks for that. And so, trial starts in April, and presumably, they need to come to some sort of ruling or decision by the November timeframe?
Exactly. Yeah. We expect to hear anywhere from late summer to November. Okay. But I think, honestly, in the first couple days of the trial, we'll have a sense as to whether or not they can assert those claims and really drive toward infringement for all the generic manufacturers. So I think we'll have a sense here, end of April, in my guess.
And then regardless, there's going to be an appeals process that plays out too, right, or will be accelerated?
Not in the US, no. Okay. Yeah, so different. I mean, in Europe, what you have is you had the ruling, which obviously went in their favor. Then you had the appeals process with a couple of scientists who took issue with the validity aspect with a different bar and probably a little different than the judge. that they withdrew the patents at that point, so there's no legal precedent that floats over to the U.S., but this will be the ruling of import, there will be no appeals process after that.
Okay. All right. So PEAT extension end of 28, so earliest basically the generics are launching in 29. If they do 180 day exclusivity with single filer, could be, you know, multiple generics later in 29, settlement would be like a 32, 33 timeframe. And then the third scenario is the TAF IP holds up, and then that's 2035.
That's right. And by the way, we think that third scenario is highly probable based on what I just discussed. But I know IPD and others believe the settlement in 32 to 33 is the most probable scenario. But we disagree. But, you know, we're obviously not IP lawyers over here. So we'll just have to see how it plays out. I think it's important to note, even past clinical differentiation, that this is a MediD-focused orphan drug space. And so, obviously, if you sort of break down the economics in the channel, patient co-pays are going to stay the same, whether you're on a generic or whether you're on a branded drug. Obviously, all the distribution networks are going to actually want branded, especially the ISPs. I mean, we see this a lot in the context of academic medical centers. And then, ultimately, I think physicians going to want to work with a branded distributor who is focused on doing hefty research like we are. I mean, I don't think anyone's running a primary prevention study like we are, a $400 Million Act Early study. We've been doing a lot in real-world evidence. We've been doing a lot in subpopulations like the variant population, AFib population, and the like. So, I think we'll continue to try to differentiate the product and learn more about how small molecule stabilizers can be used to the benefit of patients overall, both earlier and in more
severe settings. Okay great now kind of staying at a high level we have the ongoing Atrubi launch as well as the three NDA filings from the three positive phase threes that just read out over the next year or two. Can you talk about your plan to manage expenses and cash runway all well continuing the Atrubi launch in these three new product launches? Yeah I mean I think it's no
surprise that all every single one of these upcoming launches is going to be materially cheaper than the Truby launch. Obviously, the field force for TTR is larger, plus we have an already established commercial infrastructure now. So, a lot of what you need to do for distribution design, patient services, certainly market access, incentives, Salesforce training, all of that stuff is already set up. So, there will be an incremental tick up in commercial spend. I think R&D will be flat to declining, obviously, as we bring some of these large phase threes off. And so we feel like we're very well financed, given the well over a billion dollars that we have on the balance sheet to get to profitability, should we choose to do that.
What sort of head count and field footprint do you think these next three launches need? And maybe you could put that into perspective relative to the Etrubi effort?
Yeah, hard to tell. We've never really disclosed precisely the number of reps we have, I think, on TTR. But it's no surprise that one of our competitors disclosed around 140. We're not that far off. And that's probably a multiplier of four more than you need for something like a rare disease like LGV2I or ADH1. So those will be small field forces. In fact, in some cases, I think the MSLs might be half the head count of the actual
field force. Got it. And what phase of preparations are you in for these three new launches? How ready
are you guys to launch these products so the all the commercial leaders have been hired medical affairs is out there for each for each one of these pieces obviously we you know we're filing these ndas and we need to get the we need to get approved before we can really turn on the gas but you're also able to send out your frms based on your phase three data and start to learn more about what pricing could look like so so we're doing that as well so i would say everything Anything we can do right now, appropriately, we are able to do. Very unlike, actually, in the context in ATTR where we were so broke that when we hit on that face, we were like, oh, great. Let's hire a commercial for us.
