BridgeBio Pharma Inc Stock

Well, thank you so much, everybody. Thank you for joining us, Thomas and Julie from BridgeBio. It's really nice to have you here. And we'll kick it off first with you guys presenting some slides and giving an overview before we start with the Q&A.

Great. Thank you so much for having us, Jeffrey, and thanks to the whole Bernstein team. Thomas Trimarchi, President and CFO of BridgeBio, joined by Julie Miller Everett, our Chief Operating Officer of our skeletal dysplasia business. Many of you will know Julie from her critical role in the Attruby launch, and we've just moved her over to help with the infigratinib launch, where she brings more than a decade of commercial experience, particularly in the ultra-rare and skeletal dysplasia space. So really privileged to have her with me here today.

Maybe I'll start just by saying a few words and setting some context for hopefully a great dialogue here with you today, Jeffrey. So BridgeBio is a company that, at the highest level, we're here in this world to help as many patients living with genetic disease as we possibly can in the shortest amount of time that we can get that done. And we do that through creating first or best-in-class medicines and putting them out into the marketplace.

Today, the business late-stage portfolio is incredibly unique, I would say. If you've studied the industry, you certainly are looking at it today, as I know you are. So first, we've got Attruby, which is our best-in-class near-complete stabilizer for ATTR cardiomyopathy. We're about 6 quarters into that launch. That -- the importance of that launch to our business cannot be overstated. So at once, I think that has proven us as a capable commercial organization. And I think that is widely regarded as one of the better biotech launches we've seen in recent years, annualizing north of $1 billion today globally, on track to be, on a full-year basis, blockbuster status globally by the end of this year.

Really, that's owed to a few things. First, this is a large and expanding marketplace. We're seeing something like 15,000, 16,000 patients come to the bottom of the funnel every year. So really, really attractive from a patient need standpoint. And I think we have clearly a differentiated and best-in-class stabilizer, which, post some of the recent data sets, I would say, solidified as the backbone of first-line therapy. So really exciting molecule there.

And actually, this morning, we had some incredibly important news come out. We published the first-of-its-kind real-world data set comparing Attruby directly to tafamidis, where we've seen about a 1/3 improvement in the composite of including all-cause mortality and CV hospitalization. So really important data set that has not really yet been disseminated into the marketplace and impacted prescribing behaviors, but that will take place over the next coming year. So it really proves us out as a confident commercial organization and also, I think, gives us the confidence to launch the next 3 products, not only in the U.S. but globally.

So I think the truly unique thing about BridgeBio today is that still early days of one product launch and another 3 coming in the next year. So we've got limb-girdle 2I, which is a first-in-class molecule for a high unmet need form of muscular dystrophy. There, we've got a product that can actually remarkably improve function on several fronts. One, patients are able to breathe better than when they started therapy. They're able to walk better and they're able to actually, through measure of general symptom scores like North Star, restore overall function in a statistically significant way against placebo. So really, really exciting molecule there that's going to do a lot of good for patients. This is a clear $1 billion opportunity.

ADH1 encaleret is another small molecule that's read out Phase III in the last year or so. Again, basically functionally cured about 76% of the patients in our Phase III. So really important data set that's going to change a lot of lives in this marketplace. And there, again, we've got a $1 billion opportunity, no competition, looking forward to building that market.

Finally, achondroplasia, which I hope we have plenty of time to speak about given we've got Julie with us. This is today a $1 billion marketplace where we're going to come in with a clearly distinct, differentiated and unique molecule, first and only oral in the space and a pivotal data set that really is giving the market exactly what it's been asking for, for many years, which is really a profound effect on height, but more importantly, a compelling effect on the health of these children. Whether it's proportionality or some of the things we've been able to demonstrate recently, including an effect on sleep apnea and ear infection.

So overall, big picture, Attruby, we see is on track to deliver $4 billion plus in peak-year sales. And then you've got another $4 billion, I would say, derisked and about to see uptake into the marketplace next year with expansion available to us beyond that. And there's some interesting opportunities, including hypochondroplasia and other skeletal dysplasias as well as postsurgical hypoparathyroidism. So that's the opportunity in the next 18 months, I would say.

Beyond that, our hope is that we can create many, many new meaningful medicines for patients beyond the 4 that I talked about and have a durable business that can grow for many decades. And so beyond the 4 products that hopefully we'll spend most of the time on today, we've had a very prolific, productive discovery engine that's continued to put molecules in the clinic. So I think when the time is right, we can access some of that pipeline growth. It's housed today in our sister company called GondolaBio, which is private. So with that long-winded, perhaps context setting, maybe we can get right into the Q&A.

It was a great context setting. And yes, we'll definitely touch on a lot of these drugs during our conversation and excited to hear more. So maybe even taking just a step back, just as an introduction, I'd love to hear what both of you think is sort of the DNA of the company. What makes BridgeBio tick and why are you so successful?

Thank you for saying that. I would say 2 things in my mind are different and special about this company. First, and this comes back to the patient impact mission. We really try and work on diseases where there's both a tremendous unmet need out in the community, either there's no available therapy today or existing therapies are inadequate. And we try to work on diseases where we can ask how do we drive a large magnitude of impact for patients. And for us, that usually brings us to conditions where we can take a complicated biological problem and convert it to something much more like an engineering issue where we can kind of connect all the dots between genetics and what we need to do to the target and how affect it to translate to symptoms and outcomes for patients.

And when you do that, I think you can, a, drive probability of technical success even beyond the all-comer kind of genetic disease levels. And I think we've demonstrated for the first 10 years that we can do that. And b, it lets you really have a clear thesis on what your therapeutic hypothesis is so that when it's not working and it's no longer intact, you can kill it and reallocate resources elsewhere. So that's, I think, one thing in terms of the operating system that is unique and has allowed us to be successful.

Two, from a business standpoint, I think we catch a little bit of flak from time to time from investors for spending too much time talking about NPV. But it actually does matter if you want to create a business that is going to be durable for generations to come. You really have to be focused on, am I investing in a way that's going to allow me to be sustainable from an economic standpoint. And I think clearly, if you look at kind of like the opportunity for us to transition our P&L over the next 18 months, I think that clearly has benefited us to date. So those are 2 things that pop into my mind, but Julie?

Yes. Well said, I would just add one more, which is that we have truly differentiated clinical science and outcomes. And when you look at kind of the 2 pillars that we're building as an organization right now for commercial execution, we have hypercompetitive markets like amyloidosis and achondroplasia, where we have best-in-class products that are truly differentiated if you follow the science in the literature. And then we have Pillar 2, which is these traditional rare disease markets where we're building a market based on clinically defined conditions, well-articulated science, high unmet need. So I think that's really what differentiates us is having a scientific but also commercial organization that's able to develop drugs and then execute across both pillars.

That's excellent. And maybe kicking it off, you gave a really nice overview that highlighted some of your 4 current key drugs in the near term and on market now. I'd love to maybe just start with Attruby, give us an overview, any additional information you want to share beyond your nice introduction upfront and how important it is for patients and for the company.

Yes, absolutely. So -- so Attruby, yes, as I mentioned, that's annualizing today at north of $1 billion, just 6 quarters into launch. And it's a really interesting moment for this product where we see a large and continuously expanding market. As I mentioned, 15,000, 16,000 new patients a year right now today is our estimate. Just 2 years ago, that was more like 8,000. Last year it was something like 10,000 to 12,000 was our estimate. So we continue to see strong momentum for the market overall. And at the same time, we continue to grow our share of the market. And I think we're really entering, I would say, kind of a second chapter of the Attruby launch.

First 6 quarters were really about getting out there, getting into the centers of excellence, establishing ourselves as the new player, the differentiated player and really grabbing market share with our initial marketing messages that were really anchored around the primary analysis from our Phase III study, so 340, 250, 3-month separation, 42% reduction in hospitalizations and mortality and a 50% reduction in hospitalizations, which, by the way, given a shifting patient population, most events that occur in this population today are hospitalizations. So really important that we have strong data there. So I think that has gotten us where we are today, which is about 25% share of new patient starts and growing.

And really, the next leg up of growth is going to come from a bunch of new data sets that we've just put out into the market or have been shared with the marketplace through competitive updates. So on our end, we've seen 2 really important new pieces of data come out very recently. First, we published an effect that shows Attruby actually can have a kidney protective effect in these patients, right? And actually, the mechanism is something we're still working on, and I think we're going to have dedicated studies to actually demonstrate this in a prospective way. But I think that could explain why we see separation on outcomes as early as 1 month or within weeks of treatment. That's really important. I think that is just starting to be disseminated to the marketplace, and we could see an effect on prescribing behaviors there in the year to come.

Second, as I mentioned this morning, real-world data set. I mean one of the big questions we've had from prescribers that are more on the fence in terms of preference for Attruby versus anything else has been, okay, I can see scientifically that you've got a much more potent molecule. But it's very difficult for me to compare across clinical studies. They were run in different eras. The population has been shifting rapidly. How do I really know that it's going to deliver a differential outcome for patients? And actually, sometimes they ask the patient which medicine they want to be on, which is not great, if you ask me.

But -- so I think the real-world data set we've published this morning is going to be very impactful in answering that question of does more stabilization truly matter in terms of outcomes. And so again, what we've seen there is a 34% improvement on the composite of diuretic intensification, CV hospitalizations and all-cause mortality for Attruby as compared to tafamidis. And again, that effect is seen in weeks, not months or years. So hopefully, we can create some urgency to start using Attruby in new patients or even switch more of your tafamidis patients on to Attruby.

And there's going to be more to come, right? I think there is -- when you see a study coming from a sponsor, there's sometimes appropriate skepticism as to the methodology there. But there's an independent real-world data set coming out in, what is it, 2 weeks or 3 weeks at HFSA, which hopefully can provide additional validation of what we published this morning in our study. So I see Chapter 2 of this launch being driven by some of these newer data sets and leading to really a reacceleration of growth as we look into second half of next year.

That's great. And more data, especially real-world data sets are very helpful. And so it's great to see. Speaking of recent data, a bit of a different mechanism, but CARDIO-TTRansform was presented at ESC last month. Just curious what you think of that data set and how it could be impacting the stabilizer class. I realize it's a silencer, but it was a very impactful presentation last month at ESC.

Yes. And Julie, feel free to chime in here. But I think the -- a little feedback here, sorry. I think the most important takeaway from that data set was this whole concept of combining a stabilizer and a knockdown is really without any merit. I mean we've seen no treatment effect of adding a knockdown on top of even a weak stabilizer. And so for the prescribers that were thinking that might be a good idea scientifically and could lead to a good outcome for patients, I think we have just too much evidence today to continue with that. And you saw from multiple major KOLs off the podium say this is practice changing, meaning that it is no longer an approach that we should be thinking about for patients.

And that really suggests that frontline backbone of standard of care ought to be a stabilizer. And I think as we just discussed, all of the data sets coming out here continue to suggest that Attruby ought to be your treatment of choice and where you start. It's going to take some time. It's going to take some effort. It won't happen without a lot of fighting and repetition and educating the marketplace, but we're optimistic that the data is all on our side, and we can continue growing share over the next year and beyond.

I think -- yes, well said. The only thing I would add to that is I think one of the other things that clarified is this concept of, like, how do you define efficacy in cardiac amyloidosis. And mechanistically speaking, we discussed a lot this concept of the TTR tetramer and ultimately, what's disease causing is the toxic monomer. And when CARDIO-TTRansform read out, a lot of folks started digging into what is what we call like mean max efficacy. And when you look at the stabilizers, you have tafamidis, it's about a 60% stabilizer, meaning 40% monomer still forming disease. You have acoramidis that's a greater than 90% stabilizer, so less than 10% toxic monomer disease forming. And then when you look at the knockdowns, it's the inverse, right? It's like how much do you knock down and then toxic monomer remaining.

And we saw that with eplontersen as well as AMVUTTRA, they were in the 60s to 80s, right? So scientifically speaking, I think a lot of dots were connected on an outcomes basis that prior to CARDIO-TTRansform were more of a theoretical basis. So it's nice for us now to see that narrative evolve. And final point is that even with tafamidis more as that background therapy in CARDIO-TTRansform and still seeing no benefit. Now doctors are also, to Tom's point, taking into account what we've seen with the stabilization data, acoramidis being a more complete stabilizer. You now see the real-world evidence, you see the kidney protection data, and it just takes it to the next level. But even with tafamidis, the trial was not successful; with acoramidis as the backbone of care, I think it's even further differentiated from the knockdown.

I would just say 2 more things that kind of struck me.

We like this topic.

Really important for me to see. One, you've continued to see event rates go down with the shifting population and better care. That's really important because I think we can say almost definitively now, a head-to-head study is not possible. So that puts increased importance on real-world data sets like we just reported this morning in terms of providing evidence for treatment decisions.

Two, really, I think, related, it means that most of the events happening today are hospitalizations. And so it makes it that much more important to have really, really compelling hospitalization data around your molecule, and we have market-leading data there as well. So 50% reduction in hospitalizations in just 30 months. So I think we're positioned extremely well to continue growing this brand over the next years to come. It's not going to happen overnight, but with, I think, the right team, the right resourcing and a little bit of luck, I think this can be a massive product for us and a huge impact for patients.

Absolutely. Well, just asking a sales question, how should we be thinking about the quarter-by-quarter dynamics for Attruby sales?

Yes. So I think for the next several quarters, I'd say, until we get into really the end of 2027, we'd be thinking about kind of a $25 million to $30 million quarter-on-quarter absolute delta. And that's driven by a few things, really.

First would be the dynamic around second line, the tafamidis switch. So we saw a pretty significant kind of bolus pool of patients early in our launch that were coming off of tafamidis onto new products, ours and AMVUTTRA, the knockdown, which makes sense, right? This is a market where there was one player in town for a long time that was tafamidis.

It was a huge step-up in terms of care for patients, but clearly inadequate, right, in terms of the level of efficacy and stabilization. So we knew there was a big pool of patients that were progressing and worsening but had nothing to switch to, so it just been hanging on tafamidis. So we saw early in our launch, I would say, a larger-than-expected contribution from tafamidis switchers. Certainly, what we can ascertain from dynamics around the knockdowns is they were benefiting significantly from switch early on in the launch, too. And I think at this point, we've kind of worked through that initial pool and that's normalized.

So second line is growing and, I would say, steady state now, which is lower than it was a year ago. And so that's one thing that's, I think, influencing kind of like the near-term quarter-on-quarter dynamics. Two is related, which is duration related to patient mix. So as I said, early in the launch, contribution from second line was bigger than we would have expected. And that has shifted towards a greater and greater frontline contribution every quarter since launch to the point where today, new starts volume -- vast majority is treatment-naive frontline share. But we're dealing with duration from the cohort that came on drug 6 quarters ago.

So that's another thing that I think you should be mindful of as you think about quarter-on-quarter dynamics near term. And then I think come late 2027, all of these new data sets that we've been talking about should begin to get reflected in treatment behavior and share, and we'll start to see a reacceleration of sales growth at that point.

That's great. In terms of -- you sort of highlighted the Attruby launch, great data that's just being released just now, your real-world studies. And now maybe looking even beyond that, life-cycle management. Is there anything you would like to highlight or are you thinking through when you want to speak to what the potential life-cycle management of the drug could be?

I'll start, Julie chime in. I mean I think there's at least 3 important studies that we're thinking about right now. One is the ACT-EARLY study, which is the first of its kind. This is a primary prevention study in variant patients where based on high risk of progression from being asymptomatic to having heart failure based on family history and various other factors. We're randomizing patients to placebo or Attruby. And the goal there would be to prevent patients from progressing to heart failure. This is analogous to what we've seen in the statin class with some of those seminal studies there.

Practice changing, basically disease prevention is always kind of the goal if you can figure out a way to do it. So that's key. And I think that also has the effect today of helping drive the narrative around early diagnosis, early intervention even for patients that do show up to the clinic with heart failure, don't wait, right, ACT-EARLY.

Two, we've just kicked off a cardiac imaging study. The goal there is going to be to show basically to elaborate and validate a signal that we saw in our Phase III study in the sub-study that we had with cardiac imaging. We want to see actual cardiac MRI-based disease reversal. We think it's possible based on the signal we've seen and based on the potency of Attruby. But I think if we can show that in a prospective study, dedicated study, that, again, would have the opportunity to be practice changing.

And third, as we talked about, we're looking for ways to elaborate on and again, validate this renal protective effect that we've seen from our Phase III in a dedicated prospective study that really just allows physicians to understand this effect and understand that it is distinct and unique from other approaches that are out there today and really can explain some of the compelling data we've seen on the early separation of outcomes, whether compared to placebo or again, in a real-world setting compared to tafamidis where you see separation within weeks.

Well, before moving on to the next drug, any last comments on Attruby, you feel like we haven't had a chance to discuss yet, anything else?

No, I would just say based on new evidence that's emerging across the category, including real-world evidence, seamless execution at the commercial level, differentiated outcomes in terms of science and commercial delivery, we feel more confident than ever in our ability to execute on $4 billion peak or more.

I would say one last life-cycle thing that I didn't mention is we should have a once-daily form coming into the clinic in the next year, 18 months, which I think there's a minority of prescribers and patients that are choosing tafamidis due to once-daily form. But so we want to be able to provide a competitive offering on that front has the, I would say, additional business benefit of giving us a whole new 20-year patent that should protect exclusivity for many, many years to come.

Great. Well, then you highlighted 3 other great drugs that are in the process of making their way to patients. Maybe start with the first one, BBP-418. Maybe give us an overview of that drug and maybe dive a little deeper and beyond what you gave in the intro.

Yes. So 418 is -- will be the first-ever therapy for a disease called limb-girdle muscular dystrophy type 2I/R9. This is, I would say, most phenotypically similar to Becker muscular dystrophy, where really bad disease where patients experience loss of ambulation, loss of physical function. Around 1/3 experience loss of pulmonary function, cardiac issues. So really bad progressive disease that is kind of like Chinese water torture is what our patients tell us, like where every day, there's something you can do less well than you could do the day before, and you're just constantly every day losing function.

So really terrible condition, nothing available today, significant unmet need in terms of prevalence. There's around 2,000, 2,500 patients, we believe, in the U.S. today that have this condition and another 5,000 or so in Europe and another 2,000 in Japan with a related condition called Fukuyama muscular dystrophy. 418 is basically targeting disease directly at its source by -- so basically, the genetics of 2I are basically loss of function -- partial loss of function enzyme called FKRP, which is glycosylating or adding a sugar moiety to a structural protein called alpha-dystroglycan. If you're not adding the sugar, it doesn't function properly.

If you destroy FKRP, not getting that sugar, not getting proper muscle function and then you get all the symptoms or phenotypes that we see in these patients. So what our drug does is basically provides high levels of a key substrate upstream of FKRP and drives additional flux through the residual enzyme activity that these patients do have to restore that a-DG glycosylation.

So what we saw in our Phase III was basically our initial approach was to go for kind of a surrogate-based biopsy-based biomarker kind of approval, accelerated approval. And we developed this very elegant biomarker assay that actually is able to measure the amount of glycosylation that you're putting on alpha-DG. And we had a Phase III that read out 1-year endpoint, and we thought we were going to be able to see an improvement in that biopsy-based biomarker and file with the FDA and try and convince them that this was reasonably likely to predict the future clinical benefit.

What we were, frankly, blown away to see at 12 months was a profound and consistent impact on every single endpoint we measured in the study. What was to be the confirmatory functional endpoint, which is the North Star composite that we saw a stat sig benefit and improvement from baseline. FVC, we saw a stat sig benefit improvement from baseline, 10-meter walk test, we saw a stat sig benefit improvement from baseline. Basically, everywhere you look, the patients are getting better, and we've seen a highly stat sig benefit from as compared to placebo.

So really compelling data set, I think, really unique even amongst -- broadly amongst neuromuscular clinical development where you just don't see that many well-controlled, well-designed placebo-controlled trials deliver this kind of benefit. So we're really excited to get this out into the marketplace and to hopefully change a lot of lives.

That's great. Assuming positive outcome with the FDA, what is sort of your view on the potential for the drug launch and its value proposition?

Yes. So just with the prevalence numbers I just walked you through, I mean, this is a clear $1 billion-plus opportunity in the U.S. alone even. And I think there are analogs in similar markets with much weaker datasets to suggest price point could be very, very compelling here. I mean if you think about the exon skippers for DMD around the $700,000 price point. So I think we're going to have a lot of flexibility to price well. With the FDA, it's been a very constructive dialogue. So I expect we'll get approved on or before our November 27, 2026 PDUFA date.

The question there really is, will we get full or accelerated approval. And I think hopeful that we could get a full approval here. And then I think around uptake, so where do we stand today in terms of market building, market development. So today we have around 500 of the 2,000, 2,500 patients that we think exist in the U.S. identified, confirmed with the correct genotype and basically mapped to prescriber. So that's our initial pool of patients that we're going to be targeting early days of launch. And the way to think about the cadence there is we ought to be able to work through that initial pool of patients within the first 3 years of launch, so maybe 100 in year 1, another 200 year 2 and then perhaps 300 year 3.

And at the same time, we'll be growing that pool through all of our marketing efforts out there in the field with our medical affairs and sales force to drive awareness, genotyping referrals into the centers of excellence where genotyping is standard of care and really to drive hopefully broad uptake over the several years following launch.

That's great. Well, before we switch over to 305, any last comments, questions, comments on 418?

No, exciting product, I think first of its kind in the muscular dystrophy space. So really, really excited to be out there and make big patient impact.

Perfect. Well, then moving -- switching gears to 305. Maybe you could once again give us a nice overview of where it stands and outlook.

Yes. So I mean this is encaleret, which is a calcium-sensing receptor for first indication is a form of genetic hypoparathyroidism where the disease is caused by an activating mutation in the calcium-sensing receptor. So as we typically like to do, there's a genetic defect, and we like to hit it directly with a small molecule. So this is actually the first indication of a broad set of indications we'll be going after with this molecule, including postsurgical or hypoparathyroidism broadly. But for ADH1, this is, again, high unmet need where patients actually -- there's a case report that just came out of England, I think, following a family where 2 of the children in the family actually died in their 30s from some of the terrible symptoms, heart failure and just general tetanic seizures. So it is a very serious condition.

If you talk to specialists that treat this, they treat hypoparathyroidism, their ADH1 patients are usually their most difficult to manage where they see very low serum calcium driving all the symptoms. They try to manage it with supplements, which just makes the elevated urinary calcium that much worse, and it's basically creating a ticking time bomb down the path of renal destruction. So the need here was for a therapy that could basically fix the aberrant signaling in the calcium-sensing receptor and hopefully alleviate the low blood calcium and the high urine calcium.

And so what we saw in Phase III was in 6 months of therapy, we were able to completely withdraw conventional therapy, which is supplements and calcium supplements and vitamin D and put more than 75% of our patient population into the normal range on both of those aspects, urine and blood calcium, incredibly compelling. That's a functional cure for more than 3/4 of our study population. More than 90% had parathyroid hormone into the normal range almost instantly. So really, really profound effect in this population, which is incredibly exciting for this population that desperately needs care.

So excited to get out in the marketplace. Again, this is similar to limb-girdle 2I. This is a condition where there's nothing really available. There's no sponsor out there marketing, driving awareness. So that's on us to do. We're out there today with field medical and sales leadership working on driving urgency to test. Here, it's a dominant condition. So meaning the families that have this condition have about a 50% chance of passing it on.

So family testing has actually been incredibly helpful here. We actually have a mobile testing lab van that we bring to advocacy and family events. And actually, it's been surprisingly productive to date. So we'll keep driving that along with more conventional, I'd say, market development tactics.

That product has a May 8, PDUFA date, so under FDA review. And I think the overlooked aspect of encaleret is actually the expansion opportunity into a broader suite of hypoparathyroidism conditions, including the biggest bucket, which is postsurgical hypoparathyroidism, where we've just kicked off a Phase III pivotal study, dose our first patient there in the next couple of weeks. That could add, I would say, a couple of billion in opportunity to this product, and we'll enroll the study next year and hopefully read it out late next year to early 2028. So large expansion opportunity on the horizon there. That's great.

Well, then last but not least, the last drug you highlighted earlier, infigratinib. I'd love to hear your overview there, what you're thinking in terms of long-term perspective of that drug.

Yes, absolutely. So similar to what you heard Tom say about our other molecules. So infigratinib also directly targets the mechanism of this condition at its source, the genetic mutation for FGFR3, whereas some of the other products in the market today are more indirect treatment mechanisms. So scientifically speaking, we feel very good about mechanism. As many of you know about the achondroplasia space, so there are 2 treatments available today, CNP analog products that have really shaped the market and provided an option where nothing was available today.

What we feel very encouraged about, starting with the U.S., when you look at the market, severely underpenetrated. It's only about 20% to 30% of families have opted into treatment today. And that's due to some very, very good reasons. The first is that the only currently available products are injections, whether that be a daily injection or a weekly injection, very, very difficult and limiting for families.

Second is that this community has been very vocal that they want to see benefits beyond height, right? So we want to see benefits on complications, functionality, comorbidities of the condition. And infigratinib is the first product to show statistically significant benefit within 52 weeks on benefits beyond height, so specifically proportionality. So not only did we demonstrate that largest annualized height velocity across the category, but it's these benefits beyond height that are really meaningful for physicians and the community.

So just 2 weeks ago at ESPE, we also released new data. Previously, we had shared in the primary data readout as well as our New England Journal manuscript, the height velocity and the proportionality data, but we just also included data on otitis media, which ear infections, as well as sleep apnea. So 2 common and difficult complications of this condition. Also within 52 weeks, infigratinib demonstrated benefit on both of those outcomes, the only product to do so.