Moving to ATTR and Truby specifically, can you talk about the key factors driving the momentum today, the biggest contributors to the strength of the launch, and what gives you confidence that this is going to be a multi-year sustained growth of the franchise as opposed to just a strong first full year of launch?
Yeah, it's pretty multifactorial, but the strength actually to me is indicated by that second derivative that's now gone positive again. You don't tend to see that as much in rare disease launches, at least as we modeled in our revenue institute. You see this explosion and then you kind of like, you know, constant growth. But the fact that we are, you know, we're growing growth, if you will, quarter on quarter and we're having basically the best couple of quarters that we've had to date suggests a couple of things. One, I think we're doing a better job collectively as all the sponsors in the field in identifying patients and driving the call point even outside of academic medical centers to high volume heart failure practices. We obviously haven't diagnosed even maybe one fourth of the number of ATTR cardiomyopathy patients that almost certainly exist in the United States. So that's work that needs to be done. And I think, you know, I was probably skeptical on this at first, but a large part of that is these sort of AI, what people call AI, but it can sometimes be, you know, a few factor sort of red flags that say, hey, consider this FF patient. They may have ATTR cardiomyopathy, and then that drives people to think of it and go to the technetium scan. So that's number one. Number two, I would say, is the generation of additional clinical data, both in the context of the early separation, which I think is really starting to catch on. And you should stay tuned for more research on why that is occurring, I think uniquely for our compound. But I think secondly and key in certain subpopulations, like the variant population where we had a 0.41 hazard ratio with STAT-SIG, which is the best point estimate and statistical significance in the space. But also, importantly, the AFib data, recall like almost I think 60 percent of patients or so on this channel have some cardiac arrhythmic involvement. And what people often will look at is the relative risk reduction or the 17% reduction. But really what I think is most important is a TRUBI works both in the context of AFib and in the context of non-AFib. So if you're a prescriber in the field, especially outside of an academic medical center, you can prescribe a TRUBI to all the patients that may have ATTR cardiomyopathy. And I think that significantly simplifies the script.
Great, and so is it fair to say you expect significant quarter-over-quarter growth each quarter this year, and how do you think about the overall market opportunity? Do you think it has a real chance of becoming a $20 billion market?
Yeah, I do. I think from a top-down perspective, there's still no study that suggests anything south of 12 percent of FF patients having ATTR cardiomyopathy, so from that standpoint and the pricing stamp you know coupled with where price is going um and where price is actually even today i don't i don't foresee there being an issue getting to that size of market and i think from the bottom up at least for us we're seeing increasing education you know we're seeing increasing prescription base in terms of number of prescribers and so i think that that all portends
continued growth what are you seeing uh from a competitive standpoint in the market from both Both Pfizer's franchise as well as Alnylam, obviously a different approach in terms of the impact that it's having on your launch or you guys really, it just really comes down to your own execution and you're kind of unimpeded in your launch?
Yeah, I think a lot of this comes down to our own execution. To be honest, I feel like sometimes we're working all together as sponsors to really grow the space. Each one of us have a different segment that I think we're strong in, and, you know, by and large, I would say, like, for instance, Pfizer just published two papers in Jack on the usefulness of serum TTR that helps us because we obviously have a superior profile in terms of elevating serum TTR, but it reinforces to physicians the fact that for every mg per deciliter increase in serum TTR, you're getting about a 5 percent relative risk reduction in mortality at 30 months. So continuing to drive those types of stories into the marketplace I think will be to the benefit of all medicines but especially a superior stabilizer like ours so buyers getting a great
early penetration in europe with the antra so can you talk about uh the contribution of that ex-us launch uh to the bridge bio pnl and whether you expect that expect that to start contributing
this year or next year yeah i think um this year uh it should start to contribute in a meaningful way um obviously given the the high royalties uh that were a beneficiary of but i think buyers done an absolutely marvelous job of of launching in europe obviously totally different commercial dynamics uh over there and they've been able to secure a majority share um in germany and a few other marketplaces uh where were they actually the only drug um in the international bid so my we're excited to see how they continue to grow grow the brand over there and and to continue to to learn from them in terms of how best to position our product here great so we got to move to the
three phase threes that i've read out and the three new product launches so we'll start with infogratinib achondroplasia your recent data exceeded expectations on both efficacy and safety really stellar data so i guess following the data that you reported what's your latest assumptions in terms of potential market share that you could achieve relative to the injectables?