So as we are preparing for launch here in the U.S., there's really 3 distinct categories for source of business. The first is that large portion of the market that has not opted for treatment today that we believe an oral therapy that demonstrates benefit beyond height can unlock. The second source of business is those who are on an injectable therapy, but might be seeking more in terms of convenience and efficacy that's being left on the table. And the third category of source of business is those who were previously treated and have discontinued. Our evidence points resonate well across all 3 categories.

Go-to-market in the U.S., we have our medical team sized and deployed, facilitating scientific exchange today. We're building out our commercial infrastructure to really call on where we know patients are being managed and families are seeking care today as well as where some families who are not seeking care today are interacting with their -- mostly their primary care. So we have a team that's ready to educate and inform the community so that they are ready to make an informed choice about therapy.

Ex-U.S. is a very different environment. So ex-U.S. treatment penetration is much higher. It's only about 20% to 30% in the U.S. Outside of the U.S., it's more 70% to 80%. So we've created a global international commercial organization that has developed a bespoke go-to-market model based on country. So we've looked at all the primary markets across Europe, Latin America, Asia-Pacific, and we've been able to design a commercial infrastructure kind of ranging on one end of the spectrum from a direct presence at the other end of the spectrum to more of the distributor or partner market strategy. Each unique market, we've been able to design our commercial infrastructure to maximize rate of speed uptake as well as price potential. It's all about demonstrating value in these markets, and we feel we have the clinical evidence to do so as well as the medical team and the commercial team to support the launch.

Excellent. And a really nice overview of the key programs in your company. In the last minute here, any last -- any last things you'd like to share about BridgeBio before we wrap it up?

Yes. No, I mean, I think 2027 really is going to be a transformative year for the company where we're going to go from one product R&D excellence in the last year to 4 products launched globally. And I think when the time is right, there's a huge amount of pipeline we could bring back in to develop a very unique and generational integrated biopharmaceutical company that can do a lot of good in this world. So I think it's a tremendously exciting 18 months to come and hopefully beyond that as well for many, many years.

Excellent. Well, thank you both for your time today. It was great to discuss the company together.

Thank you.

Thank you.

Good morning, everyone. I'm Sean Laaman, Head of U.S. Mid-cap Biotech Equity Research here at Morgan Stanley, and welcome to the Morgan Stanley Global Healthcare Conference. Before we commence, I'll make you aware of some important disclosures. For those disclosures, please visit the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative.

For this session, we have the pleasure of hosting Bridge Biopharma with Julie Everett, COO of BridgeBio Skeletal Dysplasia and Chief Business Officer, Chinmay Shukla. Welcome to both of you, and thank you for your time today.

I've got some macro considerations. We're just talking about interest rates offline, but just some macro considerations to discuss before we really dig in on Bridge. But how is the rise of China originated innovation changing your competitive positioning, if at all? And does it influence your BD and R&D playbooks?

Yes. Happy to talk about that. And Sean, first of all, thank you for hosting us, and thank you to all the investors for joining us today and across the day as we try to tell our story. So in terms of China, we see that as an opportunity, and there are some risks, but we do see it mainly as an opportunity. I think the speed of innovation is much faster. We do have active relationships with investigators and universities in China.

A lot of it is done through our sister company, GondolaBio, which focuses more on the early-stage part of the genetic disease R&D playbook. So I think that for us, in terms of opportunities, I would say, the ability to quickly set up trials and run trials, the ability to partner with an even broader number of academics as well as get sort of genetic data from a much broader population.

Those are all opportunities. I do think that there are some threats in terms of protecting our IP, and we do think about that. We think about the fact that any time we publish a structure, someone can easily then make the molecule. So we are thoughtful about that. But on balance, we view more people trying to help patients with genetic diseases as better for patients in America and patients globally as well as for our business.

Sure. Thank you, Chinmay. And next question on the macro. So are you implementing AI across your business? And has it already changed the decision, a time line, a cost or even a POS?

Yes. So we view AI in 2 different buckets. AI in terms of increasing probability of success or telling us kind of what's the next big cancer drug is not something which we think is going to be that helpful.

But I think that there is a ton of operational details in terms of running a biotech company, which AI can definitely make better in that even in our own company, we see AI improving.

I think the 3 examples that I can give you are, number one, in the commercial setting, whether it's in terms of making it easier for folks to write letters of medical necessity, whether it's analyzing data as well as if we think about overall surfacing information to our reps in a more insightful manner, those are all areas where AI is helping in terms of biostats.

It does help a lot in terms of just code generation. That's obviously a big use of AI and probably the most validated use of AI. And then I think that we're also looking at other steps in the business, whether it's sort of site activation, enrolling trials, how can we use AI to speed up those elements.

Those are a little bit earlier stage, but I would definitely say it's having an impact now, and I think it's going to have a bigger impact in the future.

Wonderful. And I'm going to guess your next answer to this next question probably be all of the above. But which policy variable? Is it FDA Medicare negotiation, MFN, tariffs or global pricing matters most to Bridge's economics? And have you changed anything because of it?

Yes. So the answer to that is all of the above. But I think we announced a partnership with the U.S. government recently. So for us, these -- we've been working closely with the regulators, whether it's on the FDA side. We're very pleased to say that the FDA reconsidered their decision on encaleret and gave it priority review.

Whether it's on the pricing side, we announced a partnership with the U.S. government on that. We think that we are able to find ways to both help patients as well as preserve our ability to do innovation, and that is very exciting to us.

Sure. Thank you. Now we'll go Bridge specific. So I have a series of questions on Attruby because I think that's the dominating investment. And then I'll move on to some questions on the skeletal dysplasias if that's okay. So Attruby, very strong numbers, up 23% sequentially with growth led by treatment-naive starts and the switch pool has normalized. The total revenue beat was largely driven by royalty rather than U.S. Attruby. Is the U.S. line growing faster as you had expected?

Yes. So we are thrilled with how Attruby launch has gone thus far. And actually, we are even more thrilled about what's to come in the future, given all the data sets which have come out. In terms of what we think is driving that growth, let me break it down sort of near term and longer term. The biggest driver of Attruby growth is, number one, increasing first-line market as well as increasing share of Attruby in that first-line setting.

I think both of those things are big tailwinds for us. And I do think that the kidney protective data, the ESC data as well as the real-world evidence which is starting to come out will all help Attruby gain more share in the future. And the drumbeat of data from all companies will expand the first-line market in the future.

So I think that it will take -- as we mentioned on our second quarter earnings call, it will take about 12 months or so for all of this data to percolate in the community and then start to change prescribing habits. And so in the near term, we do see steady sort of expansion of Attruby of somewhere around $25 million to $30 million quarter-over-quarter in terms of sales growth.

And I think that longer term, we do expect -- we've never been more confident that we will get to $4 billion in peak year sales and maybe there is even some upside beyond that.

Sure. I guess you reiterated blockbuster worldwide sales for this product in 2026, including the partner recorded Beyonttra sales. What U.S.-only number does that imply?

Yes. So we haven't sort of -- since we're not giving annual guidance, we haven't broken down U.S., ex U.S., all of that. But obviously, a majority of the sales that we book do come from America. And so a big portion of that blockbuster status would come from America.

If you look last quarter, we had about $222 million in U.S. net product revenue. We furthermore had about $15 million or so of royalty revenue. I think we've said that our royalty from there starts at about 30% and then tiers up from there. So what you would see is the product was already annualizing to a blockbuster status, right?

Because you take the 222 plus, let's just conservatively say 15 x 3 = 45. And you can see that, a, that's greater than 250 and b, you can see a majority of that revenue is coming from the U.S. We expect that to continue in the future.

We think that the U.S. will be a much larger market than Europe, although Europe is a very, very important market for us. We are thrilled with how the launch is going there. And of course, we have a very large royalty that we receive.

Sure. Thank you. Next question to me is quite important to your story. So I'll try and work it carefully. But I guess management has framed CARDIO-TTransform miss is leading the combination case scientifically dead and reinforcing stabilizer first. But the readout was arguably anti-combination rather than anti-silencer since monotherapy showed a nominal benefit. In second line, where many physicians still reach for silencer, why is this a clean win for stabilizers?

Yes. So maybe I'll use this as an opportunity to talk more broadly about what came out at ESC and why we feel like it was a very good data set for stabilizers in general and Attruby in particular. So I think there are a few things which are very clear now.

I think the first thing is stabilizers are the first-line therapy of choice. A vast majority of the market today and in the future is going to be first-line patients. Attruby is a differentiated near complete stabilizer, which also has unique kidney protective effects and other core benefits.

So on the first-line side, the story is very clear. It's a stabilizer market, and our job there is to get as many patients on Attruby as possible. I think as I think about the second-line setting, there were physicians who are reaching for combination therapy, which I think has now been proven to be ineffective.

I think that we also saw from CARDIO-TTansform as well as some of the other presentations, which came out at ESC that the 2 knockdowns are very, very similar to each other. They both have very similar levels of placebo-adjusted knockdowns. We also saw that the knockdowns take a very, very long time to show an effect.

It takes about 18 months to 20 months for the curves to separate. And so we put all of that data together, and we do think that knockdowns will remain an important part of this market. But increasingly, even in the second line, we're going to see physicians think about if you have a patient who's progressing on a weak stabilizer, do you just put them on a near complete stabilizer? Or do you try to have a different modality.

So I think that put together, we do think that all the data sets indicate that Attruby should keep taking share in the first-line setting and should also have a small benefit in the second-line setting, although the second line is a much smaller market than the first line.

Sure. I guess on the second line, so Alnylam recently reset their 2026 TTR guidance lower on the same second line slowing. Is the switch market shrinking for everyone or just shifting?

Yes. So I think what we have said, and we've been saying this for almost 9 months now, we have always expected that the second-line market would stabilize because if you think about it last year when both us and AMVUTTRA came on the market, you had a large number of VYNDAMAX patients who were progressing and who did not have a choice other than to stay on VYNDAMAX at the time. So we knew that there would be more switching earlier on.

It's very hard to predict quarter-to-quarter how these dynamics work. And so our expectation was that, that elevated switch would last probably for about 2 years or so. And we did see -- we have seen that kind of happen where the second-line market is stabilizing. There was further fuel added to the fire because last year, Pfizer pulled VYNDAQEL off the market. And so all the -- about high teens of past patients were on VNDAQEL, they all had to be switched to VYNDAMAX.

And so that further made it such that everyone had a chance to get some of those patients, right? So Q4 of last year, Q1 of this year, the second-line market was further elevated because of that. So have started to see that normalize a lot in Q2 and beyond. And we also -- we've always expected the second-line market to be smaller.

We've always incorporated that into our thinking, into our remarks. And so we were not surprised by it in any way. And what I would say is because Attruby is positioned so well in the first-line setting and the first-line market has continued to grow, despite the second-line market being much smaller in Q3 compared to Q1 of this year.

If you look at the total volume, if you look at the net patients added in Q1 -- in Q2 and our expectation in Q3 is that, that net patient added volume is very, very similar and hasn't really gone down for us. The first-line strength has overcome the smaller second-line market.

Moving on slightly to talk about the post-hoc renal data. And maybe just for the audience who may be unfamiliar, just give us a snapshot on the data. And what is the mechanism by which post-hoc renal data could change prescribing?

Yes. So actually, I'm going to let Julie comment on how it might change prescribing because she's -- she's close to the commercial story at both Attruby and Infi. But let me just recap the data. It's really exciting data. When we got the Phase III results for Attruby, we saw that there was an acute eGFR in the early few weeks after starting therapy. Initially, that was concerning to us because normally an eGFR is concerning.

However, we looked into it a lot more closely. And what we saw is that the effect actually mimics what you see with SGLT2 inhibitors and ARBs that it's actually a kidney protective effect if you look at the UACR albumin ratios and other markers of kidney health and you look at the overall neph flow profile, what you see is that the kidney, which was in stress after the initiation of Attruby very rapidly starts to basically rest and that confers a kidney protective benefit similar to what you see with SGLT2Is and ARBs.

And we've investigated this in a lot of detail. We're very excited that now there's a peer-reviewed manuscript, which is out there, so we can go and educate on this. And we have also now started to look and survey KOLs. We had a kidney summit a few months ago.

Physicians are getting more and more excited about it, the more they learn about this profile. It's a counterintuitive profile, so it does take a little bit of time to educate on it. But once they get it, they actually have been super excited about it, which is why we announced that we are going to go into a rare kidney indication with Attruby just to further expand upon the benefit there. But in terms of how that changes the commercial.

Yes. No, I'll give a very quick answer. So I think we've gotten very positive feedback from prescribers that this is just one more data point that continues to build that clinical differentiated story for Attruby. And what's interesting is that when you look at tafamidis data, they saw a very muted impact, a very muted trend like this, and there was nothing demonstrated with the silencer therapies. So this is truly a point of differentiation. Whether we think it will inflect prescribing in the near term versus more the medium or long term, I think it's the latter because it's going to take our MSLs and our sales representatives a little bit of time to get in and educate prescribers on this data.

And as Chinmay said, it's not a simple story. You really have to understand how this is tying to outcomes. So I think it will be more like a 1- to 2-, 3-year time frame that we'll see some inflection, but it just increases our confidence in the ability to execute on that 30% to 40% peak market share.

Wonderful. Thank you. Next couple of questions. A lot of my inbound is around pricing and pricing outlook. So I'll try and wrap these questions into one. So Pfizer has reportedly being discounting and you said you will not chase price. Does holding price cost you share in the near term?

And how would you know? And the second part is tafamidis generics arrive around 2031. So what protects Attruby pricing share against a generic stabilizer in the class?

Yes. So I think the first place to start on all these questions is the fact that Attruby is a second-generation near complete, better molecule, better stabilizer, more effective stabilizer than the first-generation molecule. And that's how pharmaceutical companies have always evolved, right?

We make the first generation molecule, then we improve upon it in our second-generation molecule. So Attruby is that improved upon second-generation molecule. It is clinically differentiated across numerous axes, whether it's the near compete stabilization, whether it's really strong effects on key subgroups like Afib as well as variants, whether it's this unique nephro protective effect that we have seen.

And now what we are starting to see is in the real world, right? People are starting to compare these drugs. And we've already seen some early evidence that Attruby outperforms VYNDAMAX, and we know that there's going to be more real-world evidence coming out at HFSA. We're very excited to see what that shows and whether that continues this trend.

So you have a drug which is clinically differentiated, and it's a -- what we think is -- it has unique and superior properties than the first-generation product. I think that as we think about that, that really flows to how we think about our pricing strategy.

And what we think is that the way to win in this market for Attruby is to win on clinical differentiation. We want to go -- we want to have parity access. And if we can't have parity access, we want to at least have parity process. Currently, even when VYNDAMAX is on formulary, the process is very similar between the 2 drugs. One requires a prior auth, one requires a letter of medical necessity. So yes, of course, Pfizer is rebating.

Of course, we are working through it, and that's part of why over the next 3 to 4 quarters, we've said we're going to grow by -- we're going to grow steady even though our share is increasing. However, we do think that we've been able to work through it quite nicely to date.

The way you ask me how we know that is last year, Pfizer put up a rebate with United Healthcare. And so that's now been in the channel for almost 15 months, and we have seen appeal rate when there is -- first of all, most scripts go through just normally.

But even when there is a denial, the appeal rates are north -- success is north of 90% there. And the most important thing and the most heartening thing for us is even in the United accounts, our share has grown, right?

And so I'm sure it is having some effect. We have not run the [indiscernible] we've not run the control trial, which is without rebates, how much would we have grown. But we've been able to grow through it just because we are clinically differentiated.

And by the way, that is also what has given us a lot of confidence that post generic TA entry in 2032, early 2032, we should still be able to grow pretty nicely. Part of it is because the channel dynamics here do favor higher-priced drugs with specialty pharmacies being a key component of -- in the channel.

Part of it is because of clinical differentiation, which we've expanded upon quite a bit today and the fact that we're not just another stabilizer. We're a better second-generation stabilizer. And then the last thing is if you look at every single analog, when a second to market product is branded, better product is on the market, the first to market going generic doesn't impact the second to market sales.

Sure. A complete answer. Moving on from Attruby. So oral infigratinib and achondroplasia, I've got a series of questions here. So I believe you've described infigratinib as probably the most underappreciated of the 3 launches. And U.S. is roughly 25% penetrated, about 75% Europe. Is your thesis upon launch more about expanding the market rather than share gains?

Yes, great question. So we believe at launch that there's 3 distinct patient populations, and our clinical data is resonating very well with prescribers and families across all 3. So the first is those who are currently on a CNP product today, whether that is VOXZOGO or YUVIWEL. The second is those who are previously treated and have discontinued.

And the third and largest category in the U.S. is those who have not yet sought treatment. That's the vast majority of patients in the U.S. To understand how we can unlock that population, you really have to interrogate why they're not on treatment today, and there's 2 primary reasons.

The first is just that the CNP products are limited mechanistically and by route of administration. It's really a molecule limitation, not a category limitation. And if you think about daily injections, again, I don't know how many of you have children, but to have to actually sit down, restrain your child, try to give them an injection, whether it's daily or weekly for something that is not acutely symptomatic, the child does not feel any different, right?

So the injection, the route of administration being an injection is very limited. The second element, again, infigratinib being an oral. The second element is the clinical data. Infigratinib is the only asset of the 3 to show benefits beyond height. So pause for a moment, it also showed the greatest benefit on height, right? The primary endpoint being annualized height velocity, 1.74 centimeters per year versus 1.57 and 1.49.

So right on primary outcome alone, the most efficacious product, but also the only agent to show within 52 weeks benefits on proportionality, arm span. And just last week at the European Society for Pediatric Endocrinology, we released data showing within 52 weeks benefits on sleep apnea and otitis media.

So these are very debilitating childhood complications that can be resolved with infigratinib therapy. I can walk through the data more later. But those reasons we feel can allow us to expand in the U.S. that 25% treatment penetration to a much, much larger number, not just compete within those who are treated today, but expand the pie.

Outside of the U.S., to your question, is much more penetrated today, depending on the country, about 60% to 75% treatment penetration in Europe and elsewhere. So the good news is the data resonates with both the switch population, the discontinued population and the naive population.

So source of business may differ slightly by geography, but those proof points of clinical differentiation are consistent across geographies.

BioMarin says under 10% of VOXZOGO patients switch to YUVIWEL. Your colleagues read that as evidence of low brand stickiness rather than high. Which interpretation does the data support?

Good question. So I think it's interesting. If you look at that, we have to remember that YUVIWEL has done very well, and this is very -- I just want to say that encouraging for us as we look at the unmet need that exists in the market today. I think we're highly encouraged by the YUVIWEL launch since it is still an injection, and we know that there's a lot of patients that are injection averse.

What we're seeing is that there's a lot of patients starting VOXZOGO in that infant and toddler population where they are the only -- currently the only approved product that has that indication. So it's a little bit difficult to tease out and understand how many patients are truly switching because there's new patients being added at the same time, which is good for them in terms of their source of business.

I would actually read this as parents being loyal to their child and not necessarily loyal to a brand. So if you are a parent, you are going to want to choose the product that has the most benefit for your child and that is the least burdensome. So that's why we feel encouraged that from a stickiness perspective, we feel that when infigratinib comes to the market, we are going to see families from all 3 of those categories of source of business opt for infigratinib because there isn't a loyalty to a product that has such significant daily or weekly burden.

Sure. A safety-related question. So FGFR3 inhibition is a systemic mechanism in growing children. What is the long-term safety monitoring commitment? And how do you expect families to weigh that against injection commitment.

None. So great question. Thank you for asking. So we are very pleased with it, not surprised, but pleased with the PROPEL 3, very clean safety profile, safety package. So obviously, the NDA has been filed and it is with the agency right now. But recall, all of these assets in achondroplasia are approved with the Subpart H accelerated approval pathway, and then they require conversion to full approval down the line.

So there is no, at this time, additional safety monitoring anticipated. We will not know for sure until we receive FDA approval and any post-marketing requirements or commitments. But recall, all patients who are in the pivotal PROPEL 3 study will continue to be followed to allow that conversion to full approval. So all long-term data will continue to be captured there. We anticipate no monitoring requirements in the commercial setting.

Sure. NDA submitted accepted for priority review, I think, a mid-'27 launch, if I've got that right.

So we should hear back in the next couple of months in terms of a PDUFA date and whether it's standard review or priority review. But recall that infigratinib, just given its significantly differentiated profile, the FDA has previously granted fast track and breakthrough. Fast Track status and breakthrough designation.

So I think we're encouraged by that and the likelihood of priority review, but we should know imminently here in the next couple of weeks.

Sure. And how should investors consider the cadence of an ex-U.S. rollout for infigratinib?

Great question. So I think, obviously, U.S. first market. So MAA, the marketing authorization for Europe will be filed in the fourth quarter here coming up as well. So we're encouraged by that. Slightly different cadence of review time line for U.S. and Europe. Obviously, the procedure in Europe is very structured, very rigid.

So we'll slot right in there. We anticipate, if all goes well, a European approval end of next year, beginning of '27 and then a launch in Europe in early '27 as well.

Sure. And hypochondroplasia in the infant and toddler segments are the expansion, where do those sit in sequence? And how does the overlay look against BMN 333 and TYRA-300?

Maybe I can quickly take those and go just in the interest of time. So yes, we are -- actually, to build on one of your other questions on safety, the agency has allowed us to go into infant and toddler even before they've seen the PROPEL 3 data, right? So that tells you just how convinced the agency is in terms of the safety profile here. The trial is enrolling really well. I think that the great thing about the infant toddler study is that we're going to go down sequentially.

So first, we will do the 2- to 3-year cohort, and then we'll go below 2 years. And I think that we'll be filing and expanding the label as soon as the data for each of those cohorts is available.

And then I think similarly for hypochondria, we are currently in the dose expansion phase. Recall, we designed that trial before we saw the PROPEL 3 results. And so we are only testing 2 doses right now, and we're thinking about whether we should test more doses or not, and you can expect an update on that later this year.

Thank you, Chinmay. Moving on to BBP4108. PDUFA is set for November 27. with priority review, population roughly around 7,000 patients in U.S. and Europe and concentrated prescribing about, I think, 150 NDA centers. So what does a successful launch curve look like? And how quickly does it reach steady state?

Yes. So I think that we're very excited about the limb-girdle launch. I think we have PDUFA coming here in just about 2 months or so. So it's a near-term opportunity for us. We've already identified 500 patients, mapped them to their provider. We know that there is high intent to treat in this segment. And again, to start with the data has been transformational, right?

Because not only are you seeing a stabilization of the disease, you're actually seeing patients on the drug improve and regain function. What we have said is we expect to penetrate the 500 patients in about 2 to 3 years. That's what good launches do.

We also expect in the meantime, over the next 2 to 3 years to grow from 500 identified patients in the U.S. closer to the 2,000 to 2,500, which is the prevalent population in the U.S. So we would like to close that gap. We'll see how far we get there.

And so that should sustain our launch starting years 2 to 3 and forward. So yes, we do expect that that's what the launch curve would look like. Normally, these drugs peak at around year 6 or 7. We think that between the U.S. and Europe, this is $8 billion opportunity, and there is no competition. So I do think every patient we find, we should be able to get on our drug.

Sure. Wonderful. Thank you. I do have more questions on that one, but in the interest of time, I do want to have a few more on encaleret and then move on to the capital structure. So encaleret hypoparathyroidism is an opportunity. So we've got a PDUFA for May 8 next year, my mom's birthday. The priority review and no advisory committee in the MAA has accepted the MAA -- you've got more than 2,200 U.S. patients that have been identified under the ADH ICD-10 code at roughly 70 new diagnoses a month. What proportion convert to treatment?

Yes. So I think that ADH1 is a very severe disease. If you look at the symptoms of the disease, they really limit your day-to-day functioning. And actually having low levels of calcium in the blood or high levels of calcium in the urine, they both affect you either day-to-day or in case of high urine calcium, it affects your kidney long term.

So for a disease as severe as this, I do expect that there will be high intent to treat. Of course, we are focused on educating on this front, focused on really making sure that physicians understand that this is a disease where you do want treatment and again, it helps us a lot that encaleret is able to basically normalize function there.

Both urine and serum calcium were normalized in more than 3/4 of our patients. And so I do expect that a large majority of the patients that we identify will get on drug. We have about 2,200 patients on the claims database.

We have 500 that we have already genetically confirmed and identified mapped to a provider. And of course, the prevalence here is about 12,000 just in the U.S.

And so I think that, that's going to be another strong launch. Hopefully, we'll -- the PDUFA is on May 8, and hopefully, we'll celebrate your month's birthday a little bit earlier.

Thank you. Just in the interest of time, I will move on. I've got more questions on that one, but I'll move on to capital structure and the path to profitability. So you closed $1 billion of preferred equity, taking pro forma cash to about $1.7 billion. Total liabilities just over $3.7 billion, including $879 million of deferred royalty obligations against stockholders' deficit of $2.5 billion. What is the blended cost of capital across that structure?

Yes. So I think that we've always tried to think about what is the right form of capital to take and what helps prevent -- what's best for our shareholders who already own the company today, but also something that will attract more shareholders in the future.

I think that I'm not going to put a number on our cost of capital, but I think it has reduced over time. I still think our equity cost of capital is quite high given where we see the intrinsic value of the company. But we're focused on trying to tell our story.

And hopefully, given that right now, we don't need any capital for the BridgeBio business in any way whatsoever. We think that as we tell our story better and investors appreciate these next 3 launches as well as the profile of Attruby, there's $10 billion of peak year sales in this pipeline alone. As that gets recognized, our cost of capital should keep decreasing. So that's what I would say there.

Great. Last question. So I should remember this, but I have to be honest. I don't. So management guides to operating breakeven in 2027, still true and while funding 3 launches. So what has to be true on Attruby for that to hold?

Yes. So I think what we have said is a couple of things on this front, right? I think we've said that for the BridgeBio business as it stands today with these 4 molecules as well as the depleter, the Canavan program, we think that our operating losses the last couple of quarters has been about $100 million.

I think that, that's going to stay at that rate in Q3, start to come down from Q4, probably breakeven late '27, early '28 and then transition to being cash flow generative. Attruby is already in margin expansion phase.

And I think that the next 3 products, just given the profile of those launches can quickly transition from being a source -- being a place where we have to invest cash to actually generating cash in '28. So that's what I would say. Like I said, excited about the profile for both Attruby and these next 3 launches.

Wonderful. Given we're out of time, it might be a great place to stop there. But thank you, Chinmay. Thank you, Julie, for your time. Appreciate it.

Thank you, Sean.

Welcome, everyone. I'm Josh Schimmer from the Cantor Biotech Equity Research team. I'm very pleased to introduce from BridgeBio. We have Chinmay Shukla, immediately to my right, SVP of Investor Relations and Strategic Finance. Next to Chinmay, we have Anna Wade, Chief Operating Officer of BridgeBio Neuromuscular. And beside Anna, we have Julie Miller Everett, not Everett Miller, we caught that, Chief Operating Officer of BridgeBio Skeletal Dysplasias. So great to have the team with us.

Chinmay, maybe you want to kick things off, give us a quick snapshot of where BridgeBio is today and where the company is headed?

Yes. Happy to do that. First, Josh, thank you for hosting us, and thank you to all the investors for joining us here and as well as on our one-on-ones. So BridgeBio today is at an inflection point. We have $8 billion in post-Phase III peak year sales assets. The first of that is Attruby, which is launched, which we think is a $4 billion drug. Globally, it was already annualizing to over $1 billion in 2Q.

So we're building on our strength there. Right after that, we have 3 launches upcoming very shortly now. I think the first one, limb-girdle, is going to be in November. And then we expect to launch in achondroplasia as well as ADH1 sort of early next year. So that's where we are at. All those 4 indications put together are $8 billion in peak year sales.

What's very exciting is that right behind that, we have an expansion indication in hypoparathyroidism, which is probably worth another couple of billion dollars, especially when you put it with the depleter antibody, which is in early stage in ATTR-CM. And then that's not it. I know, Josh, you've always liked for us to think more holistically and think more broadly about genetic diseases and helping patients who are suffering with these diseases. So we have a sister company, GondolaBio, where they have a late-stage EPP program as well as some 16 or 17 very early-stage assets, which are all very exciting.

So there is a lot happening. We're trying to do a lot for patients. And my hope is that over time, that value is going to accrue to shareholders also.

Excellent. All right. Well, there's a lot to get through, so we'll see how much we can get through in the next 27 or so minutes. So why don't we start with the Attruby. Remarkable drug, remarkable progress and yet still seems like a long road ahead to achieve what that drug should achieve. Why don't we begin with, kind of, some of the takeaways after the CARDIO-TTRansform data presentation and how you think that these incremental pieces of information help position Attruby in the competitive TTR landscape?

Yes. Happy to do that. I think that CARDIO-TTRansform was, I would say, the last big data event, which has now really clarified a lot of the picture for us in ATTR-CM. So where are we today? I think the first thing to realize is that stabilizer therapies -- there are 2 main types of therapies, stabilizers and knockdowns.

Stabilizer therapy, which is the type of therapy that Attruby is, they are going to be the treatment of choice for frontline ATTR-CM patients. If a new patient comes in, which is a majority -- vast majority of patients today, they are going to be put on a stabilizer therapy. The knockdown therapies take about 1.5 years to work, whereas Attruby takes about a month to work.

And then you also have to take into account that combination therapy, which some people had hopes for was proven decisively to be inefficacious in CARDIO-TTRansform. I think the second thing which we learned is that the 2 knockdown agents are more similar to each other than different. If you look at the placebo-adjusted knockdowns and the Gilmore et al. paper, you saw that the two knockdown percentages adjusted for placebo were very similar.

And then that translated to monotherapy hazard ratios for the two knockdown agents to also be about 0.67 and 0.7 respectively. So very, very similar. And then the third thing, which I would say is we were very encouraged to see that clearly, there is room to do more beyond VYNDAMAX, which is the first-generation old stabilizer, which is where Attruby, which is our second-generation new stabilizer, has a unique differentiated edge.

And so we do think that having that near complete stabilizer in Attruby, it confers a very unique kidney protective effect. We also see the fact that it has much stronger effects on hospitalization as well as time to separation, hard outcome separating as early as 1 month. So, we think that, that is where Attruby is positioned. Today, we have more than 25% share in frontline patients. We have said that our goal is to be at 30% to 40% at peak. We are doing market research to refine that. And my expectation is that, that 30% number will probably move up on the bottom end of the range at least.

And then the last thing which I would say is, in our experience, it takes a little bit of time for all this data to really get out there in the field. We've noticed that it takes physicians multiple visits, explaining the data carefully. These are nuanced data sets. And as we do all of that, I think it takes about a year or so for these amazing data sets for Attruby to translate into script growth and then ultimately, revenue growth.

So near term, we expect about a $25 million to $30 million quarter-over-quarter sales increase for the next 3 or 4 quarters. which should then start to accelerate as you get into, call it, late '27, early '28.

Okay. And given the claims data analysis you've been able to generate, it seems to be really differentiating versus tafamidis and resonating. I'm surprised your goal is that 30% to 40% range, not 2x that or more.

Yes. So that's a great question. So we think that Attruby is the best drug for ATTR-CM patients. And we do think that everyone should be on Attruby, actually in Europe, more than 50% of new patients are on Attruby, especially in Germany, which is where the drug was first launched in Europe by our partner, Bayer.

So why is it that I'm saying that our goal in America is 30% to 40%? Well, I think there are a few reasons for that. The first reason is I don't think most investors believe 30% to 40%. So let's start there, so we can sort of walk them through it over time. Second of all, I think that there are some unique differences in our health care systems, such as the buy-and-bill economics and things like that, which do impact prescribing on the edges.

In an ideal world, it wouldn't, and I know the government is thinking about that, but it does right now. And so we have to be realistic about that. But what I would say is we have built a very strong foundation of evidence now that Attruby is a differentiated stabilizer. It's not just another VYNDAMAX, it's a much better stabilizer.

And that started with the label. As you remember very well, Josh, we're the only agent in the field, which has the verbiage near complete on our label. Beyond that, what I would say is we've done built upon that to say that, that near complete stabilization is correlated with a decrease in all-cause mortality. Then we've built upon that with subgroup analysis, whether it's the Afib patients or the variant patients. And yes, now we are expanding upon that with a unique kidney protective effect, which Attruby has as well as the claims data, which you're saying, although the claims data is maturing.

So my expectation is we'll see more independent studies come out at HFSA. We are always excited when an independent person looks at Attruby versus VYNDAMAX because we feel so good about our profile.

What should we be looking for at HFSA in terms of additional claims analysis that could either bolster the case for Attruby or not?

Yes. So if you look thus far, right, we've done analysis from our own Phase III trials, whether that's looking at Attruby versus VYNDAMAX in the trial, and we've also looked at subgroup analysis. I think some people have also done some comparisons of Attruby versus VYNDAMAX on serum TTR in real-world settings.

I think what the field is looking for is clinical worsening outcomes. So what do I mean by that? Things like diuretic intensification, hospitalizations. Those are hard outcomes. It takes a little bit of time for this data to mature, but I think we're almost 2 years into our launch. So I know that there are some systems which have been looking into this. And my expectation is that they will publish what they -- people publish what they found on Attruby versus VYNDAMAX. And really, that clinical worsening outcome should drive additional behavior with cardiologists, though I will caveat the fact that it takes 6 to 9 months for all of that data to get in the field and then start to get reflected just because we have to go and educate people on it.

And what's your confidence then when it's all said and done with all the claims data analysis that the time that generic taf enters that you have built such a strong case for Attruby's differentiation that generic taf is not going to be a problem?

So well, first, I'll answer that by saying our confidence is extremely high. That's the simple answer. And let me build upon that. I think that we already have built a solid foundation of evidence. I think that the earliest that a VYNDAMAX generic could enter is mid-2031. So we have another 4 or 5 years before that. And I've been saying it takes about 9 months, maybe 12 months to have all of these -- to have this material educated to the physician. So we do have significant time.

The second thing, which I would say, which is a little underappreciated by investors is if you look at the channel dynamics here, it's really a channel, which is dominated by specialty pharmacies and institutional specialty pharmacies. And the stakeholder dynamics there are such that branded drugs are preferred more.

And then the last thing, which you would say, and we've updated our corporate deck with some of this material, if you look at any single -- any pharmaceutical category, when a first to market, less potent molecule goes generic, the second to market, more potent molecule, the sales keep going up. And I think the best example of that, which interestingly, investors have inbounded into us and told us to talk about it is Gleevec as well as the next-generation TKIs, which came in after Gleevec went generic.

Yes. Okay. Excellent. Anna, why don't we come to you? CEO of BridgeBio Neuromuscular, that's going to be BBP-418. Is there any other programs within neuromuscular at this point? Or is that yet to come?

That's yet to come, but it's definitely something we intend to continue to evaluate. And Chinmay might speak to some of the programs within our sister company Gondola later, which includes some in the sort of neuromuscular space.

Okay. Got it. So for 418, I expect you've had your mid-cycle review now with the FDA. How are you feeling about approval prospects and/or need for AdCom or other considerations?

Yes. So we're feeling really good about our approval prospects. So just to take a step back, our PDUFA is on November 27 of this year. In our data set that we announced last October, we saw clinical benefit on functional outcomes. So we basically saw improvements in pulmonary function as well as ambulatory measures. And that data as well as the full data set that the agency has seen, it really is supportive of an approval in November, and they're also still considering traditional approval as the most appropriate path, which would not have any sort of further commitments to do a sort of confirmatory study.

Okay. So I think the estimate is around 4,000 patients in the U.S. total with limb-girdle 2I or 9R (sic) [ R9 ] with 500 identified. Is that correct? And maybe talk a little bit about the cadence of patient identification and what the addressable market you expect will be?

Yes, absolutely. So we estimate there are about actually 7,000 in the U.S. and Europe. And within the U.S., it's about 2,000 to 2,500 of which we currently have identified around 500 patients where we know where they are and they are genetically confirmed. We are continuing to see growth there as we ingest more sort of genetic testing data.

We have people out in the field and they are sort of profiling accounts, and we continue to sort of add patients on a sort of monthly basis through that as well as we actually got a unique ICD-10 code that came in, in October of last year. So it's still not particularly mature, but we are seeing current use of it, and it is growing on a month-by-month basis as well. So we're continuing to see sort of momentum there with the increase in patients we've identified to date.

And do you expect all 500 patients identified are good candidates for 418?

Yes. So we do believe that the majority of patients are really good candidates for therapy, and that's driven by a few things. So first off, if you look at the clinical trial inclusion criteria from both the Phase II and the Phase III, it's very broad. So it includes both genotypes, it includes ambulatory and non-ambulatory patients. So a variety of different functions.

I think the only sort of potential narrowing of that population is just based on the age. So basically, we were studying 12 and up in the Phase III trial. And also there's a body weight limit basically based on our current dosing. So we dosed 9 grams twice a day for 30-kilogram patients and then 12 grams twice a day for 50-kilogram patients and above. So we wouldn't anticipate that those lowest body weight, youngest individuals right now would be candidates for therapy, but pretty much everyone else should be. The HCP market research we've been doing has shown really strong adoption across all of those different patient segments that I mentioned.

Okay. Are there useful pricing benchmarks you have in mind?

The most useful pricing analogs that payers always refer to are the exon-skippers in DMD. Obviously, that's a very similar disease. It's sort of similar prevalence as well. And I think the main sort of thing to consider when you're looking at those analogs is that those analogs really were just based on biomarker data and didn't have functional outcomes. So when we have been doing payer research, the fact that we have these functional benefits that are seen in our data set means that we potentially could price at a premium to those.

How should we think about ex-U.S. commercial plans so that may actually be a good opportunity to talk about the MFN agreement that Bridge recently forged with the White House?

Yes. Maybe I'll give a few general comments, and then I might ask Julie to talk about a little bit more because, obviously, infigratinib is at the cutting edge of ex-U.S. for Bridge right now. So our base case plan is to commercialize globally with the next 3 products, whether that's 418 and encaleret or infigratinib.

Really, that comes down to a few different things. One is we are in an MFN world right now, and we're very happy with our agreement with the government and partnering with the government, which I can touch on in a minute. But you never know if you look 10, 15 years out, this is now part of the biotech business. And so we have to think very long term and strategically about these transactions.

I think the second thing is these are going to be significantly more focused launches ex-U.S. also because the patients are congregated at a small number of sites of care. We already have presence in these countries through clinical trial sites as well as deep relationships with KOLs. And then I think about the fact that while these things are capitally efficient launches, we also now are in a better capital position. We had about $1.7 billion of cash on our balance sheet as of July 1 pro forma. So that makes me feel better about our ability to actually invest properly in these geographies and get the right value out of them.

Now look, having said that, if someone comes along and makes an offer, which fits our better owner hypothesis, we -- phone is always open and we're always happy to engage. But our base case plan, given all of these considerations is to commercialize ex-U.S. on our own. We have made good progress already. We're being lean about staffing ex-U.S., but we've already made very good progress on the regulatory front and some senior international hires. Maybe I'll let Julie comment on it for a minute or so.

Sure. Yes, very briefly, I can add. I actually just flew in yesterday from France for the ESPE conference, and I was with the international team there. We feel really good about putting the right people in the crucial first roles as we expand. So at this point, we have hired our commercial and medical leadership team for the international organization. So we have people in place for commercial field, country managers, market access, which as everybody knows, is crucial for speed of uptake as well as overall price potential in Europe.

So really have a solid market access team in place. At the portfolio level and then also now at the product-specific level. So we've got our medical team sized and deployed there to initiate those discussions with customers, as Chinmay mentioned, and a really solid handoff from our clinical development organization who has deep, rich engagements already given the development programs that we've had in Europe.

We've started the relationship handoff from clinical to medical to start engaging in that dialogue to that scientific exchange. So we feel very good about knowing who the customers are, where they are, how many patients are treated at which center of excellence and how we want to size and deploy the international resourcing to accelerate uptake. So I would say very quickly, we feel very confident in our ability to execute ex-U.S. from a regulatory standpoint, medical standpoint, commercial standpoint.

And then maybe coming back to the MFN agreement and how that affects the portfolio in total for Bridge. And does this supersede any potential down the road, MFN rules and laws enacted for the broader biotech community?

Yes. So I think we're one company, so I wouldn't talk about the broader biotech ecosystem. I'll let -- you guys are closer to more companies talk about that, Josh. For us, really, it's a partnership, right? We're very excited that we've been able to expand access to Medicaid patients for Attruby, which is our -- obviously our only big commercial product right now. So that's what we have agreed to with the government.

I think that as we mentioned in our 8-K, our expectation is that this partnership will mean that we are able to get good price elsewhere so that we can take the revenues and invest it into making more medicines for genetic disease patients. And we're excited to work in partnership with all branches of the government to do that.

Why don't we come to infigratinib. And Chinmay, I guess the competitive landscape is evolving a bit. We've got combination data from Yuviwel with SKYTROFA and Yuviwel itself is off to a good start. We recently had some data from BridgeBio for infigratinib framing, I guess, otitis media and sleep apnea. As you kind of look at all the moving parts here, where do you see the real points of differentiation for infigratinib beyond being an oral drug versus injectables?

Yes. Thank you for saying that. So I think everybody know that there's extreme injection burden, whether it's a daily injection or a weekly injection. These families just don't want to have to take an injection. So just being the first and only oral agent is very profound for this community. But clinical points of differentiation, we actually are just coming off of the ESPE, the European Society of Pediatric Endocrinology Conference this week, where we are the first and only company to show clinically meaningful benefits beyond height within 52 weeks.

So we just presented Dr. Julie Hoover-Fong shared yesterday that if you look at sleep apnea, I don't know how many people either yourselves or your children suffer from sleep apnea, but very debilitating condition that can truly impact many aspects of your life, right, with chronic fatigue and other implications. We demonstrated within 52 weeks that in the overall infigratinib population on the apnea-hypopnea index, the infigratinib population only showed a 10% increase on that scale -- that apnea scale, whereas the placebo population showed a 49% increase within 52 weeks.

But even more profound, when you look at the children ages 3 to less than 8, that earlier age population where you can initiate intervention sooner, the infigratinib population saw no change in their sleep apnea, where the placebo saw a 63% in the severity of their sleep apnea. That is incredible.

But let's talk otitis media, which is ear infections. Again, not sure how many of you have children, but if you have ever had a child who has had an ear infection, this is a miserable experience. You have doctors' appointments, miss school, childcare implications, antibiotic use, chronic antibiotic use. This is, again, very impactful to functionality in daily life for these families.

We showed a 37% reduction in the event rate of ear infections in the infigratinib group versus the placebo group in the overall population, but a 47% reduction in the patients aged 3 to 8. So again, in that younger population where infigratinib has started sooner, almost half the number of ear infections. And we're demonstrating this within 52 weeks. No other product has been able to show benefits like this within the randomized, double-blinded, placebo-controlled portion of the study.

So clinical differentiation, not only do we show the greatest benefits on height, the only product to show statistically significant proportionality on -- statistically significant benefit on proportionality within 52 weeks, but now also these meaningful benefits beyond height, both of which are resonating well with the HCP prescribing community as well as the patient community.

Do you have objectives in terms of either new patient share at certain benchmarks and/or the ability to claim share amongst patients who are already treated with the...

I have objective. So we feel very confident, especially with the data that we've seen at this point within 52 weeks and some of the longer-term data, I feel very confident that we will be able to achieve absolutely majority market share at peak. We actually think it could be a high majority market share.

And I just walked you through why we believe that from a clinical point of differentiation, but also the oral is just a very, very compelling kind of proof point for families and why they would like to request infigratinib. What we're actually seeing in our market research, we do market research with both prescribers as well as families. We're seeing source of business across all of the patient categories.

So those who are currently treated with VOXZOGO or Yuviwel today, high willingness to switch, in those families who have not considered treatment previously, there is a large portion who are now saying with an oral option that is far less invasive, that benefit risk profile is much, much stronger than with the CNP therapies. So that is actually, Josh, the segment I'm most excited about, is not just cannibalizing from the competition, but we very firmly believe that there will be an overall market expansion here in the total number of patients who are treated today, especially in the United States, where we believe there's only about a 30% overall treatment penetration today, so much room to expand the treated pool.

And then finally, the third category is those who have either been on product before and discontinued or who have actually decided that treatment is not for them.

Okay. Excellent. And what should we be looking for in the upcoming hypochondroplasia data?

Yes. So I think everyone is familiar that the Phase II program in our hypochondroplasia program is a dose-finding study. So you should be prepared to hear further updates regarding what dose we will continue to explore in the hypochondroplasia program.

And just to build on a couple of things Julie said, I think really the market expansion potential in infi is, in Europe, about 3/4 of the children are on an intervention. In America, only about 1/4 to 1/3 of them are on an intervention. I think that it is very clear that we can triple the market in America. And of course, that would be of significant value.

And then just to build on the hypochon answer from Julie, maybe I'll just mention a couple of things. Just -- I know investors are aware of this, but just as a reminder, we started the hypochon Phase II dose exploration study before the PROPEL 3 Phase III results from achon were available. We were testing 2 doses, the achon Phase III dose and a dose lower than that. And then I think people know that there's a different mutation, which causes hypochon compared to achon.

So I think what's important for us is going to be able to find the right dose. And of course, given the pristine safety profile of achon in Phase III, there is some discussion of potentially expanding and increasing -- testing a slightly higher dose also. So look for us to provide an update on that. And I think that our expectation is that, that dose-finding study will continue for a little bit of time.

I've never seen a case where the FDA switched a standard review to accelerated review in the midst of an application. So what happened with that with encaleret? And how do the -- all the time lines adjust accordingly?

Yes...

Priority review, not accelerated review.

I'm sorry.

No, it's okay. Just clarify.

So yes, I think we're very excited about encaleret. I know, Josh, you're very excited about encaleret too. So I think that if you look at the Phase III data, right, first of all, let's start with the disease, right? ADH1 is a devastating disease. The effects on patients are severe. We've had patients come to our patient days and talk to the company.

And really, as you hear what their day looks like, the need to go to an ER at short notices, the need to take injections, the need to take lots of medicines, even in young children, it really -- the burden here is extremely high, and there is no option for these patients right now. And so in that context, encaleret delivered really astounding data, right? I think actually for both encaleret as well as BBP-418, it is rare to see molecules like in encaleret, we had 76% resolution of both blood and urine calcium, which is basically a resolution of the disease.

This is not something which you normally see with medicines. You see like a halting of the disease or a slowing of the decline. Here, we are showing with one drug resolution of the disease, with another drug, we are showing reversal of function and gain of function. So really, the profile for encaleret's clinical efficacy was also extremely powerful. So we felt like we had a very, very good case for priority review.

We submitted the package to the agency expecting priority review. Unfortunately, it came back as standard review. And we felt like in this situation, for the patients that we are hoping to serve, it would be prudent for us to go request the agency to reconsider, just look at all the facts again. And as we talk to them, like we have mentioned, we have a good partnership with the government, and we're working closely with them to bring medicines to patients.

As we did that, they have decided to reconsider and changed our review from standard review to priority review. The PDUFA date has not changed. So my base case expectation is still approval by PDUFA, but we will certainly be trying to work as quickly as possible to get the drug available to patients sooner because there is a desperate need in this condition.

So it's more of a philosophic approach than a technical time line difference.

That's correct. Yes. For now, that is the case.

Okay. For the broader hypo-PTH indication that you're pursuing, are you able to address the entire population? Or do patients need to have some baseline PTH level to qualify for the drug in that program? And if so, what kind of percent of the market could you address?

Yes. So we think that encaleret will work for all chronic HP patients, whether they have residual gland or whether they don't have residual gland. So I do think that that's the case. I think it is very interesting to notice that in our Phase II study, we did look at patients who had no PTH gland activity, and we were able to show a resolution on blood and urine calcium even in those patients. And so we feel confident about that.

And I think that I would strongly encourage folks to listen to our CEO, Neil Kumar's prepared remarks on our Q2 earnings call, where he went into the mechanism of why encaleret should work in HP. We don't have enough time to get into that right now. But there are multiple threads of evidence now to suggest that this drug should work. And I actually think it's a pretty high probability of success trial, and it's a huge indication. And the trial is probably going to read out late '27, early '28. So it's coming very soon.

One of the many parts of Bridge that are generally underappreciated by the investment community. So thank you to the Bridge team for coming out to join. Thanks, everyone, for tuning in.

Thanks, Josh, for hosting us.

Thank you.

Thank you.

Well, good afternoon, everyone. Thanks for joining us here after the [ lung ] session, getting right back into the fireside discussion. So my name is Derek Archila. I'm one of the biotech analysts here at Wells Fargo. Really excited to have next here BridgeBio. From the company, we have Chinmay Shukla, Chief Business Officer. Congratulations on that. As well as Anna Wade, COO of the Neuromuscular division. So thank you guys for joining us.

Derek, thank you for hosting us, and thanks to the investors for joining us. We are excited to speak to you today and excited for all our conversations.

Excellent. Well, Chinmay, maybe just to kind of level set us with the business and where you guys are. We've got a pretty solid growing base business with Attruby, a couple -- 3 launches upcoming. So maybe just give us a state of the business before we dig in.

Yes. It's a great question. So state of the business today is if you look at our post-Phase III drugs, right, that's in ADH1, limb-girdle, ATTR-CM, obviously, and achondroplasia. We have $8 billion of derisked peak year sales potential. Total, if you look in the entire pipeline, we have $10 billion of risk-adjusted sales potential. So we feel great about that.

I think if you look at Attruby, second quarter global revenues were annualizing to over $1 billion. U.S. revenues were $222 million. We've been growing very nicely at about $30 million -- $25 million to $30 million quarter-over-quarter. We expect to keep growing at that $25 million to $30 million quarter-over-quarter cadence for Attruby. I think all the clinical updates on Attruby have been extremely positive. We can get into that more. And so that gives me a lot of confidence that in '27 as we launch these next 3 drugs, that's going to add a lot of growth. And then eventually, second half '27 once these clinical messages take hold in the community, Attruby is also going to start to accelerate. So we feel very good about where we are.

And the last thing which I'll say, which is important in the long-term perspective of the business is for us, as we start to have all these revenues and generate cash flow, we think about where can we invest it. And if you look at the genetic disease landscape, innovation has never been higher, unmet need has never been higher. And so yes, of course, we have to grow into all of that, and we have to do it in the right way. But we feel like we have the opportunity to help a lot of patients, and that, I think, will accrue to the benefit of our shareholders.

Excellent. Well, maybe let's start with Attruby. You provided some good context there in terms of growth and things. But we just came out from ESC. We had kind of the CARDIO-TTRansform data and all that stuff. So I guess what's your view in terms of how the market continues to evolve and the role of stabilizers?

Yes. So there's been a lot of clinical updates in the TTR space. And so let me sort of summarize where I think we are at right now and where we see this market growing. So first of all, stabilizers post CARDIO-TTRansform, it's very clear that today as well as in the future, almost all new frontline ATTR-CM patients will start on a stabilizer. Today, that number is north of 80%. I don't think that, that's going to change given what we saw in CARDIO-TTRansform.

I also think that combination therapy is not really effective, and it's not going to be a big part of this market going forward. And so that's the second thing which we learned.

The third thing which we learned is the 2 knockdowns are very similar to each other. And that obviously feeds into why stabilizers are frontline. But if you look at the placebo-adjusted knockdowns, they are the same. If you look at the hazard ratio on monotherapy, they're the same.