Yeah, I mean, we did a preference share survey that I think I commented on in the last earnings call suggesting that we could get to 65%. I know the, you know, most of the KOLs are saying something like 80%. I think just stepping back, I don't know what the right percentage is. We haven't done, you know, the fully, the full degree of work yet, and we won't until we get the label. But one of the things that's interesting is, generally, in a marketplace like this, it's probably 25 percent penetrated right now. And at least according to our market research, maybe 35 percent of patients in the United States are needle phobic. So they're not going to be taking the existing products. And so our hope is that, like many orals from Fabry to migraine, we both enlarge the TAM as well as take significant share from the existing products. And I think the share taking would be associated with greater efficacy, a better safety profile, and obviously a more convenient profile as well. So it really does feel like, you know, this is a medicine that the community is excited to welcome. And I think we should be off to the races with this launch.
How large do you think this market is? And how does Hypocon add to that? And what are your expectations for Infogratinib and Hypocon? Yeah.
So, just as a reminder, HypoCon is a similar hyperactivating mutation in FGFR3, the N540K mutation. It's a little less hyperactivating, and again, in animal models and cellular models, Infragratinib targets this well-described condition at its source and is able to rectify not only the high symptomatology but things beyond that. And so, our expectation is that this dose, which is a safe dose, obviously, we should be able to deliver best-in-class efficacy there as well. And we think that market is actually similarly sized to acondroplasia, probably a little less well-defined, but similarly sized ultimately when you look at the statistical genetics.
Got it. So is it $5 billion potentially with acon and hypocon? Yeah.
I think that's a rough sentence. We haven't said anything about pricing yet, but yeah, that would be roughly there.
Okay. And maybe just you could talk about the status of the hypocon trial when we'll get the next data readout. what expectations should be and and also phase three start yeah it's it's hard to tell precisely
what the bar is uh yes and we haven't seen the bar from any of our competitors really um so so i'd say right now it would be statistically significant impact uh on the condition you'll see data later this year um and then ultimately phase three starting next year okay all right
Right. And Caloret also exceeded expectations there. So maybe we could start again with, actually in Caloret and Lemgirdle, let's discuss those kind of together. How do you think about the market size?
Two forgotten products.
Yeah, exactly. For both of those programs and, you know, if you had to pick, you know, one of your children, which one would you pick? Which market opportunity or launch are you most excited about?
I'm excited for both, to be honest. I mean, I think two very different profiles. So on LGMD2I, the one thing I would point out is if folks call around to muscular dystrophy clinics right now, there's a reasonable number of patients that are already identified. You can see that through natural history. It's also congruent with how quickly the trial enrolled given the prevalence. We think there's maybe 1,200, 1,300 patients in the U.S. and a lot of them are already identified. So I think that launch is going to be premium priced and go fairly quickly if we can serve of those patients well as quickly as possible, I think that's what we'd be intending to do. ADH1, a little different. Obviously, the statistical genetic prevalence is massive, 10,000 to 12,000 in the United States alone, but that is not the number of identified patients. You know, we think that there's maybe 2,000 to 3,000 hypersymptomatic identified patients right now, and we've rolled out a genetic testing program that I discussed at someone else's conference that we continue to build upon in the non-surgical hypopera community to find more and more of those patients that are really hiding within that space with hyperactivating mutations, the CASR. So, I think that actually launch will be kind of a slower build, but ultimately we'll get to similar peak year sales.
Maybe you could just elaborate on that genetic testing program, how you expect it to progress, and how you expect to diagnose these additional patients.