And then the last thing, which I think ESC told us, which I think is a little lost sometimes from investors, is there is meaningful room to help beyond Vyndamax. And so obviously, today, a ton of patients -- majority of frontline patients start on Vyndamax, which makes sense given it's the established product. But we think Attruby as the next-gen, second-generation differentiated stabilizer will take more and more share and more patients will start on that drug because simply put, it's a better drug.

And so I think that we feel very good about where we are, whether it's because if you look at subpopulations like Afib variant, whether you look at unique kidney protective effects of Attruby. And now what you're starting to see, which is really interesting is real-world evidence start to come to the front, right? And so you've had one publication. We've heard talks about there being more independent real-world studies, which are coming out. So we have to see what happens at HFSA and AHA. But I think all of that will mean that stabilizers will continue to be the frontline therapy of choice. And then over time, we do expect Attruby to keep taking more and more share and become the preferred stabilizer.

So what -- you talked about some of these data sets that are coming, whether they're yours or externally, like what other evidence do you want to generate between now and maybe the tafamidis patent expiry to really drive home what you're talking about in terms of that differentiation?

Yes. So all of our work on this front stems from what physicians tell us is most convincing to them. And what we have learned is, number one, subgroup data, right? So that's why this Afib data really drove -- Afib and variant subgroup data which showed that Attruby confers a very large benefit amongst the Afib population and has the highest point estimate in the variant subpopulation. Actually, it has a stat sig benefit on variants, which is really remarkable if you think about it, given the low number of patients in that segment in the trials, right? I think that, that is convincing.

I think we have now built on that with this very unique nephro-protective effect that Attruby has. That is still in its early days right now. I don't think that, that message has fully gone out to the community. We just published a paper on it a couple of months ago. I think it's going to take 6 to 9 months for people to fully appreciate just how profound that renal protective effect is that Attruby confers.

I think the third thing which we've heard from physicians is real-world evidence. And so of course, the most convincing real-world evidence is when it's not published by us. So far, there have been, I think, 3 studies to my understanding. One, we've been involved with, the other 2 we haven't been involved with. Even in studies where we are not involved, you are seeing that acoramidis outperforms tafamidis in real-world settings. We hear that there is going to be a big publication at HFSA on real-world evidence, which I think will further move the field in terms of understanding how to use these drugs in the real-world setting. So those are the kinds of things which I think are going to be important.

I think our job right now is to educate physicians on all these benefits which have already been generated. I think the other factor, which we don't need to educate physicians on, but which maybe we need to do a better job educating Wall Street on, is things like channel dynamics, which mean that even in 2031, when Vyndamax does eventually go generic, because this is a channel controlled by specialty pharmacies, institutional specialty pharmacies as opposed to payers, we do think that volume for Attruby is going to remain high. And I actually think if you look at drugs like this, and we updated our corporate deck, so you have some examples there now. If you look at these kinds of situations, you always see that the second-gen differentiated product continues to grow after the first-gen product has a loss of exclusivity. And I also know that some of your own work suggests that. So I think you can also help us with that.

Yes. Well, I was going to say also when you think about kind of the dynamics and some of this kind of came out at ESC in terms of we're treating these patients earlier. And I always kind of feel like there's this -- maybe it's a wrong way to think about it, but like after 2031, generic tafamidis comes and Attruby like goes off a cliff. But the fact of the matter is if you're putting patients on 2029 and 2030, they're probably going to be on drug for 4 to 5 years and the payers are not really going to make you switch a patient that's doing well, right? So like you have that maybe at least giving you that kind of revenue tail, and then it's up to you in terms of -- like again, talking about those channel dynamics in terms of just even keeping the volume increasing maybe slower, but you're still growing.

I agree with you.

Yes. See, we've done our homework. I guess...

Well, you've done a lot of work on this, so I know you're up to date on it.

Yes. So I guess when we think about TTR in general, I guess, were there any other kind of takeaways from ESC in terms of where you think the field is going just from an overall perspective in terms of the diagnosis rate and the growth because you've got a lot of tailwinds just in that sense as well.

Yes. So that's a very good point. And actually, if I think about the 2 biggest tailwinds for Attruby, one of them is the fact that the frontline market continues to grow. So before we launched in 2024, we were saying that there are about 8,000 to 12,000 new patients, frontline patients who start an ATTR-CM therapy every year in the U.S. I think about 6 to 9 months ago, we updated that to say that there are, call it, 12,000 to 16,000 patients. And I think now what we are seeing is that there are at least 16,000 patients.

So if you see, you've gone from 8,000 to 16,000 over a period of 2 years, and it's still growing, right? And our share in that market is also growing. So that is a big tailwind. Nothing at ESC -- everything at ESC reinforced that. The more awareness about ATTR-CM, the more patients people find with this disease. So I actually feel every time we have these big conferences where there's a lot of focus on this disease, it helps a lot with diagnosis. It helps a lot with awareness. So that is definitely a big tailwind for us. And I actually think that, that tailwind, coupled with the differentiation and slow gains in share, are the 2 reasons why despite the fact that we have some headwinds such as the second-line pool normalizing, such as Pfizer rebating, we are able to keep growing consistently. And that is why if you saw last quarter, we had nice growth quarter-over-quarter. And if you look next few quarters, we expect that to keep going.

Got you. And not to put you on the spot, but in terms of like silencer uses in the front line, I mean, I guess Alnylam say they're growing. You guys are saying you're growing. So is Pfizer not growing? Like -- or is everyone growing? Like how are the share dynamics going? And I guess, where do you guys think you'll be? Because I think one of the things that you guys had said in the past was like your assumption was it was going to be a 4-player market and what your share was going to be. So will you update some of those estimates?

Yes. Great. I'll take that in the reverse order. Yes, we have said before that we expect at peak Attruby to get 30% to 40% share. We are doing more market research now, and we will update it. I will say that, that is at peak. I do think, as I mentioned, it's going to take a year or so for these messages to truly get understood by the community. So I do think for the next few quarters, we will keep growing by that $25 million to $30 million quarter-over-quarter sales absolute number that we have said before. I do think we will update that 30% to 40% peak share number. Does it go 35% to 45%, 35% to 40%, wait to see that. I will not create that much news right now.

The second thing which I would say is how are the frontline dynamics evolving? This is a stabilizer-first market, right? So more than 80% of frontline patients by our calculation start on a stabilizer. That number is not really changing. And really, what's changing is a majority of patients today start on Vyndamax. Little by little, I think we're making inroads such that we are getting a little more share, right? So if you think about it, let's try to make it very rough. If more than 80% are on a stabilizer, that means less than 20% are on a knockdown. Most of that is obviously going to AMVUTTRA. Of the remaining 80%, if I say half of the stabilizer patients more than that are on Vyndamax, that means 55% or so, 60% are starting on Vyndamax. We have said our own share is north of 25% and growing slowly. And so that is how that is evolving.

Excellent. Maybe let's shift gears to the pipeline because there's so much to talk about, but I think Attruby seems like growing base business, durable and more to come in terms of some data on differentiation. It seems like that's the message.

Yes.

Okay. Awesome. So I don't know, it's like kind of dealer's choice, what we should start with.

We should start with limb-girdle...

Yes, let's start with limb-girdle. Yes, let's do that because I mean, this is probably one where maybe the unmet need is the highest. But Anna, maybe you want to kind of just lay the foundation in terms of like the indication and basically the therapy that you guys will be bringing to the market.

Yes, absolutely. So BBP-418 is being developed for limb-girdle muscular dystrophy Type 2I/R9. There are no currently approved therapies in the space. And the -- as you said, the unmet need is incredibly high.

We're super excited about the potential that BBP-418 has in this indication. So we read out our interim analysis from our Phase III trial last year. In that study, we not only saw differences from placebo that was statistically significant and met all of our primary endpoints, but the differences observed were actually on treatment, there were improvements from baseline, which is pretty much unprecedented in the muscular dystrophy field. And then there were declines on placebo that were consistent with the natural history. Overall, this patient population is around 7,000 patients in the U.S. and EU. We estimate currently in the U.S. is about 2,000, 2,500 patients.

Got it. So I guess what's the launch in this indication look like?

So yes, it's basically a very concentrated call point. So around 150 to 160 MDA centers in the U.S. where the vast majority of these patients that are genetically diagnosed are currently treated. So it's a very targeted like capital-efficient launch. We're very focused right now on finding patients. So we've mentioned that -- we've identified over 500 patients currently. And as I said, most of those patients are currently at these concentrated call points. So our field force is currently out educating physicians, payers. And yes, we're anticipating that adoption will be very strong based on market research so far.

Yes, I was going to say. So like in terms of like the doctors and the education process, like how long do you think that will take? And is it -- because this is an indication where there's really no therapy, is this going to be where basically every -- or every patient is a candidate essentially? Or are there going to be some kind of narrowing of the actual true candidates that would actually be best to respond on the drug?

Yes. Great question. So what we're hearing right now is you're absolutely right. So most patients are going to be considered a candidate for therapy here and adoption is very high across all patients. The main sort of drivers of that are obviously that currently, there are no available therapies. These patients are anticipating that they have declined year-on-year. And we actually saw in the interim analysis there were benefits as early as 3 months on the ambulatory measures, which is really driving urgency to treat.

I think currently, what would might -- there's a lot of, obviously, patient need that will be driven by very strong patient advocacy groups, too, that are doing a lot of the education on the patient side. And then in terms of physicians, as I mentioned, we already have the field force out there. I think we're not anticipating a bolus, though, just because I think the dynamics in these centers are that you're not getting -- that the patients currently go into centers about once every year or twice a year. So that might mean that sort of patients calling up physicians might have some -- there might be some delay in them getting into the centers.

I mean, I guess when you think about these patients in their kind of the journey to diagnosis, like how long does that take? And what's kind of your method of even just finding these patients? Are there good ICD-9, ICD-10 codes to locate these patients? Or is this still kind of like a lot more kind of digging in work that you need to do?

It's a combination. So basically, right now, there is a dedicated ICD-10 code, which is great. It went into effect last October, though, so it's still relatively new. We are seeing uptake already, and it's continuing to see new patients come in every month. We also have data from genetic testing databases where we've been able to identify patients as well. And we're anticipating that, that genetic diagnosis will continue to increase.

Based on market research now, it seems like the standard of care in these specialist centers is that people are getting genetically diagnosed as standard of care. So it's really about patients getting to those centers, which is probably the delay in diagnosis. But once they're there, they are getting diagnosed efficiently with genetic testing.

Got you. Now this is a different type of launch than I would say, Attruby, like more rare disease, more focused. So I guess are there any key learnings that you can take from kind of the Attruby experience and kind of apply it to the BBP-418?

Yes. I think that there are 2 different archetypes of launches, right? There is launch in a competitive market, which is Attruby and infigratinib. And then there's launch in a market which you're building, which is 418 and ADH1, encaleret, right? I think that some of the similarities, there are some differences such as marketing and things like that. But there are some similarities such as how do you design a process which quickly gets patients on drug, right? So not the kind of payer side of access, but more the patient and physician process side of access. Sure, I'll let Anna comment on that because one thing which, obviously, Attruby, we have white glove service, really working closely with the physicians' offices as well as the patients to get them on drug. And that is going to be key here also. So maybe, Anna, I'll let you comment on how you guys are thinking about it and learnings from Attruby.

Yes. So I mean, we're out there right now talking to payers. The payer research has been incredibly positive as well, like they're very receptive to the data that we've seen. As we mentioned, this is like they're not used to seeing placebo-controlled data in the neuromuscular space and then also seeing these improvements from baseline and the functional measures is pretty differentiating. So we're not anticipating sort of big coverage hurdles for access or reimbursement. We are planning on offering a similar suite of services to what was mentioned for Attruby for getting patients on drug at launch.

I guess what's a good pricing analog for limb-girdle?

Yes. So we -- the payers always refer to the exon skippers here as the most relevant pricing analog. I think, as I mentioned, the main difference here is that we're seeing functional benefits in a placebo-controlled setting, which they haven't already seen in that case. So I think you could think about those as like an analog as sort of the anchor and then we might think about premium pricing on that.

Got you. And the 3 launches, we'll discuss the other 2, but do you think limb-girdle has the potential to be the fastest ramping? Or do you think there's kind of like some, I don't know, friction points just because it's a new indication, it's never had a therapy approved there?

Maybe I'll start and then I'll ask you to build on it. So I think that -- we think all these 3 launches are going to be really good, strong launches. As Anna mentioned, we don't expect there to be a bolus or anything like that in any of these launches. Look, there are going to be new-to-market edits. These are markets which we are building. There's going to be diagnosis, which we are educating people on. All of that, especially for limb-girdle and ADH1 that is true. But nothing specific that I would call out as a pain point. It's all things that our team has diligently mapped. Actually, these guys have done a great job of mapping each step of the patient journey as well as each step of the physician journey and making sure that at every point where there is potential for friction, we have a plan for how to overcome it.

And so I think that it's -- they're all going to go really well. We feel good about them. And then I think your question was if this one will be faster than some of the other ones. And on that one, I'm going to ask you guys to do some work.

You don't want to pick your favorite child, like...

I am told that that's not nice.

He can't do that when I'm here.

Yes, exactly.

That's fair. All right. Well, maybe moving on, let's maybe talk about encaleret and ADH1. So a smaller population. You guys have been doing a lot of work in identifying patients. So maybe just talk about the setup there for that launch.

Yes. So very excited about it, right? Because these patients who have ADH1, first of all, the prevalence is probably about 12,000. So there are a ton of patients who are suffering with this disease. Currently, we have only genetically confirmed and identified about 500 patients. But we know that in the claims data, there is already about 2,200 patients. So we know that there are more patients that we can go after and try and convert. So a huge unmet need.

The drug basically normalizes the patient, right, because your blood and serum -- blood and urine calcium levels become normal, PTH levels become normal. That is a profound effect. So we're very excited about that. I think that the call point is concentrated, but not as concentrated as limb-girdle, right? I think here, you're going after a slightly broader pool of endocrinologists. But what's very interesting is that there is extremely high overlap with hypoparathyroidism. Actually, if you have nonsurgical hypoparathyroidism, the guidelines recommend that you get tested for ADH1.

What that means is we have a group of physicians who we can identify and target at launch and really try to, a, drive diagnosis there; b, drive awareness there and then also try and convert some of their patients who are ADH1 patients onto our drug. In terms of, I think, how we expect the launch to go, very similar to limb-girdle. I think that it should be a strong, steady launch, building on top of each other. It is an autosomal dominant disease. So one thing which we have seen is once we find a few people in a family who have the disease, we can do sponsored family testing and find a lot more people who have the disease. So that's actually a pretty interesting kind of difference between these 2 diseases.

And I definitely do think that pricing here is going to be less than limb-girdle, but still extremely strong. I think the comps that we've given on the low end are YORVIPATH, which is about $300,000 and then on the high end, Yuviwel, which is about $500,000. I do think it's possible we're closer to the high end than the low end given the drug is significant -- has significant benefits. And that's how we think about it.

And of course, what's very exciting about encaleret is, and I know you're probably going to want to talk about this, is there is a huge expansion indication in hypoparathyroidism right behind it. We are very excited that we have kicked off a Phase III trial there. We expect that trial to read out pretty shortly here by the end of '27, definitely by early '28. And that we have a beachhead with ADH1 and then we have a giant expansion opportunity with HP, and it could be the first oral agent approved in that condition, which I think patients will really wait for and want to be on.

Got you. Okay. And I guess maybe just talk to the strength of the data and what you believe mechanistically for kind of the expanded opportunity in just general hypoparathyroidism versus ADH1 and what gets you confident in running that Phase III?

Yes. I think the first thing which gets us confident is our Phase II dataset, right? So we did a small study, small Phase II study, 10 patients. These were some of the sickest HP patients, they didn't have the parathyroid gland. And completely independent of PTH, we saw normalization of blood and urine calcium in a majority of those patients, that's really profound benefit, especially normalization of urine calcium, which is a key unmet need area.

I think second -- and I'm going to be a bit quick here because I know we are running out of time, but we expand -- Neil actually expanded upon this in our -- on our earnings call. But mechanistically, there is a strong rationale for an agent acting on the calcium-sensing receptor in the kidney to have an effect on -- in HP. And so I would really encourage you guys to listen to that, and I think he goes into a good amount of detail, which I can't cover here due to lack of time. So that's just the papers which are coming out. Some of that is very new. They've come out this year, has also really encouraged us to go after it.

And then the third thing really is we derive a lot of our confidence from experts in the field like Dr. Mike Collins at NIH as well as other folks who really understand these endocrinology diseases. And I think that, that KOL excitement is the third thing which has made us excited about starting a Phase III here and helping a lot of patients.

Got it. So yes, maybe let's move to infigratinib just so we can get through it. But this is one excellent data, Phase III data in achondroplasia, first oral agent in that indication as well. And with the launch of Yuviwel, we're definitely learning that the market is getting larger, and there's patients that were not really being -- they didn't want to go on Voxzogo. So I guess now a couple of months now into the Yuviwel launch, where are you guys kind of thinking about -- or are you more excited about the infigratinib upcoming launch and ultimately, the opportunity there for an oral agent?

We are extremely excited about the infigratinib launch. We have been for a long time. What is remarkable is that we have a best-in-class drug, oral, best-in-class estimate on efficacy. But what is even more exciting, and we presented at ESPE, and we had a press release on this earlier today, is we are moving beyond height now, right? The benefits are not just on height. And yes, we talked about proportionality, which is a big deal in this community with our top line. And now at ESPE, we talked about sleep apnea, ear infections.

The fact that infigratinib is able to show clinically significant large benefits on these things which are on these measures beyond height, I think is -- means that this will be able to grow the market significantly. If you look in Europe, about 3/4 or so of patients, of kids are on some achondroplastic option. In America, maybe 1/4 are. And really, that difference is moving beyond height and having an oral option. And that, I think, is the opportunity for infigratinib. And I think that is why we are very excited to be able to -- we've partnered with the community, learned so much from them along our development journey, and now we are excited to serve them in the commercial realm, assuming the FDA approves the drug.

Got you. I mean do you -- is this mostly like new start market? Or do you think you'll switch patients? Like how do you think you'll get your foothold? And as you said, I think your data on body proportionality and that is going to be pretty meaningful for docs and for the patients. So what do you kind of envision early in the launch?

Yes. So we are going to be pulling from 3 segments of children. The first segment of families and children that we're going to be pulling from are children who are on Voxzogo or Yuviwel today. They are on it because there's no other option. They understand that moving beyond height is what they're looking for. They don't want to take injections. And so an oral option, which has benefits -- significant benefits beyond height would be appealing to them, right? And that's going to be a key market for us. But of course, that's a smaller portion of the children in the U.S.

The second group of children are children who have tried Voxzogo. And for whatever reason, either because there was no benefit beyond height or because they could not take the injections, they've decided to go off of Voxzogo. We know that those children and those families want something. We suspect what they want is an oral option, which moves beyond height. And we think that we'll be able to offer it to them, and that's the second group.

The third group of families and children that we are hoping to help are folks who have never tried Voxzogo or Yuviwel, some of them are needle-phobic. Some of them really want to be on an agent which helps on things like proportionality and not just height. And so that's going to be the third sort of segment that we're going to be targeting. And I think we're going to see uptake in all 3 segments. And I think that what we are most excited about is growing the market, so segments 2 and 3, but I do think segment 1 is also going to be important.

Got you. Maybe with the last 2 minutes here, Chief Business Officer. Like as you think about the kind of overall business, Attruby, pipeline launches, like so we're going to have these launches are going to be 2027 event. That's going to be exciting. But what's kind of next, right? That's we're all -- like what's kind of next in the pipeline? Where are you guys going to be kind of focusing your efforts? And as you said, kind of where are you going to take your resources and deploy the capital?

Yes, that's a great question. And I'm not surprised that Wall Street is asking what's next.

Yes, exactly.

So here's how we think about it, right? I think our first priority is funding and accelerating the Attruby launch as well as the launches in limb-girdle, acor and ADH1, best and highest use of our capital. I think that's what shareholders will reward us probably for over the next 12 months. Beyond that, I think that we really want to invest in our pipeline, whether -- and the main idea there is our hypopara trial. And so that I also think is on investors' radars and something which we're prioritizing.

Beyond that, if we have excess capital, which we do right now, we are in the lucky position of having excess capital, having our losses come down over time. We always think about what's the right way to deploy capital. It could be through share buybacks, but it could also be at the right time and our preferred path is to do it through organic growth. So we want to start new R&D programs, like I mentioned to you, and I think you are pretty close to this. You cover a lot of genetic disease companies. There is profound innovation happening in our space and the opportunity to help patients is immense.

So we have a sister company called GondolaBio, where we own about a 12%, 13% stake in it. At the right time, maybe it's sooner, maybe it's later, but I hope it's sooner. We would like to integrate these companies, use the cash flows and the capital which we have to accelerate that and to really make not just 4 medicines, but to make 40 medicines. And I think that, that's the shape of company which investors, patients and the community can be very excited about, and that's what we are aiming to build.

Chinmay, I think we'll leave it there. Anna, thank you so much.

Thank you.

Good afternoon. I will be your conference operator today. [Operator Instructions]. Before we begin, I would like to remind everyone that today's call may contain forward-looking statements within the meaning of the federal securities laws. including, but not limited to, statements about BridgeBio's future operating and financial performance, business plans and prospects and strategy.

These statements are based on current expectations and assumptions that are subject to risks and uncertainties and which could cause actual results to differ materially from those expressed or implied in these forward-looking statements. For a discussion of these risks and uncertainties, please refer to the disclosure in today's earnings release and BridgeBio's periodic reports and SEC filings.

All statements made here are based on information available to BridgeBio as of today, and the company undertakes no obligation to update any forward-looking statements made during this call, except as required by law. With that completed, BridgeBio, you may begin your conference.

Good afternoon, everyone, and thank you for joining BridgeBio Pharma's Second Quarter 2021 Earnings Call. I'm Chinmay Shukla, Senior Vice President, Strategic Finance. With me today are Neil Kumar, our CEO, who will walk through our commercial pipeline and business updates; Matt Outten, our Chief Commercial Officer, who will provide additional detail on our [ Tubi ] and our launch readiness; and Tom Trimarchi, our President and CFO, who will review our financial results.

During today's call, we will cover another quarter of consistent growth for Attruby, along with new data reinforcing its clinical differentiation, including the first evidence of direct kidney protection and ATTR-CM. We will then turn to the pipeline where the quarter, all three of our late-stage programs move from data into being with the FDA with our first PDUFA date now set for November '27. and we will review our financial position, including the $1 billion preferred equity financing completed on July 1 and how it supports the 3 launches ahead of us. Following our prepared remarks, we will open the call for questions. For the Q&A session, we will be joined by Ananth Sridhar, Christine Siyou and Justin To, who lead our programs with Encaleret BBP-418 and infigratinib, respectively. With that, I'll turn it over to Neil.

Thanks, Chinmay, and thanks, everyone, for joining today. As always, these calls are where we communicate relevant aspects of our business to investors, and so we welcome your questions and feedback. In sessions past, we've had occasion to marry comments on the portfolio with comments regarding financing and strategy. Today, however, I want to focus entirely on the portfolio itself and the progress being made across research, development and commercial.

I'm going to do so because I believe as I hope you might appreciate at the end of my somewhat lengthy comments that this is an important transition point for BridgeBio one in which if we continue executing at a high level, sets us up well for delivering substantial returns for patients and investors alike. Put more simply, it feels like we're at tequal0ro in BridgeBio's next chapter. I don't say this glibly, but rather due to the following and overlapping advances. First, as we will discuss, the combination of learnings from cardio transform, our own unique kidney protective data and extraordinary real-world evidentiary results. come together to provide the basis of what I'm calling Launch 2.0 for ATTRUVI.

I believe we will start to see significant commercial fruit from this in the 6- to 9-month range and beyond judging from analogs. We think the market is shaping up to be a stabilizer first market with a constrained number of competitors and 1 in which we have increasing numbers of proof points that our near-complete stabilizer is superior to Pfizer's partial stabilizer. Second, all 3 NDAs for LGMD2I ADH1 and achondroplasia have been submitted with LGMD2I and AH1 garnering priority review and are hoping that a contemplation might do. Our commercial readiness work is on track, even ahead of what we were able to do with ATTR cardiomyopathy given our relatively lean resourcing at the time to deliver strong launches.

Third, our chronic hypoparathyroid Phase III, which we believe is overlooked, has commenced and will read out in the next 18 months with potential to provide a differentiated efficacy and safety profile, as we will discuss, in addition to being the only oral in the space. Finally, we anticipate novel trials in areas like Turner and hypochondroplasia for infigratinib a new trial in a [indiscernible] disclosed high [indiscernible] orphan kidney disease for acoramidis and the advancement of a potentially best-in-class TTR antibody into the clinic in the coming 12 to 18 months.

All of this activity together provides a substrate for well over $10 billion in risk-adjusted revenue with $8 billion of that being post Phase III today. In addition, our interest in earlier, but still advanced genetic medicine R&D within our gondola pipeline continue to bear fruit. So this is a company with no dearth of pragmatic ideas that can drive a continued flux of important medicines on a risk-adjusted basis for the next decade or more to come.

I'll begin my portfolio comments with Attruby. First and most importantly, we observed continued commercial momentum this quarter with Attruby being the fastest-growing brand in the space at 23% and this growth does not account for the impacts of cardio transform our kidney data and most of the real-world evidence data to date since that occurred after the quarter end. We've always said that the most important thing commercially and medically in this whole space is diagnosing new patients.

To that end, we were heartened to see the substantial overall market growth of 19% this quarter, representing a 51% increase year-on-year and substantially outstripping the market growth observed in the last 3 quarters. Consistent with these numbers is the growth in frontline patients where stabilizers have dominated share, a trend that we think will strengthen as we learn more from cardio transform important results. Indeed, we observed a slight downtick in numbers of second-line patients in the second quarter. We believe our share in frontline has grown some 2 to 3 percentage points, although it's hard to tell precisely, given some of the inventory dynamics from our competitor, Pfizer. Our gross to net also remains within the 30% to 40% that we have indicated previously.

Going forward, we expect that the first line market will continue to grow, and we intend to continue growing our share in it, which should translate into continued steady sales growth. Attruby's strongest tailwind, however, is it's continually growing clinical differentiation story driven for the most part by the expanding body of real-world evidence as well as the now documented renal protective effect.

In July of this year, we published a circa failure on agramadus driving the first ever early and sustained direct kidney protective effects in ATTR cardiomyopathy, including chronic eGFR slope improvement and urinary albumin to creatinine ratio reduction. The upshot of this is that a tube may protect the heart and the kidney simultaneously in ATTR patients, a hemodynamically mediated effect, which we do not observe with other ATTR cardiomyopathic medicines, either knockdowns or other stabilizers.

Critically, as pointed out in the paper, the dynamics of this effect mirror the early separation uniquely observed with Attruby in terms of clinical outcomes, helping to explain this early impact. Furthermore, and intriguingly, the magnitude of the acute dip in EGFR on Attruby is actually important and suggestive of downstream benefit. More specifically, comparing acoramidis versus placebo subgroups with acute EGFR dips greater than or equal to the median of $4.89 per meter per 1.73 meter squared favored acoramidis for all-cause mortality or cardiovascular-related hospitalization with a whopping hazard ratio of 0.42 with an associated p-value of 0.006 and cardiovascular-related hospitalization alone with a similarly impressive hazard ratio of 0.3 and with an associated p-value of 0.002.

In treatingly, within the placebo arm, EGFR dips portended worst outcomes. So something initially thought to be a crush has now been shown to be an important differentiator for our product. The observed effect compares favorably to what we see in other kidney protective cardiac treatments like SGLT2 inhibitors. In a recently held meeting of nephrologists and cardiologists, 1 KOL explained to me, it looks like you have a kidney drug here. Building on that, as referred to above, we intend to further interrogate the signal by conducting clinical studies in an orphan kidney indication. More information on that in the weeks to come.

Meanwhile, the generation of real-world evidence continues to pace. When one looks at analogs in the cardiovascular space, where double-blind head-to-head were not immediately possible. real-world evidence sets the bedrock of ultimate commercial outperformance. The most story of these analogs is likely the Eliquis Sorolto marketplace. Calling back to last quarter, there was an independent propensity score matched analysis presented at SCAI and since published, which continues to resonate with physicians. That analysis associated Attruby with a 37% reduction in composite cardiovascular events and a 34% reduction in hospitalizations at 6 months relative to tafamidis with an effect deepening at 9 months.

Remarkably, there was no observed clinical outcome that did not favor Attruby versus [indiscernible] in all measures, except for dizziness and syncope reached statistical significance of less than 0.01 with an [indiscernible] of 600 patients. Building on this data, we have our own now soon to be published and available online today preprint analysis that parenthetically has been downloaded more than 400 times now, showing again a truly outperformance as compared to [ Vindamax ].

Importantly, in this study, a 34% reduction in diuretic intensification, heart failure hospitalization and mortality was observed. Again statistically significantly, and separation is again observed as early as 30 days and continues to improve over time. These types of analyses are what the community has been asking for. Importantly, a large-scale independent EHR-based analysis will be coming at HFSA. Our hope is that Attruby continues to perform well there. and that then these several RWE studies will form the basis for decision-making and guideline updates. The growing body of research supporting Attruby clinical differentiation will take place alongside evidence from other studies in this rapidly evolving field of ATTR cardiomyopathy.

Last month, as you all know, the top line results for cardio transform studying a planterson in ATTR cardiomyopathy readout and the study did not meet its primary efficacy endpoint with no benefit observed with combination therapy. At this point, we mostly want to acknowledge that this is a blow to the patients who participated in the trial and their families and the investigators and we feel for them as part of the ATTR cardiomyopathy community. The case for combination therapy seems to day now from a trial data perspective.

Given the similar degrees of knockdown between aplontrasin and vitrisiran, we'll be interested to see how the knockdown performs in two settings. Number one, does the monotherapy relative risk reduction continuing to underperform what we observed from Attruby 30 months. And two, does monotherapy knockdown actually not outperform a partial stabilizer in tafamidis as we actually observed in HELIOS-B. Recall, of course, that in addition to the real-world evidence I just cited, everywhere we looked in our Attruby trial, acoramidis outperformed tafamidis.

The conclusions of this important study run by AstraZeneca and Ionis, we believe will likely reinforce the case for stabilizers first. And if the monotherapy benefit, again, lags in time, this is observed with vutrisiran and a magnitude of effect as compared with Attruby, we believe this begins to make an even stronger case for using Attruby first in the second-line setting. Now I'd like to discuss the 3 pipeline programs that have moved into regulatory review this quarter and which we are preparing to launch. For BBP-418, our LGMD2I program, the FDA accepted our NDA on May 27 with priority review.

The PDUFA date is November 27, 2026, and there is no advisory committee plan. We continue to have positive interactions with the agency. This is in line to be the next approval in our portfolio, and it would be the first approved therapy for LGMD2I a devastating condition affecting a little more than 1,000 patients in the U.S. alone with significant unmet need. There's really no displace incredible competition in this space with gene therapy, really the only other pipeline approach, and it suffers from safety and efficacy issues, coupled with the fact that too much FKRP is toxic.

So dosing might well be an issue. I'll remind everyone as well that the data generated by our program are easily the most profound ever in the LGMD space and perhaps the broader muscular dystrophy space, given that biochemical improvements tied strongly to functional and statistically significant improvements in ambulation, breathing and other outcomes and that the drug promoted improvements as opposed to the ever worsening observations on placebo. From a clinical perspective, our goals are number one, to educate broadly on already established data; and two, to reinforce our observations in the nonambulatory and severe patient population that may initially be reluctant to try anything. Recall, we observed remarkably consistent benefit in our trial across ages, degree of severity and the homozygous and compound heterozygous populations.

Building on that, we'll be analyzing whether our established functional impacts also marry what some cardiovascular benefit, which affects many patients on the severe end of the spectrum. Our plan is to cut that data and present the results at World Muscle Society in late September, early October. So we are hopeful for a good outcome for the patients we serve there. As we prepare for launch, our neuromuscular commercial and medical field teams are hired, trained and in the field, and Market Access is engaging with payers in a preapproval information exchange.

There are approximately 500 genetically confirmed patients today in the United States, with many who remain unidentified and misclassified within the broader LGMD or betromuscular dystrophy space. Our goal is to find every patient who can benefit and be ready at the moment we're able to reach them. Turning to Ocaliva for EH1. The FDA accepted our NDA on July 22 with a PDUFA target action date of May 8, 2027 and no advisory committee planned. At the end of July, the agency granted priority review, and we have announced that today. We have also submitted our MAA to the EMA on July 27, and it is under review.

[indiscernible] would be the first therapy approved for ADH1 in both United States and EU, and we are excited to serve this patient population. Speaking of that population, our patient finding efforts continue and more than 2,200 patients have been identified in the ICD-10 claims between October 2023 and June 2026. That is an increase of about 300 since the first quarter, and it's been driven by genetic testing, awareness education, use of the ICD-10 code and BridgeBio supported family testing events. We have also completed enrollment in the first of 4 cohorts in our pediatric ADH1 study and are preparing to open Cohort 2.

But 881 approval is the beginning of calories potential, not the end. Chronic parathyroidism affects some 200,000 patients in the U.S. and EU, a blockbuster opportunity in and of itself, where as discussed last quarter, we see a real appetite for an oral option that corrects both hypocalcemia and hypercalciuria. I want to spend a minute on this opportunity because I think it's been overlooked significantly by investors. First, there may be a belief that PTH replacement is the beginning and end of the game here with advances around dosing, for instance, going from daily to weekly being the only salient dynamic for patients. But that overlooks a couple of key facts.

First, that benefits of existing therapy do not importantly extend to normalization of urine calcium with some 40% of patients not normalizing and some 50% of CHP patients actually being hypercalciuric. Two, there's a well-documented decrease in efficacy of PTH replacement over time, suggesting that other approaches may be important here. Third, perhaps most importantly, there is a need for a drug that spares the impact of PTH mediated bone issues, especially considering that in a recent survey of 160 patients, 48% of them had osteoporosis or osteopenia. And fourth, that many individuals would prefer an oral medicine. I think some may have discounted this opportunity based on likely probability of technical success.

That, I believe, is a mistake. First, the path of mechanism here is well described, recall first that the hypercalciuria in chronic HP arises from 3 independent contributors: one, loss of calcium reabsorption at the distal nephron that's PTH driven second, decreased calcium reabsorption in the FICC ascending limb that's calcium sensing receptor driven; and third, obviously, exacerbation by conventional therapy. Analogous to PTH activity in the kidney to mediate reabsorption of calcium in calories action on the calcium sensing receptor has been shown to increase paracellular reabsorption of calcium in the thick ascending limb by reducing clad 14 expression which in turn, decreases the amount that integrates into the [indiscernible] complex, which acts as a calciuria promoting poor blocking component.

This mechanistic rationale helps to explain the observation from our proof-of-concept Phase II where of full surgical parathyroid patients administered within [indiscernible], achieved both normal blood and urine calcium within 5 days. Okay. So we understand how negative allosteric modulation of the calcium hunting receptor can mechanistically raise serum and lower urine calcium even in a wild-type setting. But for those of you who don't want to bet on mechanism, recall also there's clinical evidence in the wild time setting that exists for these drugs. Namely the extensive data from the legacy clinical development program of encalerate in osteoporosis participants expressing wild-type calcium-sensing receptor like the chronic hypoparathyroidism population that we intend to study in the reclaim HP trial.

And recall that in that osteoporosis study, the drug demonstrated dose proportional increases in serum calcium at daily doses of 15 milligrams or above. So we believe, given the end point of serum and urine calcium normalization, with all that we've seen to know and the stability of those endpoints statistically that we have a high probability of technical success trial on our hands. Secondly, investors may believe that the opportunity is not near term, but this is a relatively quick trial given the aforementioned endpoints and the rapidity of onset of our drug. And as mentioned in our press release, we have already activated our first sites for the reclaim trial, our global Phase III and have begun screening with FTI imminent in a trial readout expected in the next 18 months.

Okay. Finally, I'll come to infigratinib, our oral treatment for achondroplasia, where we presented our Phase III PROPEL II results at the International Conference on Children's Bone Health on June 30 and simultaneously published them in the Newland Journal of Medicine, the only 800 Plaga program with Phase III results in the Newell Journal. Following that publication, I'm excited to announce we've submitted our NDA, and we are targeting an M&A submission in Q4 of this year. We hope to see NDA acceptance and ideally priority review in Q4 of 2026 and with approval following in mid-2027. Approval would make infagratinib the first FGFR3 targeted oral therapeutic for achondroplasia. And on top of its oral dosing advantage, it remains the only therapy with efficacy measures beyond annualized high velocity demonstrated in a placebo-controlled setting of 52 weeks, including proportionality. Adding to this, we demonstrated a clear functional differentiator in our Phase III results with a statistically significant 0.37 standard deviation improvement on [indiscernible] with a p-value of less than 0.0001.

This is the first-ever placebo-controlled arm pan benefit in an achondroplasia trial. We look forward to presenting more data in the second half of this year and continuing to build infagratinib's scientific story through the preapproval period. On the commercial front, our regional sales directors and medical affairs personnel are onboarded and the field medical team is fully built. Our RSDs are building team for meaningful share of voice in a market where 2 competitors are already present and where we see a real gap, especially in the U.S. between kids confirmed to have achondroplasia and those on treatment. We continue to think our peak achievable share in this space is above 65%. Finally, I also want to make mention of the critical work occurring off our balance sheet at GondolaBio, where BridgeBio shareholders retain exposure via our ownership stake and ongoing operational support.

Our program in announced positive Phase IIa data in June and following a productive EOP2 meeting with the agency, we will be initiating a Phase IIb/III study in Q3 of this year. Critically, given the 80-plus percent magnitude of PB9 reduction, coupled with the quick onset of action and safe profile, the agency suggested that the 2b could form the basis of registration. If PPI lowering was met statistically and other functional trends lined up with it from the point estimate standpoint. Meanwhile, the rest of the pipeline continues to progress with some 17 programs and indications, including ADPKD, alpha-1 atrypsin, neurofibrtosis type 1 and CMT1A. In total, the activity has potential to yield 5 additional INDs by the end of this year, with some 8 clinical proof-of-concept readouts to come in the 2027, 2028 time frame.

Of course, despite all of this, we continue to stay focused on delivering our important medicines to patients in the commercial setting. And for more information on that, I'll pass it over to Matt.

Thanks, Neil. Q2 was another strong quarter that demonstrated consistent growth in the treatment-naive segment for TUV as physicians are increasingly starting and keeping patients on accruing. Net product revenue was $222.4 million, marking another quarter of $35 million or more of sequential sales increase. I want to spend a moment on the composition of that growth because that is the part that matters most for how we think about the franchise from here. The engine is the first line. Our first-line share stepped up again in Q2 on a first-line market that held roughly steady quarter-over-quarter and new patient starts were consistent with the first quarter.

That is the durable driver of this franchise, and it is what we are building against. The second line or switch segment is behaving differently, and I want to be clear about it. the forced Vinda kill switching that inflated that pool in the fourth and first quarters has now largely been worked through by roughly 18 months post launch, the switch opportunity is settling into a lower and more normalized steady state. What changed there is the size of the pool, not our performance within it. So the shape of our growth is evolving continued first-line strength partially offset by a smaller switch market.

That is the mix we would expect going forward, and it is the mix we are planning around. Neil covered the clinical differentiation data. So I want to speak to what it is doing commercially because this was a meaningful quarter on that front. The endpoints Neil walked through are the ones practicing cardiologists managed week-to-week such as hospitalizations diuretic escalation and kidney function. And because much of that work was conducted independently of us, it carries the credibility with physicians and with payers that sponsor generated data does not.

We expect additional independent real-world work to read out over the balance of the year. On cardio transform, the outcome was disappointing for patients, who had hoped combination therapy would improve on stabilizer monotherapy. What it did do is reinforce stabilization as the first-line standard of care. As the only near-complete stabilizer available we believe Attruby is well positioned in that setting. That said, the first line remains competitive, and we expect it to stay that way. Our job is to keep earning share on the strength of the data quarter-by-quarter.

Neil noted last quarter that we expected [indiscernible] to reach blockbuster status in 2026, and we remain on track for that. To be precise about what sits inside of that number, we are referring to worldwide sales of acoramidis, which includes BeyondTrust sales recorded by our partners outside of the United States. It is not a forecast for the U.S. attribute net product revenue. For the balance of my time, I want to focus on the 3 approvals ahead of us. The Attruby launch gave us much of the infrastructure any future launch requires. -- and we have been hard at work making sure each of these goes as well as that one did. These would be the fourth, fifth and sixth launches in BridgeBio's history.

Let me take them an expected order of approval. First, 418. LGMD2IR9 has never had an approved therapy. Approval would mark the first for LGND2iR9 and the first for any form of limb-girdle muscular dystrophy. We have submitted a brand name and have conditional acceptance of a proposed proprietary name from the FDA, which we will announce at approval. Our field medical team sales leadership and sales team are hired and in field.

More than 95% of the sales team has prior neurology experience with an average of 9 years in rare disease. These patients are diagnosed and managed by neurologists and neuromuscular specialists working with a multidisciplinary team to our target universe is concentrated. Roughly 700 institutions and 5,300 target specialists with priority reach against approximately 150 parent MDA centers. Ahead of any approval, the team is focused on disease state education and genetic testing awareness and we continue to build a scalable patient identification engine that has already identified eligible patients.

We are also engaged with payers through preapproval information exchange so they understand the value story ahead of the decision and we will bring the same patient support programs that have supported our prior launches. Second, encaleret in ADH1. At the end of July, the FDA granted priority review for Encaleret. The PDUFA target action date is May 8, 2006, and no advisory committee meeting is currently planned. We have built an equally strong field team here with nearly 90% bringing rare disease experience.

ADH1 is a genetically distinct condition driven by gain-of-function mutations in the calcium sensor receptor, which causes low serum calcium, low or inappropriately normal PTH in a more pronounced increase in urine calcium than hypoparathyroidism generally. Encaleret is designed to target that receptor directly with the potential to address both serum and urine calcium. If approved, it would be the first therapy specifically indicated for adult and adolescent patients with ADH1. As with BBP-418, we are engaged early with payers so that the clinical rationale is well understood before a decision.

Third, infigratinib and achondroplasia. We have submitted the NDA and we anticipate approval in mid-2027. Unlike the other 2 launches, infigratinib enters a market where competitors are already established, we have delivered against that kind of setup before. What we hear consistently from families from our HCP and community steering committees and for market research, is that there is real anticipation for an oral option and awareness of infragotinib is high. The ability to give this medicine as a small once-daily capsule is about considerably more than convenience. Aversion to injections is one of the primary barriers keeping families from starting treatment at all, one of the leading reasons they discontinue and a persistent burden on daily routines and family dynamics.

And [indiscernible] can be swallowed or the capsule can be twisted open and sprinkled over food, no refrigeration, no reconstitution. Now working out how to travel with it, no injection site reactions and no shops. Stanleys and physicians also see the differentiation as more than the capsule. They consistently point to the efficacy in the PROPEL 3 program and in particular, the proportionality data in the prespecified 3- to 8-year-old subgroup. Operationally, our commercial infrastructure continues to build, and we are being deliberate here because this community is unique and requires a different kind of support when families are weighing weather to start therapy. Our partnership with the achondroplasia community over the past 7 years is underpinning how we are approaching this launch. In short, we are on track across all 3 programs. With that, I'll turn the call over to Tom.

Thank you, Matt. Good afternoon, everyone. I'll now walk through our financial results for the second quarter. Our commentary will focus on GAAP financials unless otherwise noted. Total revenues for the second quarter of 2026 were $243.7 million compared to $110.6 million for the same period in 2025. The $133.1 million increase was primarily driven by a $150.9 million increase in approving net product revenue. Attributed net product revenue in the quarter was $222.4 million compared to $71.5 million in the same period last year. Royalty revenue increased to $15.4 million compared to $1.6 million in the same period last year. primarily earned from net product sales of [indiscernible] in the EU and Japan. License and services revenue was $5.8 million compared to $37.4 million in the same period last year, which included a onetime $30 million rigor milestone recognized under the electrical agreement following pricing approval in Japan.

Total operating expenses for the second quarter of were $335.7 million compared to $241.2 million in the same period last year, a $94.5 million increase reflects deliberate and disciplined investment in Attruby and preparations for 3 upcoming launches. It was primarily driven by scale-up of sales, marketing, medical affairs and pre-commercial product supply related activities. Turning to the operating line. In the second quarter, we recorded a $107.1 million loss from operations compared to $134.3 million loss in the same period last year. an improvement of $27.2 million or approximately 20% year-over-year.

Now on to the balance sheet. As of June 30, 2026, our cash, cash equivalents and marginable securities were $72.2 million Subsequent to the quarter end, on July 1, 2026, we closed a $1 billion of preferred equity investment led by Six Street with participation from healthcare royalty, putting our cash balance at approximately $1.7 billion as of July 1, 2026. We believe our current cash position provides us with a significant runway to fund our operating activities, execute on 3 potential launches over the next 12 months. and continue to invest in Attruby commercial growth, all while maintaining the financial discipline we have demonstrated to date. With that, I'll turn the call back over to Chinmay.

Thank you, Neil, Matt and Tom. Operator, please open the line for questions now.

[Operator Instructions]. We'll go first to Tyler Van Buren at TD Cowen.

Congratulations on another strong quarter. It's great to see the more than $35 million in sequential U.S. revenue that true added again this quarter. But as the release specifically calls out Attruby growth led by the treatment naive segment as physicians increasingly start and keep patients on Attruby. Can you discuss what is driving that consistency in the first line and perhaps, most importantly, given competitive developments, why those drivers are durable. And perhaps you could also layer that in with expectations for the potential impact that the cardio transform failure and upcoming data ESC could have on a Attruby treatment naive share as well?

[indiscernible] to pass it on to Matt to comment on some of the commercial dynamics. And then I'll pass it on to [indiscernible] if he wants to add things on cardio transform expectations at ESC.

Okay. Thanks for the question, Tyler. I think there's 2 interesting components here. there's the reason that Attruby has done so well to date, namely how quickly a truly separates from placebo along with the incredible reduction in hospitalization rates. And then there's the new data that Neil discussed today. the performance you've seen to date has been rooted in the clinical differentiation story. Now we can add to that with compelling insights from the real-world evidence, kidney data and cardio transform. And this is going to add on to the earlier messaging and continue to push share forward in the future. And I'll let Neil add-on with the cardio transform cells.

Yes. Thanks, Tyler. I guess I'd just say, I mean, we have to see what the data looks like. But by and large, I would expect that stabilizer frontline will do nothing but a gain of the cardiotransform data set. So just be a larger pool. And in that pool, I think to Matt's point, we'll continue to differentiate. And I think we're going to see the fruits, as I mentioned in my comments, of the real world evidence, kidney differentiation appear really kind of like half a year from now or so if you look at analog, it generally takes about 6 to 9 months to pull through some of this data, obviously, also dependent on what HFSA looks like in terms of the independent RWE analysis.

But if everything continues to go the way of a truly, I mean, as you well know, it's sort of like as you start to connect all the dots from biochemistry to serum TTR, [indiscernible] 5% decrease in mortality risk in 30 months to all of the real-world evidence against both survival, at least we'll see that at HFSA, and we saw some hints of that with the Monteria independent more data around the time that we launched and hospitalization and ODI as we mentioned today, I think all of that comes together to say we have a superior stabilizer.

And that's really the message we got to continue to hit. I mean, my expectation would be that we really hit a positive second derivative here and continue to grow pretty aggressively in the front line over the coming 12 to 18 months of [indiscernible].

We'll go next to Cory Kasimov at Evercore ISI.

Perhaps not surprisingly, I also want to ask a question regarding cardio transform missing the primary end point. So at this point, we obviously know there was substantial background stabilizer use and putting the silencer on top of it didn't improve outcomes. So I know you touched on some of this in your prepared remarks. But in your view, does this not only cement stabilizers as kind of the first-line backbone here in future treatment. But also, do you have any feedback at this point from your KOLs and payer discussions as to how prescribing and reimbursement of any combination therapy may evolve from here?

Yes. Thanks for the question. Maybe I'll start and Matt, you can add on. I'd say it's a little early for us to get feedback from payers/on the KOL side, for sure, I mean, we've been hearing, I think, a bit of a surprise, honestly. And there are folks that can be convinced with biochemistry and biophysics, but I think a large trial like this convinced a lot of folks and might be changing folks' mind. So do you think stabilized will be an increasingly large part, they already are a large part but an increasing large part of the top line. And I think that's where the real action will be in this category.

I'd say the 3 things that we're looking for with regard to cardio transform, I do [indiscernible] a very similar knockdown profile we have to and see whether ponderings slightly superior to [indiscernible] wood obviously took a long time to get to its mean max knockdown, but that will be the first thing that we'll be intriguing to look at. And then within the context of the clinical data, First and foremost, what's the 30-month data look like. Is anyone getting to 340, 250? And to Matt's point, how quickly are folks separating in terms of effect.

Because I think if you look at the totality of evidence of my suspicion will be that not only do you get the magnitude of relative risk reduction that basically attributable look superior at 30 months. But if there's no early separation, it really starts to suggest that you ought to be using a true in that switch setting, just given both its magnitude of benefit and the early onset now well described by this kidney data that we put out and we'll continue to elaborate on. I think the second super intriguing point will be to see whether or not monotherapy noncontent actually outperforms a partial stabilize. People sometimes -- I know you and I have chatted about this, but people won't ask forget that at Helios speed in that [indiscernible] Jack favor that who didn't significantly outperform TAP, which was a bit of a head scratcher to me based on the toxic monomer hypothesis until you look at the pharmacokinetics.

And here again, if a knockdown doesn't outperform a partial stabilizer recall, we've got a stabilizer outperform TAP in every single part of the attribute trial that we looked at in all major RWE studies. And so again, it starts to establish, I think, Attruby is a superior efficacious agent as compared to both knockdowns and the partial stabilizer of Pfizer. So that will be the second big thing we're looking for. Tom, anything you want to add?

No. I mean, that's well said. I think we're interested in seeing the full data set ESC, but certainly the results don't appear to support combination therapy which just then reinforces stabilization of the backbone of therapy. And again, your comments, I think, on the partial stabilizer versus a complete stabilizer, that's kind of where we are, and I don't think anything we see at ESC is going to change that based on the initial results that were posted.

We'll go next to Ellie Merle at Barclays.

Congrats on all the progress. So the sizer release cited net price erosion from new payer contracts, while your gross to net has remained stable within the range you've added to given it's truly launched at a list price below tafamidis, do you see any need to respond on price? Or is clinical differentiation carrying access and share on it?

Yes. Thanks, Ellie. It's an important question. I mean I think we like clinical differentiation to continue to carry the day here. We -- there's some way that we could respond and meet closers rebates if they're going to be aggressive in that channel. Notably, I think we need to. I think we've had productive discussions with our partners all the way through based on the channel standers and what we're trying to accomplish in terms of clinical differentiation in terms of the added reduction in hospitalization is where the real world evidence really comes at handy.

I mean, the 35% or 34%, in an independent study reduction in hospitalizations as compared to TAF, that's super meaningful. These are patients that are quite expensive. And there's some untoward things that can also happen when you favor one brand over the other. So I think long term, these brands will be at parity generally in terms of access. And then I think clinical differentiation will be where we're with. So we do not intend to chase any 1 down the route of a whole of target paying near-term price dynamic games.