Yeah, so about 130 different hyperactivating mutations in the calcium sensing receptor, we know what they are, we've characterized them. We published a paper on this last year that I think you and I discussed, and so we've got a panel. And what we can do is we can offer that panel at cost to potentially prescribing physicians in the future. Today, physicians, I just want to understand better what the genesis of calcium-induced regulation might be in, let's say, a Hypopara patient or someone who's sort of classified as a Hypopara patient today.
Is it fair to say that both of these opportunities, ADH1 and limb girdle, are billion-dollar-plus opportunities in your view?
Yeah. I would think so. And that's, you know, I would say for LGMD2I, it's not obvious what the additional indications might be associated with BBP418. There's Fukuyama syndrome, you know, ISPD mutations, but there's not a whole lot else in that pathway. It's interesting to speculate as to whether or not hyperglycosylation of the complex might be relevant in the context of some other muscular dystrophies, but we haven't seen a genetic signal therein yet. So I think that's one piece of it. On ADH1, obviously, we'll be kicking off a Phase III in chronic hypopera, and I think that is another very, very large opportunity for us. So that could be a billion, but it could be well over a billion if we hit on that Phase III.
So, yeah, the Phase III reclaimed HP study in hypopera, maybe you could just reiterate what you all saw in Phase II that give both what you saw in Phase II and also mechanistically why you have such confidence in incalorate and hypopera.
Dr. Yeah, it's a little different than our normal approach, right, because typically we start with pathomechanism and we try to target the well-described condition. At its source here, we were looking at the phenotype of the drug, if you will, and trying to match it up with an unmet need. So in the context of chronic hypopera, it's obviously a disease that's solely about calcium dysregulation, but it stems from a lack of PTH. So giving back PTH would make sense, and that's obviously what our competitors do. There are some issues with that long term in terms of bone abnormalities because you're not doing it in a physiologic way. And when we look at our drug, what we realized was we were able to normalize urine and serum calcium through antagonism of the calcium-sensing receptor and to do it in a PTH-independent way through really the action of the kidney. And so that's what got us excited about exploring the agent in that space. We did a, you know, I hesitate to call it a phase two. It was really a signal-seeking 10-patient study, but what we saw was 80 percent normalization of urine and serum calcium in the context of chronic hyperparapar patients. And that's what gave us the confidence to really move it into phase three aggressively. It would be the only oral agent. I think it would be actually something that the community would welcome if we're able to deliver on the promise of the phase two or signal-seeking study.
So I guess just to follow up on that, you think mechanistically there's a chance that it could be superior to the PTH analogs and hypopair?
Yeah, I think it would mechanistically it should be able to deliver better urine normalization, and calcium normalization, and it should be safer. And it's oral, so at the very least, it should be competitive.
Great, and you know, when the ADH1 data came out, some folks were like, the PTH analogs can treat ADH1 patients. So curious to get your thoughts on that, if currently ADH1 patients are being treated by uorgopath or?
No, almost none of them are, to be honest. There was that very, very small study that was published in the New England Journal, suggesting inferior levels, obviously, of urine normalization, of urine calcium normalization. So I don't think it will be competitive in the context of ADH1.
Great, okay, all right. And just, you know, going back to Lim-Girdle, can you elaborate on those conversations with the FDA where they supported a traditional full approval with the NDA and how those conversations went?
I mean, I would say that, generally, this division has not seen a whole lot of data sets that were as uniformly consistent, and when I say uniform consistency, I would talk about two real measures of it. Number one is across different functional outcomes and inclusive of modified North Star, which I think was quite surprising even to us and hardening, and then the second is across subpopulations, so, you know, heterozygous, compound heterozygotes and L276I, old and young, ambulatory, non-ambulatory, so I think all of those things together, really the agency is looking for that level of consistency to make sure it's not outliers driven, it's, you know, it's a true statistically significant impact, and that's, I think, what all led to the enthusiasm around submitting for full approval.