Our next question comes from Salim Syed, Mizuho.

Congrats on the quarter guys. Just 1 from us on this heart failure publication data on the kidney protection. So obviously, the better stabilize everybody knows that all the real world -- the real word curves show that also Attruby better than TAS. Just wondering how this adds into sort of that thinking here?

Like when you guys are talking to physicians, how important is this kidney protection? How meaningful is it in terms of how they're prescribing it stabilize or choosing a stabilizer? And if we kind of like drag that forward a little bit with the list price already been below TAF, what does this eventually mean for Attruby as the market evolves and when [indiscernible] goes generic?

Yes. Salim, thanks for the question. I'm going to let Matt handle how the kidney data is being received by KOLs and then I'll cite back on the generic questions. But Matt, why don't you talk about the concatenation data.

Yes. I mean I think First thing to note, this is new. So up to this point, it's been about the 340 250, as Neil mentioned, it's about early separation and not only how fast Attruby works, but how well it works. How many people it keeps out of the hospital, how soon you see the curves separate. So that's what's led us through Q2. I think in terms of the kidney data, it's very important to physicians.

And you're going to see that impact moving forward, which I think is -- that to me is probably one of the most exciting things about the call today because the kidney data hasn't been up. It's brand new. So you're going to see that impact now as we move forward over the next couple of quarters.

Yes. And just to bet on that, to discuss this, I'll on this. But -- we do expect the brand to keep growing even after [indiscernible] in mid-2021 in the U.S. And there 5 reasons for it, right? I think the first Attruby is clinically differentiated. You've heard a lot about that on the call today. that is driving the strength in treatment manual for us. And I think on the keep driving strength there. The second, which I think is less understood by folks is that stakeholder economics in this market, especially the they don't largely support a preference for generics.

I think you can also see that Pfizer has been successful and depending on other franchises. And I think that there is a potential for some upside because if Pfizer to promoting post ROE, in fact, would increase relative share of voice for Attruby. So I think if you look at all of this and you look at all the analysis on analog, which I know you and Bennett have done a deep dive on it. I think that we expect that even as opposed to market [indiscernible] generic and Attruby keep growing.

So can I just build on 1 point that Matt made because I think the kidney data is super fresh.

So we're going to have to see in the next 6 to 9 months kind of how it changes is pro behavior. But first and foremost, I think it's important because the actual mechanism of turning down toxic monomer, you wouldn't expect to pick up impact as early as 28 days or 1 month. So here now, you have a viable mechanism by which you have this early onset of efficacy. And as I mentioned in my remarks here I hinted that, like it was previously sort of considered a harmful piece of our label. But I think now what you see is the greater than munition early, the better off you are later in terms of both cardiovascular hospitalization and death.

So that's also a profound suggestion here that I think will be very important on a go-forward basis. And you've got to remember, like 50% of the patients, close to 50% of patients with the aromatase some sort of kidney involvement. So this is an important. This protective signature is going to be an important piece, we believe, the emerging story here and potentially an interesting piece of the story as if we can move Attruby into novel indications.

We'll move to our next question from Andrew Tsai at Jefferies.

Congrats on the solid execution. So I think this was a quarter where all 3 of your pipeline programs moved from the clinic into the regulatory phases. You got LGMD submitted within 5 months of the top line, 2 prior reviews. No AdComs plant. So it seems like your relationship with the FDA is quite healthy, but maybe talk to us in detail what your regulatory engagement has been like and how you're feeling about the review time lines from here also be curious about your ex U.S. interactions, too.

Sure. I'm happy to take that. I mean, I think, first and foremost, as you probably know in the rare disease setting, kind of the gold standard is the ability to run an RCT, a solid RCT with a placebo arm, and we've been able to do that across all 3 indications here and demonstrate profound functional benefits. So I think one of the senior administrators at the agency once said that we're kind of the poster child of what 1 price to do at least in a ready disease setting is not obviously always going to be the case, for instance, in [indiscernible] disease, we may not be able to run an analogous trial. [indiscernible] terms for these 3 data sets with the [indiscernible] values where they are, what the safety word is. I mean, people forget that would be small molecules we've been able to provide an exquisite safety profile.

So the risk benefit is pretty straightforward as well. So yes, based on all of that, we've had productive discussions with the agency to date, and we look forward to it engage them on that front. And similarly, I'd say, in Europe as well, there has been a dichotomy between the tenor of our obligations there yet.

Our next question comes from Anupam Rama at JPM.

Just thinking a little bit about the November 27 PDUFA for 418 and limb-girdle muscular dystrophy. It sounds like you guys have made a lot of progress here on the field team, the neuromuscular field team being hired, trained deployed. Can you walk us through what the near-term focus here to be ready on your launch readiness? And then how you're going about identifying more patients heading into PDUFA to go beyond that, I think, 500 patients you talked about being identified today?

Yes. Thanks, No. We're going to pass on to Christine to talk about the [indiscernible] launch.

Just as a reminder, this is an opportunity where we think it's a $1 billion peak sales opportunity. We think there are 7,000 patients in the U.S. and EU with 2,000 to 3,000 in the U.S. In the U.S. in terms of launch rate, we do benefit from having a concentrated prescriber base, with the majority of patients treated about 150 NDA centers. So as we mentioned, we do have a dedicated sales force that's been fully higher in trains or in the field now, really focused on disease awareness and site profiling before the launch.

Our MSLs are also fully trained. They've been in the field for over a month. They're also focused on to awareness and increasing the awareness of genetic testing. And that's been key for driving increasing patient ID and genetic SC. On the patient side of things, we have identified over 500 patients who are genetically confirmed that's actually grown over the course of the year, and we would expect it to actually continue growing. We have seen that genetic testing rates have also increased over the past 9 months, and that is key to increasing the number of patients that are identified, including the fact that we now have a dedicated sales force as well as MSLs in the field driving awareness.

There's also a new dedicated ICD 10 code specific for LGMD2i/r9, and that's also going to help with tracking patients and just greater visibility as we commercialize -- on the payer side of things, this is an area of strength for this launch where we can really maximize access and price. The market research with payers has been consistently positive. They've been quite receptive to the strength of our data and the unmet need on the patient side. They view the closest price analog as the exon-skipping DMD drug as a comparable patient population for them.

And I guess the ones have it here, they even acknowledge that we have much stronger data because we actually have the functional data. It's not just based biomarkers. And so that's an area of strength for us [indiscernible].

We'll go next to John Boyle at William Blair.

Congrats wanted to ask on encaleret. Now that you have a priority review that MAA submitted and diagnoses are increasing each month at the ICD-10 code, Wondering if you could walk us through the launch setup into the May 2027 PDUFA date? And as a follow-up with reclaim HP screening, hoping you could walk us through how you view the size of that opportunity and how you're viewing it as the next leg of growth for the franchise.

Thanks, John. Really appreciate your questions. I'm going to pass on to Ananth to talk about [indiscernible].

Sure. John, thanks for the great question. On the setup in advance of our PDUFA date for intolerant H1, as we shared today, we see about over 2,200 patients uniquely coded under the dedicated IC 10 code, which is 2.810 for autosomal dominant hypocalcemia. What we see in about 70 patients per month have been diagnosed and coded recurring that code in the claim of databases. And it's suggestive of what we would have anticipated, which is the availability of promising and positive clinical data driving awareness and suspicion to test for ADH1 in the clinic.

And between now and PDUFA, as one may expect, we're investing further in raising disease state awareness, and we have our medical team meeting with institutions and providers amplifying disease awareness efforts and growing familiarity with our evidence. And between now these, we will continue to engage with our payer audience to date. The interactions have been quite positive.

The anticipation for a new in first modalities directly targeted to treat ADH1 has been quite well received amongst the payer audience, and we anticipate a constructive dialogue as we approach up more closely. And then to your second question regarding reclaim, it's a really exciting update today, as we shared that screening activities have started for that Phase III study. We anticipate deliver top line results from that [indiscernible] about 18 months or so. And it might be a great opportunity for us to grow the clinical utility of encaleret into the broader product hypoparathyroid population.

We see around 200,000 individuals in the U.S. and Europe to be applied in chronic hypoparathyroidism. If we're successful in this indication, we see another blockbuster opportunity for us to grow into.

We'll move to our next question from Derek Archilla at Wells Fargo.

Just a quick one. So I know in the past, you had mentioned like 30% to 40% peak share for Attruby assumed a 4-player market with combo use expanding. So I guess how does the failure of cardio transform raise that ceiling? And just curious if you plan to update that assumption anytime soon?

Yes. Thank you for the question. We're conducting market research, and I think that we'll probably kick it off more after the cardio transform results come out more fully at ESC. And so at that point, we can more formally talk about what we expect as seashore. I think, as Neil mentioned in his prepared remarks, we do think that the case for combotherapy scientifically is quite [indiscernible] and so I think that, that does benefit. And I think the size also remains front line as weaker cut.

So we expect those things to be positive, but we don't have new market research to share at this point. It would be a bit preliminary to do the Board the medical conference will happen and positions of a cation. Really appreciate your question.

Our next question comes from Luca Issi at RBC.

[indiscernible], obviously, by Marin last week mentioned that 100 patients have switched from [indiscernible] or less than 10% of all the Bogo patients. they're obviously arguing at 10%, such a low number to suggest that the market is very sticky and the patients are loyal to [indiscernible] and -- so just kind of wondering what's your comment on that? What's your view on that number as we kind of think about the launch of the rate potentially next year?

Thanks, Luca. I appreciate the question. I'm going to pass it on to Justin to talk about the enpogratinab program.

Yes, thanks so much for the question. Yes, I think we've been really pleased by what we proved in the last few weeks from both [indiscernible]. I think there's a lot of favorable tailwinds for our upcoming launch on environment side of things, they continue to increase the treatment rate and build the market globally, really enlarge pie for everyone across all markets. We call it easier to a switch and to get a patient who have never been on treatment before. I think that's been really great to see the launch can accelerate there.

Now based on the recent incentive numbers, really validated to our key assumptions for launch. The first is that there's really not that much brand stickiness in the space. families want their kids to switch the motion of Vancocin. And when we're on the market, not only will we have those will be an option, but by far the most aspect. And [indiscernible] a strong launch here is good for us. if families and HP think about switch antibody of option. And ever since the seniorities a huge uptick in orient agencies.

The second key assumption that [indiscernible] late is that adenosine optional to expand the market. Now I think Ascendis is being a good chunk of their treatment naive scripts from families [indiscernible] some of the math based on borrowing centers. And we know from multiple analogs from prior launches that availability of the first oral tend to expand the market by 2x at 3x. So we think in totality, some of the numbers we're seeing for [indiscernible] in the remarks is going to be 10 valor launch.

Next, we'll go to Jason Zemansky at Bank of America.

Congrats on the nice quarter, [indiscernible] royalties just reached $15 million for the quarter. It looked like they're starting to scale -- so as in colored for '18 and now infigratinib move towards their respective European decisions, how are you weighing potential partner structures like the BeyondTrust agreement versus commercializing independently ex U.S. And I mean is there anything you can extrapolate from your experiences about maximizing value abroad?

Jason, it's great to hear from you, and thank you for the question. Our framework for any partnership decision always remains. We want to do what is going to be best for patients and shareholders alike. And we want to put the asset in the hands of the person that is the best owner. I think that we think for these next 3 launches, we feel very confident about being able to commercialize them globally on our own. I think we've learned a lot from the Attruby launch.

And I think we are excited to grow our footprint internationally as I think actually serving those countries and is going to help us improve our development engine, too. So that's how we are thinking about it. Obviously, it's the fact that we have about $1.7 billion of cash on our balance sheet. We're very well capitalized to fund those launches. And I think that the footprint is also going to be light as we've discussed before. So I think that's how we are thinking about it today, but we're always open to interesting suggestions and ideas and I'll evaluate is what is best for our shareholders and patients that we wish to serve.

No. Also, it's important to your control price globally in a world. So that's what we intend to do.

And next, we'll move to Danielle Brill at Truist Securities.

Congrats on the really strong execution this quarter. So it looks like operating loss improved roughly 20% year-over-year despite the added investment required to support potentially 3 new launches over the next 12 months. So as a truly continues to scale and the portfolio transitions to a multiproduct commercial business, how should investors think about incremental margins and operating leverage from here? What are the key milestones that ultimately drive bridge to profitability and sustainable cash flow generation.

Danielle, thanks for the question. So I would say with another quarter behind us, we are increasingly confident in the evolution of the P&L towards a point where we'll start to see breakeven profitability and ultimately cash generation in the relative near term. Just to give you a sense for how we think of it. So we look year-on-year, we're seeing an improvement on the operating line, which has been pretty consistent year-on-year for the last few quarters. Quarter-on-quarter, though, we're pretty much stable. We expect to be stable on the operating lines for the next several quarters before that starts to improve again towards the end of the year into next year.

Just to break that down a bit further, you've got 2 pieces really driving this. One is Attruby, which is in basically, I would say, margin expansion mode, where OpEx is relatively stable, but we're seeing, obviously, sales growth continue to improve the margin. that's pretty much offsetting the investment we're making into the upcoming launches. So we're scaling up all the activities around field medical marketing as well as expensing pre-commercial inventory right now. So as we get towards steady state on those activities towards the end of next year, we'll start to see again a trend toward improving the operating line also breakeven on the horizon as we look into.

And that concludes our Q&A session. I will now turn the conference back over to Chinmay for closing remarks.

Thank you, everyone, for joining us for our second quarter earnings call today. We appreciate your interest, and we look forward to seeing many of you at our Commercial Day in New York on October 8, where we will go deeper on commercial readiness and launch strategy across our 3 upcoming launches. Thank you.

And this concludes today's conference call. Thank you for your participation. You may now disconnect.

Okay. Good morning, and thank you for joining us on day 2 of the 47th Annual Goldman Sachs Global Healthcare Conference. I'm Paul Choi, and I cover the mid-cap biotech sector here at the firm. It's my pleasure to host the BridgeBio management team. But before we get started, I'm required to make certain disclosures. These disclosures relate to investment banking and other relationships that Goldman Sachs may have with the firm's companies discussed today.

These disclosures are available to you as clients of the firm on the research portal. We are prepared to read them aloud, but they are available on our research portal. But otherwise, after that, I'd like to welcome BridgeBio here. To my immediate left is Tom Trimarchi, CFO. Next to him is Chinmay Shukla, SVP of Strategic Finance; Anna Wade with the neuromuscular business. And we're also, last but not least, at the end, Julie Miller Everett, who runs largely Attruby business here, among other responsibilities here in the U.S.

So maybe what we'll do is kick it off with Tom and maybe talk about what are BridgeBio's strategic priorities for the remainder of this year and going into 2027, and then we'll get into Q&A.

Sure. Yes. Well, thank you so much for having us, Paul. Wonderful to be with you in Miami once again. I would start by saying it's an incredibly exciting and energizing moment to be at BridgeBio. We're transitioning from a single product company with Attruby, which is continuing to show strong momentum and uptake in the first-line setting, which I'm sure we'll spend plenty of time talking about transitioning to a product commercial business, global footprint.

And I think one thing that's getting missed by Wall Street is really what that can do to the top line in the '27, '28, '29 and beyond time frame. I think really just a unique growth profile enabled by that. And so our priority today is to continue demonstrating with Attruby that we have a differentiated product.

So we're 25% a share -- north of 25% share of treatment naive today and growing. We're also seeing good use in the second-line setting, which is also important for patients because if they've not been well managed on a first line, they need to get on a more potent stabilizer. And so our priority on that front is to continue driving that story, driving differentiation. We do it with data. We do it by being persistent out in the field. We do it with strong marketing messages that you've seen so far.

Second, third, fourth priorities are to file our NDAs for the next product. Get approved on time with great labels and launch well. Hopefully, we can spend plenty of time talking about BBP-418 for limb-girdle. Thanks for having Anna here. And actually infigratinib which is now...

I meant to say Scott...

So really, if I step back and put all those things together, like priorities are to continue delivering on Attruby and to continue scaling up to be really, I think, a generational and special multiproduct partner and commercial organization serving the right community.

Okay. Great. Maybe since it's top of mind with investors, let's start maybe with the ATTR market. It's been evolved in the last year from a single player in terms of Pfizer with tafamidis to a multiplayer market in the past few quarters.

And I think one of the key things investors are focusing on is sort of what is the rate of market growth? How many more patients are being identified? And how has this changed versus, let's say, a year plus ago when tafamidis was the only available option for patients?

Yes, Paul. Happy to take that one. So we're incredibly pleased to see the strong growth of the ATTR-CM market. Maybe I'll just break apart the market into the two segments, first line and second line. On the first-line side or the treatment-naive side, before we launched, we were saying that there are about 2,000 to 3,000 patients diagnosed every quarter in the U.S.

Today, there are 3,000 to 4,000, probably closer to 4,000 than 3,000, if I'm being honest, new patients diagnosed every quarter starting therapy in ATTR-CM. So of course, that's a remarkable amount of growth in just a year. We are not seeing any slowdown. I think that we have heard a little bit of rumors about PYP tracer shortage. But we've -- so far, it seems like been able to work through it, at least on the Attruby side.

What's also extremely encouraging to us is our treatment-naive share has continued to go up. And every single month of the launch, we have received more treatment-naive patients than the previous month. That really has been the engine which has propelled the Attruby launch. It's been the key driver behind our momentum.

Now let me turn for a second to the second-line treatment market, which is a very important market, too here, right? So -- these are patients who are on tafamidis, which is a partial stabilizer and who've been progressing and then get put on either Mono Attruby, Mono AMVUTTRA or a combination approach.

And here, what we have seen, this market tends to be a bit more volatile quarter-to-quarter, but we continue to see strong steady growth. I do think that Q4 '25 and Q1 '26, the switch market was a little elevated than usual because VYNDAQEL was being pulled from the market, which allowed more potential switches. For us, I would say we split this market roughly 50-50 with the other players. And what we've also been very encouraged to see in the second-line setting is that our combo use has tripled from Q4 '25 to Q1 '26.

And I think that's really because physicians are recognizing that the most important thing that you can do for your patient is to first put them on a near complete stabilizer. And I think with all the data that's being generated on Attruby as well as the strong label, we've had a lot of receptivity to that message. So that's kind of how we're seeing both the overall growth as well as the two subgroups grow.

Okay. Great. Can you maybe speak to where you're seeing the most utilization of Attruby? Is it more academic centers or centers of hospitals -- heart failure centers of excellence versus community prescribers? Are you seeing preference for one modality or approach? And is that what is driving your NRx share or new-to-brand share?

Yes. Happy to talk about all of that. So we have seen really strong broad-based growth Attruby amongst all HCP segments. So academic medical centers, high-volume heart failure clinics, regional academic centers, community doctors, we've seen strong growth throughout. I think one thing which we've been excited about is that we've been able to unlock a lot of high-volume heart failure practices.

A couple of key reasons for that, right? The first reason is that we have a safe oral small molecule, which is what these physicians are used to prescribing. The second key reason is the fact that we've been able to generate really strong data on Attruby.

And I would like to highlight specifically a couple of pieces of data which have been generated, right? The first is 40% to 50% of ATTR-CM patients have some component of AFib. And these patients are traditionally considered to be difficult to manage patients.

And Attruby, we have shown that is able to reduce AFib-related events by 43%, which is the strongest data that any agent in the space has been able to show. So we've been able to go out and educate physicians on this data. That has given them a lot of confidence to keep the patient in their practice and just put them on a Attruby as opposed to refer them out somewhere else. That's been a big driver for us.

I think another big driver for us has been the fact that we have very, very strong variant data, right? We're the only agent which has shown a stat sig effect on proportionality -- on hospitalization and mortality. We stat sig on so many different things across our programs that I sometimes confuse it. So apologies for that. But stat sig on mortality and hospitalization in the variant subpopulation with the strongest hazard ratio, which has been seen to date in this category, right? And that's also a segment which is extremely underserved today.

And as we build on this with real-world evidence and other pieces of literature, I think our strength is only going to get amplified. So those are some of the things which have driven the impact more than other kind of things that we have done and -- but the growth really has been quite broad-based, which is encouraging.

As we think about where the stock is, I think probably one of the things that's top of mind with investors is how to think about maybe the intermediate-term outlook for the Attruby franchise once tafamidis generics become available following the recent news of the settlement. And so I guess from your perspective, have you seen any, first, changes in the field in terms of physician behavior now that this news has sort of become more public and they know 2031 will be 2032 will be the sort of launch time line for a generic?

And then second, with this revised time line versus sort of what Pfizer had previously been guiding, how are you thinking about the growth outlook Attruby and the ATTR market evolves in the early to mid-2030s?

Yes. So we haven't seen any changes from physicians in terms of prescribing behaviors or anything like that. And that's to be expected. The potential genericization is still almost 5 years away, probably a little more than that away in terms of the price actually coming down. So we've seen no changes on that front.

In terms of our own perspective, of course, we agree with you that the settlement was a bit of an upside, right? Because I think initially, everyone had assumed that the ban goes away in -- Vyndamax ban goes away in '28. Now I think it's at least here until mid-2031, more likely to early '32 when generics -- more generics can actually come in. So that's been a bit of an upside.

For Attruby, though, it doesn't change anything. We've always maintained that Attruby is a differentiated molecule that starts with the label. It's the only near complete stabilizer. It's the only stabilizer which works as quickly as 1 month. Those elements of differentiation really are the core driver of the strength of the molecule today and in the future.

In terms of how we think about it sort of in the intermediate term, I don't think that randomized generics are going to have any meaningful impact on Attruby. I think that by the time this event happens, Attruby will be at peak share, both in terms of patients and likely also in terms of revenue. There's no defined marker of progression in this disease.

So it's very hard to kind of possibly switch patients especially given the fact that the molecule is differentiated. So I don't think that we expect to see any impact from that. We were encouraged because it reduced the error bars of our NPV and it took out some tail risk. So we felt good about where things landed.

And then the last thing that I'll say is actually something that investors have told me, I see some of the ones have told me here in this room, is when you look at other markets like this, right, the prostate cancer market is one which frequently gets brought up to us. When the first to market goes generic, the differentiated second-to-market molecule does not have any impact on our sales. In fact, the sales continue to go up. So that's kind of what we expect to see here. And so we continue to build on that.

You're talking about the ZYTIGA, XTANDI?

Exactly.

Okay. Great. Maybe just a couple more, and then we'll bring Anna and Julie into the conversation. First, where is the market in terms of combination therapy penetration based on your field research? And what pushback, if any, are you seeing from insurers on this for either combined use with your drug or competitors' drugs?

Yes. So maybe I can take that and add on here. So what we're seeing today is fairly low rate of combination use in the second-line setting. We're not hearing really any use in the first-line setting. And as Chinmay mentioned, although we're not primarily out there with message around combination use, our story around differentiation is leading to growth in this segment, which may continue to grow, by the way.

So we're positioned well in case that does happen. And I would say, from an insurance standpoint, certainly, the commercial plans are trying to manage that and avoid that. But for Medicare, right now, it seems not to be much of an issue at all. I don't know if you'd add anything to that.

No, I think that that's well said. Sorry, the one thing that I would add is the combination is not recommended by guidelines, which I think is a key point. So there's no real benefit of combination, which has been shown thus far. I do expect CARDIO-TTRansform will change that, but that's a weak stabilizer and a week knockdown. So it's a little different. And so there's just a few nuances to keep in mind there.

That's right. We have a limited subset from the HELIOS-B study, at least currently undergoing combination use. But on the subject of CARDIO-TTRansform, I think this is the other thing that's top of mind with investors in this category, at least over the near term.

And if the study is positive, which I think is sort of the consensus expectation, the real question being what does the combination arm look like given that it will be a more substantial portion of patients versus HELIOS-B. How does that affect the market dynamic post the potential approval of that combination regimen or therapy for ATTR-CM?

Yes. So happy to talk about that. So I think we agree with you that the study, including all the subgroups, including the combo are likely to be stat sig and positive given the size of the trial and also given the fact that you're using a weak stabilizer in the background, so it's possible to show these kinds of effects. So that's kind of our expectation. That's always been our expectation.

And when we have said that a Attruby peak share will be between 30% to 40%, it considers a 4-player market with this kind of properties for eplontersen. I think that the way this will evolve is combo could be used by more physicians. But again, I think the physicians are going to recognize as they already do recognize, right, that you want to start the patient on the best stabilizer and then put them on the best knockdown also.

And so I think our job is to win the argument to be the best stabilizer. That's kind of where we're focused on. And so I do think that it's not really going to affect Attruby in any meaningful way. I think it's going to make physicians realize that the more you are able to reduce the toxic monomer, the better you do, and that helps Attruby.

As a scientific matter, I'm personally very keen to see some of the relative risk reduction, right? I think we were able to see a 50% reduction in hospitalization at 30 months. We're also able to see a 1-month time to separation on hard outcomes. I'm curious to see where -- what this trial is able to show for the other agents. I think that's going to be informative.

And then the last thing which I'm, again, scientifically interested is just on the safety side, right? Because there have now been many studies which talk about the long-term safety aspects of having the tetramer around. Here, you're going to see this in a larger population of knocking down the tetramer. So what effects do they have? Let us see that.

And some of that also then pertains to the AFib data and other things that we've seen in HELIOS-B. So those are some of the things that I'm scientifically interested in. But commercially, I don't really think it's going to affect Attruby in any way. I think the two stabilizers will compete with each other and the two knockdowns are going to compete with each other.

And just high level to add a reminder that this is primarily a second-line study. We think the impact on the market is going to be felt primarily in the second-line setting, certainly over the next several years. which is an important and growing segment of the market, but much smaller relative to the opportunity in treatment-naive frontline where we continue to focus our resources and continue to see nice share growth.

Great. Tom, you began earlier with talking about your late-stage pipeline and NDAs that you're planning to file. I guess maybe at a high level, can you maybe explain to the audience why you think each of these assets could be blockbuster opportunities of themselves?

Okay. We have 18 minutes left, so I'm going to model on that question. No, I mean, it's a great question. So I mean, I'll make a few general statements that are consistent across the three. These are three areas where you've got a tremendous unmet medical need. So in the case of limb-girdle or ADH1, there is literally no medicine today, a population that is experiencing serious debilitating symptoms or as we'll get to, I'm sure, in limb-girdle, consistent decline of function over time. So there's a real need there.

And in the case of infigratinib in achondroplasia, we have a couple of approved agents, but I think there's a huge unmet need still to address some of the burdens of injecting small children, but importantly, to really deliver in a more meaningful way on efficacy in the way we have with our Phase III data.

So first of all, there's a huge unmet need for us to solve. Second, these are all three conditions that while they're considered rare and orphan are on the higher end, I would say, in terms of Epi, you've got about 2,000 for limb-girdle in the U.S. alone. You've got probably 3,000 to 4,000 in ADH1 diagnosed today, potentially up to 10,000, 12,000 in the U.S.

And infigratinib, you've got 3,000 to 4,000 actionable children in the U.S. All of these have also expansion indications that we could -- that we're looking at to grow the opportunity for us. And so -- when I put that together with the unmet need and I put that together with the likely ability to price very competitively here, given the overall value proposition, I think there's a clear path to meaningful peak year sales for all three of these products.

Great. Anna, maybe on the subject of Limb-Girdle, can you maybe help us understand how many patients are being actively tracked based on claims data here? And how does that stand relative to the prevalence pool that Tom was just talking about?

Yes, absolutely. So as Tom mentioned, we estimate there are around 2,000 patients in the U.S. with Limb-Girdle Muscular Dystrophy Type 2I. Currently, we have around just over 500 genetically confirmed patients that we currently are tracking. And then we currently have ongoing efforts on patient finding. So that is leveraging the data and analytics that supported the Attruby launch as well as sort of deep account profiling with the field teams currently.

And we anticipate here that there is a very engaged patient community already. So the Phase III trial actually overenrolled by around 20% and also 8 months early. So we know that there is a very engaged patient pool. And I think we really anticipate that, that 500 is going to grow relatively quickly.

This week, actually, there is a patient conference that is the patient conference in the U.S. this weekend called the Wellstone Conference. And there, we are doing -- we have a strong presence, and we are educating on three key things. So one is obviously genetically diagnosing patients. So what is your genetic subtype.

The second piece is ICD-10 code. So a new ICD-10 code came in last October. We are seeing that being taken up right now, but we're really encouraging patients to go into their physicians and get encoded correctly to the specific ICD-10 code to the subtype.

And then thirdly, ensuring that patients are engaged with their physicians so that really on day 1 of launch, everyone is sort of -- the patient community is ready for a potential available therapy.

You mentioned earlier genetic identification of some patients, but broadly, how is this in terms of either U.S. or European or other sort of clinical guidelines for identifying patients? Is this something that just becomes emergent as the child gets older? Or are there sort of active guidelines from MDA and other regulatory societies here?

Good question. So basically, in the neuromuscular space, patients can be quite nonspecific -- sorry, symptoms are quite nonspecific. So basically, genetic diagnosis is pretty common as a step in the diagnostic pathway. Limb-Girdle 2i is included in most of these neuromuscular panels or actually all of the neuromuscular panels. So as long as patients are getting into that stream, they will be getting genetically confirmed.

I'd say right now, it is definitely standard of care to be genetically diagnosing patients within these specialized care centers. So in the U.S., there are around 150 MDA centers, which will be driving a lot of the diagnosis. But we are trying to educate to actually increase that outside of just the specialized care centers. So yes, I'd say it's standard of care to be genetically diagnosing right now.

Great. I think when Wall Street saw the BBP-418 data, it was surprised to the upside. I think that's fair to say. But can you maybe share what physicians or KOLs have said in sort of the MD muscular dystrophy community on the data? Specifically, what are they focusing most on? Is it dystroglycans? Any other particular measure? And what has stood out most to KOLs that you might think drive adoption here in the future?

Yes, absolutely. So we presented our data at the MDA conference in March, and it was incredibly well received. So I'd say, overall, the entire data package is overwhelmingly positive and very consistent, and it's pretty much unprecedented in the neuromuscular space. So typically, what people are expecting here is you have a progressive decline and people are hoping to sort of slow decline.

And what we're actually seeing is improvements from baseline and then decline in placebo consistent with the natural history, which is pretty much like unheard of. And so we saw that across all of the primary and secondary endpoints in the interim analysis as well as across all subgroups. So it's not even being driven by just one particular sort of subsegment of the population. It's actually seen across all patients that are in the study.

And we're seeing that across the biomarkers, as you mentioned, the glycosidase Alpha-Dystroglycan, CK, which is a muscle marker of muscle breakdown, but we're also seeing it across the functional outcomes. So breathing and walking, which is pretty much -- which is really incredible.

So the KOLs at the conference and since and also HCPs we've spoken to are really kind of blown away by the data. If you ask a HCP in the space sort of what would you want to see in a theoretical TPP, they actually just don't even describe something that is as good as what we're seeing, and it is anticipated to be driving sort of high adoption rates across really all eligible patients. So yes, I think overall, it's been very, very positive. And since the data has been published, we've been hearing from centers that there has been significant patient outreach.

So I had the pleasure of attending MDA with the team. I can tell you, it was easily the most important data at the conference. And really just to step back and put it in perspective, you have a well-designed, well-controlled trial that delivered stat sig on every endpoint and not only significant effect versus placebo, an improvement from baseline on drug is just something that these prescribers, families, patients have never seen in the muscular dystrophy space full stop. And so to say there's excitement is a large understatement, I would say.

Given what you've just said, what analogy or guidance would you provide to the Street in terms of what the launch trajectory might look like as we as analysts think about things like in the DMD space or SMA space, do you anticipate a bolus? And then how quick is that bolus if there is one? And does it become growth more based on the incidence rate of patients? Or are you thinking about more penetration of the prevalence pool over the near to intermediate term?

Yes. Maybe I can say a couple of lines and then pass it on to Anna to add more color. So we are incredibly excited about the data, and we are extremely excited about the launch. I think just as a reminder, PDUFA here is in -- towards the end of November. So we are actually going to very, very quickly come up to that. The program is also eligible for a priority review voucher, which, of course, also has some monetary value to it. So I just wanted to make sure that was on everyone's radar.

In terms of the launch, we expect a very strong launch. I think that it's not going to be a bolus-driven launch. It's going to be more of a sustained long-term launch. And I think that the initial target is going to be the 500 or so patients that Anna mentioned, we are tracking. So it's going to take us some time to penetrate into those.

And then while that's going on, we're going to be trying to expand that base and grow it out further from there. So I think that's kind of what I would say in terms of that. And it's a little too early for us to provide super specific analogs or guidance, but look for us to do that in a month or 2 months we sharpen our pencils on that. But Anna, I don't know if you want to add anything.

So yes, basically, I agree. I think there's going to be a strong, sustained launch here. We mentioned that there is this like a very engaged patient community, and we know where a lot of physicians and patients are because we have these concentrated -- the concentrated the MDA centers in the U.S. I think the sort of what's tempering maybe sort of an incredibly fast sort of bolus type launch would be that typically, these patients are going to see their physicians maybe once or twice a year.

And so really, we are trying to drive urgency to treat, but that's something that I think the physician -- like more of a change in clinical practice than right now. So typically, right now, patients are seeing physicians are seeing their patients about once a year. So to change that dynamic will take probably a little bit longer.

Okay. [indiscernible] space, one of the things I think investors are trying to figure out is sort of what the U.S. market dynamic look like versus the ex U.S. market dynamic. Historically, we know about 3/4 of BioMarin's VOXZOGO sales have come from the ex U.S. markets. And so as you think about infigratinib more steady state down the road, how does that U.S. versus ex U.S. split look like for BridgeBio?

Great question. So I think for us, we anticipate it being a little bit more even moving forward between U.S. and ex U.S. And part of that, if you take a look at the U.S. market specifically, we know that there's about 3,400 patients that are eligible, pediatric patients eligible with opens epiphyses for therapy. And what we know with VOXZOGO is that the product profile of VOXZOGO has really maximized its potential in terms of treatment penetration in the U.S. today as a daily injectable.

We believe there's about 700 patients on therapy out of that 3,400. We firmly believe that infigratinib has the potential to grow the treated population in the United States. At launch, we're going to be looking at three key patient segments. So first and most importantly, it's those that are not on treatment today. There's a variety of reasons. It could be that the benefits that VOXZOGO showed were not in line with their treatment goals.

This is what we're so excited about. Chinmay actually said it earlier because he's so excited about it, is our stat sig proportionality. We are the first product to demonstrate statistical significant proportionality benefit within a placebo-controlled study in 52 weeks. So we show benefits beyond height, which can help us unlock those who have chosen no treatment today.

Our second segment is those who have potentially tried VOXZOGO but stopped. And then our third segment is those who are currently on VOXZOGO. We do believe that we will see uptake within all three segments in the United States. But similar to what Anna just said, looking at the practice dynamics in the U.S. are also coming in to see their treater about 1 to 2x per year.

So really, we anticipate a wonderful launch through the first couple of years here with a very high peak. I think we've said to you before, Paul, we think it's about $2 billion peak global sales eventually, and we do believe about split evenly between U.S. and ex U.S., which is a different dynamic.

Just on that sort of $2 billion aspirational peak sales or goal for peak sales, is that inclusive of hypochondroplasia? Or is that just achondroplasia?

That's just achondroplasia. Yes. So that's just our primary indication. I'm glad you brought that up. So we do have a very rigorous life cycle plan for the molecule, which we actually started hypochondroplasia in the works right now. And it's funny, you'll hear me say, as many of you I spoke to, I was a Attruby lead for a long time and recently have moved to take all that learning and apply it now to infigratinib.

But one of the things that we learned a lot when we were launching a Attruby was that being second to market also has its advantages because you can deeply interrogate everything that the first-to-market product did learn from their experience.

We are actually really excited to see now BioMarin go out and build the hypochondroplasia market so that when we launch a more convenient option, we'll be able to leverage all those learnings from the achondroplasia launch that's upcoming and apply that to the hypochondroplasia space as well.

I think investors are generally comfortable with the notion of an oral therapy versus a daily or even a weekly injectable probably likely to outperform in terms of market share. But on the subject of hypochondroplasia, Julie, we saw numerical outperformance from vosoritide based on their recent top line data.

Do you expect sort of a similar result here for infigratinib as you prosecute this indication or opportunity? And maybe just how do you think about the data that might be coming out in terms of your pending updates?

Yes. Maybe I'll take a couple and then I'll pass on to Julie to add more color. So Paul, just to set the stage on this. So obviously, incredibly excited, as Julie was mentioning, to see the BioMarin data. I think that it's going to help us -- it's going to make sure that there is a market build, which we can then penetrate into really well. So that's been a big source of excitement for us.

We have seen a lot of excitement in our hypochondroplasia study. Recall, we enrolled this trial even before PROPEL 3 read out, and it enrolled extremely quickly, significantly ahead of our expectations.

Just as a reminder, the team actually has come up with a very innovative clinical design. It's a seamless Phase II, Phase III trial. So we -- once we find the right dose in Phase II, can immediately start the baseline portion of the Phase III and not waste any time in terms of getting this important medication to the children who really deserve it.

Currently, we're in the Phase II portion. We are testing 2 doses, the ACON Phase III dose and a dose lower than that. So I think we're going to have an update on what that looks like some point this year in the second half. I do think that ACON and Hypocon are caused by different mutations.

And so it's going to be key for us to find the right dose here, and we will make sure we optimize that similar to how we did in the ACON Phase II study back in 2023. And so that might involve actually going up the dose also. So we're exploring all of that is coming from our clinical development team as well as KOLs, given the safety profile, which we showed in PROPEL 3. We didn't know that when we started the study.

So that's kind of where we are at right now. I think work's ongoing. But July, do you want to talk more about how convenience is going to be a big factor in [ cypocon ] and how we're looking to just see statig here as the bar.

Yes, absolutely. So as we all know, there's a large portion of the achondroplasia market that is not able to handle injections, and it's definitely not preferred. All the market research points to that being even further more the case in the hypochondroplasia population because it tends to be a slightly attenuated symptomatology. So we do believe that the oral option will be even more strongly preferred in the hypochondroplasia space as opposed to achondroplasia.

Maybe last one, just both for -- as it applies to Limb-Girdle and achondroplasia. Can you maybe talk about how you're going to -- or what you have in place already in terms of your ex U.S. commercial infrastructure how much is going to be direct versus partner or distributor programs for your 2 assets here?

Julie, do you want...

I love this question. So we are very excited to launch this outside of the U.S. So we have built a very appropriate infrastructure. So really what's beautiful about the achondroplasia market, and this is different from our first asset, right, from acoramidis where we did partner this, is that the medical home, the treatment home is very centralized in Europe and other parts of the world.

So you're able to launch this asset with a very highly targeted specialized team that's much, much easier to do than if you're looking at a broader like cardiology space product. So we've hired the right people. We've looked at like a regional structure with also country-specific resources.

And to your very specific question about doing it ourselves versus partnering with like a distributor model, we're taking it on a region-by-region, country-by-country basis. But right now, we have the people, the process, the system and the asset to do this on our own.

And I guess just to add to that, so for Limb-Girdle, we are going to leverage whatever is getting built out for infigratinib, but our time lines are a bit more uncertain. So as a reminder, our strategy here was accelerated approval in the U.S. But because we saw such profound and incredible benefits at the interim analysis, we're now targeting a traditional approval in the U.S. this year with the PDUFA in November.

With the EU, we're currently engaging regulators there to see what our time line could look like to really bring in our European time line. So our European launch is a little bit more uncertain yes.

I know we're almost out of time, but I will just say very briefly, too, that what we're really focusing on is bringing on the right team. So we're hiring people who have launched either other skeletal dysplasia products globally or other rare disease products globally or those who have launched second or third market products and very quickly cannibalize the existing market. So we're putting the right global leaders in place for outside of the U.S.

Great. We're coming up on time. And so I want to maybe ask one more for Tom here to close out, which is that you recently announced a share repurchase program. You haven't necessarily utilized all of it yet, of course. But just sort of as you think about the opportunities internally versus repurchasing your stock, how did that decision come about?

Yes, great question. So I would start by saying the first priority always with every dollar is to fund the business so we can grow and reach patients in the right way. So nothing gets done on the repurchase side if that's not taken care of, and we feel very comfortable with the level of resourcing and the balance sheet today to take care of all of that. I would say just a bit about the rationale there.

So we feel our job is to create value by making drugs that matter for patients. I think we've done a fantastic job doing that. Attruby is out there growing. Next 3, we're very confident are going to be important products out in the marketplace.

Beyond that, we think given where we are as a firm, given where we see the P&L shaping up over the next year or 2, we wanted to have access to an additional tool to capture value when we see an opportunity. And just quite frankly, like when we see the stock go $65 a share, there's an opportunity to capture some value. So we wanted to have access to that tool when the time is right in a disciplined and intelligent way.

Great. Thanks, Tom, and thanks to the BridgeBio team for joining us. We'll end it on that note.

Thank you...

Thank you.

Welcome to the afternoon session on this, our first day of the Annual Healthcare Conference in Toasty Las Vegas. My name is Jason Zemansky, and one of the mid-cap analysts here at BofA. Very pleased to have join me the team from BridgeBio. I have Thomas Trimarchi, CFO and President; and Chinmay Shukla, Vice President, Strategic Finance. Gentlemen, thank you so much for joining us.

Thank you for having us. It's great to be back in sunny Las Vegas here with you.

Excellent. So we'll end with maybe 2 or 3 minutes. So, if you have a question from the audience, we'll pass around a microphone. In the meantime, maybe let's start with a little bit of background for those newer to the story. Can you just give us an overview of BridgeBio and Attruby?

Yes, sure. I can start and maybe pass it over to Chinmay to fill in some blanks. So BridgeBio is a biotech company that was founded just over 10 years ago now, and we were created to do 2 things. One was to deliver as many meaningful medicines as we can to patients in the shortest-possible time frame. And two was to really be focused on things like NPV and cost of capital so we could make our business sustainable, so, we could be around for generations and generations to leave a big impact on the world and hopefully deliver a lot of medicines to patients that desperately need them.

One decade in, 3 approved products, including Attruby, which is our main commercial product today, just reported our first quarter where $180.6 million in U.S. revenue. So annualizing about $720 million in the U.S., clearly on track to break blockbuster status globally this year. And right behind that is a pipeline of products that are post-Phase III now. Actually, the news of the morning is that our second of 3 NDAs was just submitted. So we'll have 3 launches in the coming months.

First, Limb-Girdle Muscular Dystrophy Type 2i, that's BBP-418. Second would be encaleret for ADH1 and chronic hypoparathyroidism. And third would be infigratinib for achondroplasia, hypochondroplasia. Now just to give you a high-level view of what this all looks like from a financial picture, we see Attruby clearly as a multibillion-dollar product. We think it's about $4 billion in peak sales here in the U.S., rapidly expanding market that we think can reach $20 billion. And then I think the next 3 products together can do at least $4 billion in aggregate. So we see $8 billion plus in peak year sales here de-risked and in striking distance in the portfolio.

Yes. And just to build on what Tom said. So beyond the $8 billion, we have expansion indications. Hypoparathyroidism and encaleret is being investigated there. That probably adds another couple of billion dollars to our peak-year sales. And then obviously, we have the hypochondroplasia trial with infigratinib. So I think that 10 years in, I think the company has de-risked $8 billion of peak-year sales and probably will de-risk about $10 billion in a couple of years.

Great. Just to dive right in, you reiterated guidance today and last week during earnings that Attruby could be a $4 billion drug. So maybe can you discuss some of the assumptions here, be it in terms of market growth, the competitive landscape, or the potential of your depleter program?

Yes. Happy to expand upon all of those questions, Jason. So let's first start with the size of the market. So ATTR-CM is a market which is already very large today, and it's growing significantly every quarter. So I think we believe that it's a $15 billion to $20 billion market. We are already at north of 25% share in treatment-naive patients. We think we'll be at 30% to 40% share at peak. This is all based on volume, of course. And we think all of that translates to about a $4 billion or so peak-year sales estimate for the U.S.

Now beyond that, I would say we don't count our depleter program in any peak-year sales estimate just because it's a little too early; it's still preclinical. We're very excited about the program. I think that it's very synergistic with the stabilizer, which Attruby is, right? I think the stabilizer makes sure that you don't have any toxic monomer, which is being formed and being deposited in the heart. The depleter goes and actually clears the toxic monomer already deposited in the heart and elsewhere. So, we think actually the 2 of them can work well together. Of course, more to be seen on that front, and we're excited to likely have it in the clinic next year or early '28.

Got it. So again, you bring up a good point. I guess what would make a prescriber opt for a stabilizer like Attruby versus a Silencer and we may have two on the market in short order.

Yes. I think it comes down to 3 things, right? I think one is the efficacy. If you think about what is causing this disease, it's the dissociation of the tetramer into toxic monomer. So the more you can reduce the toxic monomer from forming, the better you're going to do on efficacy. And actually, this experiment has now been proven out with all these trials having read out. Attruby is the only near-complete product on the market. It's a near complete stabilizer.

So that obviously has translated into really strong efficacy, whether it's -- if you look at the -- when we disclosed our top line data, 50% reduction in CVH at 30 months, immediate increase in serum TTR. What's most profound is separation on hard outcomes like ACM and CVH as early as 1 month. So that, I think, is the first big driver, right, efficacy. I think physicians want to first look for efficacy because this is a deadly disease. The second thing becomes safety. And again, I think given Vyndamax's long history in this category, I think physicians are very comfortable with the safety profile of stabilizers.

Attruby also has a very, very benign safety profile. And so I think that, that's also been very helpful. And then the third thing really becomes convenience, right? I think for many physicians, for many patients, it's much more convenient to take an oral pill. It's safe. You can take it every day. You don't have to drive into the doctor's office as opposed to having to schedule injections, which come with a lot of complication as well as injection-site reactions.

And also, by the way, even with the injection, you still have to take vitamin A every day, so you don't really get rid of the pill burden. So those are the 3 axes that I think is the reason why physicians prefer stabilizers in the first-line setting. And then increasingly, what we are seeing, and obviously, we -- again, I'll just say we've already said that we have more than 25% share in treatment-naive patients. So you can really see a lot of physicians are choosing Attruby over any other product in this category.

Maybe if we could dive a little bit deeper on the efficacy front. You recently indicated you're going to present more data at ESC. Obviously, without giving away too much. Can you frame what we're seeing thus far and how that compares to not only the other silencers, but you're dealing with a gorilla in the room in terms of the other stabilizer.

Yes. So there are really 3 things that I would probably put these ongoing research efforts into, right? The overall goal is to continue to establish Attruby as a differentiated unique molecule in the ATTR-CM landscape. And the first thing that obviously, we've come out with on that front, which we actually came out with last year is the importance of serum TTR, right? And we again reinforced it in the recent presentation. But we have shown that moving patients from Vyndamax to Attruby causes their serum TTR to increase.

You don't see that effect when they move from Attruby to Vyndamax. And then what's most important is we've also seen that every 1 mg per deciliter increase in serum TTR is correlated with about a 5% decrease in all-cause mortality. So Attruby increases serum TTR by about 3 mg per deciliter in the publications that we have shown. That translates to about a 15% -- anyhow that's over Vyndamax. So that translates into about a 15% or so benefit on ACM.

And that story is, I think, the first part of the story, which has resonated. I think the second part of the story, which we got out last year, and we continue to push on is really strong data in key subgroups. So the 2 subgroups, which we've talked about a lot are the AFib patients. About half of these patients have AFib. So the fact that we showed really strong data in that patient population showing reduction in AFib-related events, also has been quite profound and has actually been a contributor to the second wave of acceleration that we have seen.

And then the third thing, which I think we are expanding upon right now is really the unique renal protective effect of Attruby as well as interestingly, a bunch of real-world evidence. So both real-world evidence from independent groups as well as real-world evidence published by Bridge, which kind of compares Attruby and Vyndamax on various outcomes, such as cardiovascular hospitalizations and other items. So in all of these things, we've seen Attruby show a clear and consistent benefit. And it's not really one piece of data. It's the totality of the data, which when physicians look at it, gives them confidence to use Attruby in a lot of their patients.

Maybe let's pivot to the near-term sort of growth outlook. What should investors be thinking about as they update their models heading into 2Q and the rest of the year? What dynamics, either tailwinds, or headwinds might the Street be overlooking?

Yes. So I would say the tailwind would be simply that we continue to drive growth in the frontline setting. So we've, from day 1 in this launch, been focused on gaining share and positioning Attruby as the first-line go-to agent of choice, maximal potency, near complete stabilization in the disease driven by destabilization of the tetramer. So we've grown share up to north of 25% through today.

And I think we'll continue to do that into 2Q while the market expands. Now at the same time, we've seen roughly a splitting of second line overall with the knockdowns. And interestingly, this is a more recent trend.

While combination use is a relatively small piece of the market, our share there has grown 3x in the last quarter. So increasingly, that tells us that physicians are believing that Attruby is the best stabilizer. And so when they want to reach for a combination, they're putting the best stabilizer on plus whatever knockdown they have available to them.

What about the potential for further acceleration? I know one of the hallmarks of your patient assist program is 30 days free drug. As those patients start to become paying customers, what kind of boost and how do we model that moving forward quarter-to-quarter?

Yes. So as we discussed early on in the launch, this really is more of a timing from demand to revenue issue where when you first receive a script, if it's a fill using the first month free, it's simply 1 month delay until you start getting a paid script that translates into net sales. And so that was a much bigger impact on quarterly numbers early in the launch than it is today. The program is still very popular, although in any given period, fills that are new starts are a smaller and smaller proportion of total volume. So less impactful today than it was a year ago. Next quarter and the following quarters, it will be even that much less impactful.

What gets you more into some of the prescriber offices? Is there a friction point at this point? Is there something unsettled? Same with community prescribers? I mean, how do you reach those who either aren't treating ATTR patients or alternatively are reaching for the silencer first?

Yes. That's a very good question, Jason. I think it comes down to 2 or 3 things, right? The first is it takes time, right? It takes time for us to go visit everyone to make sure that the systems are wired and to get the physicians comfortable with using Attruby.

What's interesting is we have noticed that once a prescriber starts using Attruby, they're actually quite likely to keep using it and use it in more and more of their patients. So we've only been out there for about a year or so.

So I definitely think that's the first angle. I think the second angle is it takes a little bit of time also for the data that we generate to really be out in the community. For example, the serum TTR data as well as the Afib data, which I talked about a few minutes ago, we generated that kind of Q1, Q2 of last year. And really the acceleration that we saw in the PSS, which we were -- we used to report under February was really in Q4, really in Q1 of this year. And so that's still a 6- to 9-month lag. And that's just because we have to go to a conference, present it, make sure that physicians actually know the information.

And then as our salespeople always remind us, we have to tell the physician 7 times before they retain that information. And you start to drive some of the changes in behavior, which are very important here. So that certainly is also an element.

And so we do expect that as we get more real-world evidence data as we get more of our kidney protection work out there, we'll be able to talk about it with physicians. And as there is more awareness, eventually, it will lead to an increase in -- further increase, I'll say, in treatment-naive patients as well as switch patients being on or should be.

Maybe one on the -- probably one of the biggest overhangs until recently, the IP case going on with one of your competitors. When you were discussing this in last week's call, you indicated this added confidence to that $4 billion peak potential number.