And so I guess just to round it out, for both of these indications and potential launches, ADH1 and limb girdle, based upon your filing timelines, you guys could be launching both of these drugs in the first half of next year?
Yeah, that's right.
And then infagratinib for achondroplasia obviously would be after that next year?
Yeah, I think the first half of next year is doable as well, but we'll have to see.
How do you think about, again, balancing, executing on these launches and building out the pipeline? What might we see from the internal pipeline over the next year or two as well as potential external opportunities? Yeah.
So, I mean, when I talk about the external pipeline, I include our sister companies and probably most relevantly, Gondola Bio. And so, within that, I think we have a vast array of technologies that we're working with. Obviously, we've talked about what we think is a best-in-class EPP program. We have two other clinical programs, one in CMT1A, one in alpha-1A trypsin. We have some seven development candidates that we think we'll hit on, varying from TSC and REV inhibition to a novel mechanism in the context of ADPKD. So there's a lot to be done. And I think we've already proven that we have a very efficient late-stage development, and hopefully we will prove that we have a very efficient commercial engine that can be deployed at scale at Bridge. So bringing all these things together makes a ton of sense. Timing of that is TBD, I would say, like a couple of things have to go right. Number one, first we have to really focus on the execution of these three opportunities for the patients that we serve. So we've got to nail the NDA submissions, make sure we get strong labels, and launch these three programs that we've been talking about. Secondly, is we obviously have to correct our cost of capital and find a way to capture the value for the folks in this room and investors as we continue to make progress in the pipeline. So those two things have to come together for us to start to refocus on growth, but I would say the opportunity has never been more exciting in the area of genetic disease as far as I'm concerned.
DR. Great. And a lot of interest from the audience on disc medicines and EPP in particular. So maybe you could just elaborate on Gondola's EPP program and why you are so excited by that program and the early data that's been reported.
DR. Yeah, I would say EPP is almost uniformly a disease of too much PP9 in the sera, as many people know. It arises typically from mutations in ferret kilotase in the red blood cell, and so approaches that have been explored in the past, obviously Mitsubishi Tanabe and others have quote-unquote tanning agents, but the first disease-modifying approach was DISC Medicine's approach to inhibit glycine uptake into the red blood cell, and really we just, you know, we looked at that and we tried to understand how we can do one better for the patient community. a couple of things that suffers from is a long time to depress PP9 levels in the Sarah second is not as not as profound a magnitude of depression as we think is necessary for optimal efficacy and then the third is obviously where that compound hails from is is schizophrenia and and there's significant amounts of dizziness and and some suicidal ideation as you get down get down into adolescence And so, we would have liked to have seen a more benign safety profile. The final thing that I think is underappreciated is this is a disease not only of phototoxicity, but also one that affects the liver. And so, one would like a mechanism that could uniquely impact both the liver and the skin associated phototoxicity. So our approach is actually to inhibit the egress of PP9 from the red blood cell by blocking its transporter, which is ABCG2. So we have an inhibitor that we co-developed with a professor at University of Pittsburgh, and that has shown, as I presented earlier this year, profound both in terms of rapid descent of PP9, up to 80 percent reduction in a phase two, and doing so very safely. So we're excited about the profile. We also know that it affects the liver, and we've shown that in animal models. There will be a longer-term clinical trial to prove that and point out, but we're excited about that. meeting should be in about a month and a half so we'll learn more about what the
what the path forward there is when you say rapid how long is it taking to get
to maximum reduction like within two days versus with the weeks that it takes
for glycine uptake great we have a minute left so maybe in closing Neil I'll ask you what you believe is the most underappreciated aspect of the
bridge bio story by investors I mean bless you traditionally I would have probably pointed to one of LGMT2I or ADH1 to be honest. But honestly the last couple days or last couple weeks I feel like it is a Truby. I feel like with the TAF IP overhang here people are really discounting the potential for a brand that to my eyes is growing really nicely and a marketplace that continues to have significant on met need and where we're cranking out really really compelling clinical data. So I'd start with a Truby.
Yeah, great with that Neil. Thanks for a great discussion. Thank you