I guess, can you, A, talk a little bit about when you expect sort of to reach that peak market share? And then B, in terms of the payer response once a stabilizer becomes generic, and what's the impact there? And again, gives you confidence that it's really not going to be as big a hit as I think some of the more concerned investors were?

Yes. Happy to touch upon both of these points, Jason. So in terms of peak year sales and when do you reach time to peak and all of that, the way I always think about it is we already know that we have north of 25% treatment-naive patients today. Our goal, we have said is 30% to 40% there. So in terms of patient volume, we've made a lot of progress already. It usually takes a few years for that to translate into peak year sales.

And that's kind of why on our call, we mentioned, given the fact that we now have 7 years or so for Attruby to truly be on the market with only a branded stabilizer competitor, we feel like we will be in a very good spot and kind of reach peak by that time, maybe with some room to spare. So that's on the first piece. And that's one of the big reasons why we feel very confident about the error bars on our valuation, as we say, as having narrowed quite a bit.

The second thing, which I would say in terms of the payer response, we don't really see this category as being highly managed. The first thing is Attruby is a differentiated product. And you can see that in terms of despite having an incumbent on the market within just a year, more than 1/4 of new patients are started on Attruby. That tells you that we've been able to overcome a lot of resistance from physicians, which really is because they do view the product as a differentiated and unique product, which is right for their patients.

So that, I think, is the first part, which gives us confidence on the payer side. And then on the second side, what I would say is if you map just the ecosystem dynamics, given this is Part D and a lot of volume flows through specialty pharmacies, usually, you don't see any difference to the patient cost as well as to there's no real incentive that we would see negative incentives.

So that's on that piece. And again, what I would say is it's fine to talk about it on a theoretical basis, which we're happy to talk about. But if you just look at analogs such as the prostate cancer market with ZYTIGA or Gleevec, you can see that when Part D -- first to market, Part D molecules go generic, the second to market, definitely the second to market, more differentiated molecules, don't see any really hit to their sales. It's really the growth rate maybe slows down a little bit. But as we were just discussing previously, we think we'll be at peak by then.

Excellent. Well, you have a rich pipeline. So I'm going to -- let's switch to that, Jackie, from the team.

Yes. So let's pivot to BBP-418. So from a commercial standpoint, can you discuss the efforts to identify the roughly 7,000 patients? And is this likely the biggest challenge?

Yes. Great question. So just to start with a little bit of background. So BBP-418 is an oral small molecule for a disease called limb-girdle muscular dystrophy Type 2I. We think there's about 7,000 patients between the U.S. and Europe and probably another 2,000 that are actionable with this molecule in Japan. So fairly large in context of other types of genetic diseases. And you're spot-on. I think much of our effort today in developing this market and shaping the market is focused on creating awareness that there's a drug coming so that there's some urgency to get in.

If you're not genotyped, get in your office -- get in your physician's office and get a genotype test because that will make you eligible for therapy when we're approved. And two, I think just driving awareness of the remarkable data that we've delivered from the Phase III study that read out last fall. I think it's worth taking a moment to rehash a bit of that. So this was a placebo-controlled randomized Phase III study in patients with limb-girdle 2I.

We read out what was meant to be a 12-month interim readout, mainly focused on a biopsy-based biomarker that was meant to demonstrate that this biomarker is a surrogate. And what we saw surprisingly was statistical significance on every endpoint we looked at, including all of the functional endpoints, including the -- what was meant to be the full approval endpoint, the North Star test as well as walk and other function-based endpoints, all at 12 months.

Not only that, but patients who received 418 actually improved from prior to starting therapy. So a really profound effect here and a data set that is really unique in context of what's been shown to date in any type of muscular dystrophy. So we were at the major conference in this space, MDA in March. I think it was one of the most important presentations at that conference.

There was a hugely positive response from the KOL community and a huge amount of inbound either from patients to their prescriber or directly to us through advocacy groups on the back of that. So we've got great momentum, great product, but there's still work to do over the next couple of months to continue expanding our pool of diagnosed eligible patients and driving awareness and urgency to act when we do get that FDA approval.

Yes, you bring up a great point. I think the FORTIFY study, you were meant to have an additional 24 months of analysis in order to evaluate the North Star, this metric that tracked function. Absent that data or as that data is still evolving ahead of a likely your submission and then potential approval, is that going to affect things at all? Do you think some docs are waiting for the kind of final read-through? Or is it potential that we might see even better data as there's greater exposure and kind of maintenance of some of the function?

Yes, great question. So I don't think physicians will be waiting to see longer-term data here. I think these data are very convincing and really unlike anything they've seen in caring for certainly limb-girdle patients, but patients of all types of neuromuscular conditions, quite frankly. And so I think the fact that we were able to see such a robust and rapidly occurring effect, not on just one endpoint, but all of the endpoints, right? We had FVC. We had North Star.

We had a walk-based endpoint as well as all of the biomarkers like CK and the biopsy-based endpoint. I think it is as convincing as the data set can be. So I think there'll be -- I think physicians will want to use this drug as soon as they are able to have access to it. Now there is one question around whether we would receive accelerated versus full approval and that has some implications on what happens to the ongoing 3-year endpoint here.

And personally, I don't see it as ethical to continue the study given the results to date, but unfortunately, it's not up to me. And so we'll be waiting for some feedback from FDA on this. But our base case is that the study will continue and that we'll get approved on an accelerated basis and complete the study.

Let's pivot to encaleret, ADH1. You announced this morning that you had submitted the NDA for FDA approval. I guess one of the biggest inbounds we're getting here is what gives you certainty that the market for ADH1 is 3,000 to 5,000.

Yes. So as we think about encaleret and especially in ADH1, there are really 2 factors which give us confidence on the $1 billion estimate, which we've put out for peak year sales. On the prevalence side, I would say we have already identified almost 2,000 claims analysis patients. And as we drive further diagnosis, whether that's through screening, we sponsored genetic tests for patients. And the guidelines say that if you have nonsurgical hypoparathyroidism, you should get tested.

And almost 1/4 of the patients are positive. So that's been a big source of new patients which we have found. Another thing is, given we have claims, we've been able to leverage a lot of machine learning and artificial intelligence tools to further identify patients. And then the last thing is we've been doing sort of sponsored testing at family events because this is an autosomal dominant disease.

And so if you find one person in the family who has it, it's quite likely that there are other people in the family who have it. And so I think that that's been another source. And of course, all these sources will just accelerate as we get on the market. And people actually feel better and are benefiting from the drug because then they have even more incentive to, for example, tell their family members that, hey, not only might you have this, but there's this wonderful drug, which can probably help you a lot.

So that's kind of on the prevalence side, where I do think that we have about 2,000 patients in claims today. And as we keep up with our efforts, that number should only go up in terms of patients who we've diagnosed who can be on therapy, ultimately probably reaching close to that 12,000 number is the prevalence. In terms of the price, though, because that's the other big component here, right?

And I think that just given the high unmet need in this patient population and given the complications here as well as just given the profound data that Encaleret has generated with more than 3/4 of the patients normalizing their disease. That's pretty remarkable. I mean you don't really see data where disease is not just stabilized, it's actually reversed it, right? So you've kind of normalized the whole thing. So I think that, that means that we are set up well for really premium pricing here.

And so normally in these settings, what we tell people is CRYSVITA is probably on the low end. And EXONDYS is probably on the high end. But you multiply -- it's a pretty good range for pricing, multiply the patients you already have today with that kind of price point gets you very close to that $1 billion number.

Yes, I would say for both limb-girdle and ADH1, we're more and more confident every day that these can both be $1 billion-plus products for us here. When you consider the strength of the data we reported plus everything we're learning out in this market between response for advocacy, response from KOLs, and just the patient counting that we're able to do now that we're out there in a more of an organized way developing this market, I think we -- our confidence is growing.

You bring up a good point. As you expand into the chronic hypoparathyroidism indication, the number of patients there are about 200,000, about tenfold more than what you see for ADH1. So in terms of pricing, I mean, both indications you've indicated could be a $1 billion opportunity. Does that mean that you'll maintain sort of that premium pricing and look towards maybe, those who are underserved by the analogs? Or is there something else in play here?

Yes. So of course, the $1 billion we saved for encaleret is just for ADH1. It does not really include the HP opportunity at all. So I just want to make sure that we start there because it's important. Second, in terms of pricing, the way we think about it is we're going to first launch in ADH1.

That's the community we have an opportunity to serve here at the start. So we are going to price it kind of thinking about that community. In the future, my hope is we certainly get the opportunity to serve the HP community also. And at that point, we can look at the pricing, but we also have to look at the data, which we've generated before we think about pricing.

And then the other thing which I'd say is, look, it is an oral option, which convenience is a big factor, and it also has some unique benefits in HP in terms of normalizing both blood and urine calcium. So premium pricing is not unjustified in any way. But let's first look at the data and then decide for now, I would say, let's just think about ADH1 for the pricing side.

One quick one on infigratinib. Obviously, the data PROPEL 3, very strong. But if you talk to most physicians, height is sort of less of a factor than the medical sequela of the disease. At the same time, there are some concerns about the MOA just given the history of the molecule.

So do you think that prescribers are going to wait and see what both the kind of the longer-term endpoints and the longer-term safety are going to look like before feeling comfortable here? Or do you think that there's kind of strong adoption point just given the convenience of the pill?

Yes. So I think really, it's 3 legs on the stool that make this a really exciting product. One, first and foremost, is the efficacy we've seen. So category-leading effects on the primary endpoint, which is change from baseline in annualized height velocity, which is not the most important health issue for these children, but it is a marker of potency here.

Second, we've seen, for the first time in this space, a statistically significant effect on proportionality, which suggests in a time frame that's relevant to these children and their parents, they should expect to get some benefit on functionality, physical function due to the disproportionate short stature of this condition. So that's efficacy. Second, the convenience of this product when you compare it to a daily injection or even a weekly injection is a huge deal here.

These are children that will be treated from the time they're toddlers at first and then eventually we will get all the way down to infants through when their growth plates close, which can be as late as 18 years of age. They really want something that's more convenient, easy to give, less conspicuous is something that matters also. It makes them feel -- sometimes we've heard from the community that the fact that you have to have your pen with you and always have an injection if you're at summer camp or something, it makes you feel different, which is not always something children want to feel.

And third is safety. I mean, as far as I can tell from reviewing all the data, infigratinib in the large Phase III and all of the Phase II data to date has got the best safety profile. So it's kind of like what more do you want? Can safety, great efficacy, best form factor and route of administration.

Got it. Maybe we have time to squeeze in one more, and naturally, it will be complex and difficult to answer. But you've had an amazing run of success in terms of the clinical output. That said, you're looking at 3 nonoverlapping launches. How do you manage these at the same level of execution that you've hit with Attruby?

Yes. So first, I would start by saying we're privileged to have tremendous leaders across the board here, Matt Outten, that leads our commercial team, but also the CEOs that sit on top of each of the affiliates who we're about to launch these products are really remarkable, leaders and operators and colleagues. So I think that's crucial here. So a great team. Second, yes, they are in distinct conditions, but we do benefit from some of the more general commercial infrastructure that we could spread across where we've already demonstrated excellence.

So access, for example, or hub services, these kind of things, one team that gets deployed across products. So there's some efficiency and synergy there. And then I think we benefit from having a very close and dedicated relationship with each one of these prescriber, patient communities, advocacy communities at the level of each asset.

So we already have a strong foundation to build upon. And so from here, the -- really, the lift is just bringing on sales forces for each one of those products, which are relatively small and manageable and of course, field medical. We're in the process of doing that right now.

Excellent. Tom, Chinmay, thank you so much for joining us.

Thanks, Jason. The floor is yours.

Good afternoon. I will be your conference operator today. [Operator Instructions]

Before we begin, I would like to remind everyone that today's call may contain forward-looking statements within the meaning of the federal securities laws, including, but not limited to, statements about BridgeBio's future operating and financial performance, business plans and prospects and strategy. These statements are based on current expectations and assumptions that are subject to risks and uncertainties, which could cause actual results to differ materially from those expressed or implied in these forward-looking statements. For a discussion of these risks and uncertainties, please refer to the disclosure in today's earnings release in BridgeBio's periodic reports and SEC filings. All statements made here are based on information available to BridgeBio as of today, and the company undertakes no obligation to update any forward-looking statements made during this call, except as required by law.

With that completed, BridgeBio, you may begin your conference.

Good afternoon, everyone, and thank you for joining BridgeBio Pharma's First Quarter 2026 Earnings Call. I'm Chinmay Shukla, Senior Vice President, Strategic Finance. With me are Neil Kumar, our CEO; Matt Outten, our Chief Commercial Officer; and Tom Trimarchi, our President and Chief Financial Officer.

On today's call, Neil will walk through our commercial pipeline and business updates with Matt providing additional promotion detail and Tom covering financials. Following our prepared remarks, we will open the call for questions. For the Q&A session, we will be joined by Ananth Sridhar, Anna Wade and Justin To, who will lead our programs with encaleret, BBP-418 and in sorafenib, respectively.

With that, I'll turn it over to Neil.

Thanks, Chinmay, and thanks, everyone, for joining us today. As always, this is a form in which we communicate sale and aspects of our business center of interest to investors, and we welcome your questions and feedback along the way.

I want to spend the bulk of my time today talking about 3 things. The first is the Attruby franchise, and I want to talk about our continued commercial momentum there and how we think about clinical differentiation. Importantly, these 2 things plus the economics associated with the RD orphan drug channel underpin our confidence that Attruby will continue to grow even past 2032.

The second thing I want to discuss is launch readiness against the 3 exciting first-in-class or best-in-class brands we have in AV H1, LGMD2I and achondroplasia. Although there are no major near-term clinical catalysts for any of these brands, there is a tremendous amount of activity going towards ensuring expeditious and high-quality approvals and launches. In its history, BridgeBio is demonstrated across now 3 approved products with hopefully 3 more to come, the ability to take on post Phase III regulatory submission activities at very high quality, and we intend to build on the tradition for these new brands.

I'll end my comments by addressing the current gap between our intrinsic value and where our shares trade today. I've heard from investors in the past that too much NPV talk. It's not what people tune into these calls to hear. But at this point, it is my responsibility to discuss matters related to capturing the value that investors who have been in our stock for a long time have helped create.

Our focus on BridgeBio has always been a long-term value creation and on reliably being able to take in money to do more work over time. And by the way, our activities across the BridgeBio ecosystem show that there are many more of these R&D opportunities out there. but this model is reliant on capturing the value of the work for investors, which is why today, I'll be discussing a share buyback program that will commence immediately.

Let me begin my comments by talking about Attruby. As many of you have read in the press release, we've had 186 -- we've got $180.6 million sales in U.S. Attruby net product revenue this quarter, which represents a 24% growth from the last quarter and a 392% growth year-on-year and is consistent with the brand globally becoming a blockbuster in 2026. Our focus continues to be on winning in the front line, where we believe the 95% stabilizer that preserves the native tetramer is not only the optimal solution but even against combinations is the only solution 1 you start with as it provides the highest degree of management of TTR monitor deposition provides impact more quickly and is consistent -- which is consistent with the pharmacokinetics of TTR stabilization and ultimately achieves all of this in a cost-efficient and easy-to-access manner.

Trenthetically, our data suggests a tripling in combo use with Attruby with the various knockdowns, suggesting that the message that once you reach for a better stabilizer even in combination is resonating. As it relates to the front line, our major competition continues to be Poser and our best understanding of our share is that it has grown from the NBRx share I quoted at the JPM to even further more, but still remains behind what Poser has been able to accomplish in the front line. We believe that in this quarter, total new patient starts in the category were in excess of 6,100 new patients, and we believe that for the first time, we are convincingly the second brand by volume in this space. There's more work to be done, but all of these trends continue to be in the right direction for us.

So how do we port some gasoline on these growing sales? The obvious way to do that in normalized is through clinical differentiation. We began to see reasonable inclines in the second derivative of our growth as the serum TTR story began to evolve in the marketplace with multiple papers adjusting the iron levels of serum TTR associated with lower levels of mortality at 30 months. As a reminder, every made per deciliter of incremental increase in serum TTR seems to lead to a 5% decrease in mortality risk at 30 months, meaning a more potent stabilizer and we do not hear from any physicians equivalent with the fact that Attruby is a more potent stabilizer it is, should lead to better outcomes for the patients that we serve.

Building on that, we are now beginning to explore and are confident in the outperformance of acoramidis versus diamides in the real-world setting. There were only really 2 real-world evidence studies reported to date, survival studies done in Colombia and by Dr. Masri that showed outperformance of acoramidis both but those were comparing our trial data and not at that point -- we didn't have enough time at that point to be in the market long enough to demonstrate anything in the plastic real-world evidence setting. That is now changing.

At SCAI, an independent wheel world evidence study presented by the Valley Health System of Nevada revealed statistically significant outcome improvements associated with acoramidis as compared to tafamidis. Building on this, we have a study in Med Archive that we will publish shortly in a major journal, showing that Attruby reduces diabetic intensification by 43% as compared to tafamidis. We intend to continue studying and publishing on Attruby's differentiation in the real-world setting and are glad to see the cardiology community doing so independently.

Interestingly, 1 of the benefits of acoramidis that was identified in the independent real-world evidence study was a lower incidence of acute kidney injury. As I mentioned in my JPMorgan talk, we are driving towards what we believe will be a seminal publication with potential impact for patients, physicians and even on our label as it discusses an observed rapid hemodynamically mediated renal protective effect, which is unique to Attruby as opposed to the other stabilizers and knockdowns in the space.

We continue to present and publish on a parameters and major medical meetings as well. At ACC recently, we've presented long-term efficacy and safety data from our Phase III open-label extension showing sustained clinical benefit from acoramidis at Monty 54, including a remarkable statistically significant risk reduction of 45% in all cost mortality with a p-value of less than 0.0001 and a 49% reduction in cardiovascular mortality, again with a similar fee value versus placebo tuspamidis or acoramidis.

All right. I'd like to turn to the rest of the pipeline now. On LGMD2I as I alluded to in my earlier comments, our team was able to go from top line unit to NDA submission in 155 days, consistent with our ethos at every many counts and the fast pace that we have previously set with regard to our TTR regulatory submissions. We continue to work closely with the agency and foreign regulators to bring this medicine as expeditiously as possible to the patients who need it. I had the opportunity to attend the top line result presentation recently in Orlando at the FDA meeting. It was a trip I won't soon forget. I was struck by the excitement that our data generated, not only within the LGMD2I community, but more broadly, given the striking results associated with BBP 418 suggests that functional improvement is possible when targeting well-described conditions at their source.

Given the already 500 or so genetically confirmed patients in the United States today, the highly engaged patient community and physician education being conducted by the team, all of this augurs well for a positive launch dynamic.

Moving to ADH1, I'll be leaving from here to a very similar gathering on top line presentation of our calibrate Phase III data at the European Congress of Endocrinology in just a matter of days. Here again, we'll be looking to drive segment the broader physician community and to educate the patient community and establish a base of data that together with our publication of our Phase II data can ensure the market building exercises can continue with high fidelity.

Importantly, BridgeBio has been supporting via grant family genetic testing events in the United States that continue to identify new patients with relatively high yield, although we have been launching at a time when a vast majority of patients with ADH1 have not been identified yet. The combo and genetic testing, ICD 10 cos and broad disease awareness education such our belief that we will be able to find ever more patients in need of this compelling drug products.

Furthermore, our Phase III and choice thyroidism will be commencing this summer and is bolstered by a recent published work that illuminates the central role of the calcium sensing is after in the kidney plays in regulating calcium metabolism.

Finally, moving to achondroplasia. The results from this trial came after LGMD2I and ADH1, but I suspect given the strength of the results prominence of the condition and the remarkable KOLs we're privileged to partner with that the Phase III manuscript will be forthcoming in a major medical publication, and we anticipate presenting the full PROPEL 3 data set and a medical conference in the second half of 2026. Early commercial research shares suggest unaided awareness in excess of 40% from this the prescribing physician community, which for those of you who are commercialized know is a very high starting point and certainly higher than what we've seen before in our own portfolio.

Finally, I want to touch on the share repurchase program that we announced today. To do so, I'd like to go back to BridgeBio's founding principles. The company was built on a few things to help as many patients as possible and to establish a corporate and financial model that creates and captures value in predictable responsible ways. That value capture has always been part of the mission when we talk about NPV, while we anchor to intrinsic value while we try to make the right economic decision at every part. The reason for that is because of the capture value, more capital flows into drug development over time and more patients get served by us and others employing our decentralized diversified model. Unfortunately, at this moment, we have not adequately captured value for the investors we serve given the large distinct between our NPV per share and our firm's intrinsic value. Even with the revision of Vinda Max's entry from 2035 to mid-2031 or early 2032, our in intrinsic value remains markedly higher than where we've been able to get the shares to trade to today for investors.

To that end, the Board has authorized a $500 million share repurchase program. These repurchases should allow our shareholders to concentrate their ownership in our portfolio whose risk profile has fundamentally improved. Of note, we have employed this technique in the past some 6x.

In aggregate, even accounting for the free part day buyback, we have driven substantial returns for investors with our share repurchases. While we have this lever, we still believe in putting capital into our launches and advancing our clinical trials, repurchases are additive and opportunistic, not substitutive and are a direct result of our strong balance sheet.

On the balance sheet point, we will always size deployment such that we preserve full flexibility to finance every critical program and activity in our portfolio. Plenty of liquidity and the ability to easily service our liabilities is a requirement before we deploy dollars into the buyback.

Okay. With that, I'll turn the call over to Matt to talk more about our commercial leverage.

Thank you, Neil, and good afternoon, everyone. Q1 was another strong quarter for Attruby, delivering an impressive a 24% increase in net sales from Q4 and a 392% year-over-year increase from Q1 2025. Growth was driven by our existing and expanded sales teams, accelerating new patient starts and first-line share gains. There are several factors which contributed to these results. Market momentum has remained strong new-to-brand market share hit its fastest quarter-over-quarter growth since Q1 2025 and first-line patients have increased each and every month of the launch. Fill rates, cap rates gross to net, compliance and persistency all continued to remain in line with expectations. Insurance reauthorization dynamics has been a topic of industry discussion this quarter, and I want to address them directly. Attruby did not experience reauthorization disruptions for 2 reasons. Part D as in David is a continuous plan-based model, which avoids the annual renewal friction of Part B as in Boy. That structural advantage matters. In addition, in 2025, the average co-pay for Attruby patients was only $190 for the entire year, making many patients pay only $0 out pocket as well. Our field teams executed with exceptional discipline to keep patients on therapy with valve interruption. We hire exceptional people and those people make sure that any patient who wants a near complete stabilizer can get a truly and importantly, and stay on Attruby.

Turning to our pipeline. We are encouraged by early indicators across our 3 anticipated near-term launches in LGMD2IR9 ADH1 and achondroplasia. In LGMD2IR9, we are entering a disease area where no approved therapy exists. We've onboarded a commercial leadership team and have set up a specialized patient identification and field reimbursement infrastructure. Our goal is simple, to find every patient who can benefit and be ready to serve them from day 1 of approval.

In ADH1, our claims analysis has already identified nearly 2,000 patients in the U.S., and that number continues to grow. We've built a dedicated sales leadership team and patient infrastructure tailored to this community. Encaleret would be the first medication to target the disease mechanism directly and it's orally administrated Position excitement is high, and we are ready to move immediately at approval.

In achondroplasia, we are preparing for a global launch with a truly differentiated clinical profile infigratinib is the first medication to demonstrate statistically significant improvement in body proportionality, not just improvements in average high velocity and the only oral auction in the category. For family seeking an alternative to injectables or returning to treatment after a negative experience, the clinical profile and route of administration of infigratinib is very compelling.

To summarize, Q1 continues to reflect a durable growth trajectory for Attruby and proof of the commercial capability we've built at BridgeBio, an organization that knows how to launch, scale and build franchises. We remain focused on execution for patients, for families, for prescribers and for long-term value creation.

I'll now turn the call over to Tom.

Thank you, Matt, and good afternoon, everyone. I'll now walk through our financial results for the first quarter of 2026. Our commentary will focus on GAAP financials unless otherwise noted.

Total revenues for the first quarter of 2026 were $194.5 million compared to $116.6 million for the same period in 2025. The $77.9 million increase was primarily driven by a $143.9 million increase in Attruby net product revenue. Attruby product revenue in the quarter was $180.6 million compared to $36.7 million the same period last year. Royalty revenue increased by $9.3 million to $9.5 million, primarily earned from net product sales of Bandra in Europe and Japan. License and services revenue was $4.4 million compared to $79.7 million for the same great last year. The decline reflects the recognition of onetime $75 million regulatory milestone for the prior year.

Total operating expenses for the first quarter of 2026 were $290.5 million compared to $218.4 million for the same period last year. The $72.1 million increase reflects deliberate and disciplined investment in Attruby and preparations for our 3 upcoming launches.

SG&A expenses were $163.9 million an increase of $57.5 million compared to the same period last year, reflecting measured investment in our core activities. R&D expenses were $126.6 million an increase of $15.2 million driven by investments in medical affairs and CMC in support of our next launches.

Turning to the operating line. In the first quarter, we recorded a $106 million operating loss. For the last 5 quarters, our loss from operations has narrowed by more than 50% due to OpEx discipline here with strong execution on Attruby.

Looking at the quarterly trend, if we back out onetime milestone payments, we've seen an improvement in the operating line every quarter since it truly launch.

Looking ahead, we expect the trend new loss from operations to flat over the next 2 quarters as we ramp up launch trading activities for the next few products and continue narrowing towards the end of this year to 2027, we transitioned to a P&L breakeven followed by cash flow positivity, which we expect to be sustainable for that going on.

Turning to the balance sheet. We ended the first quarter with $940.2 million in cash, cash equivalents and marketable securities compared to $587.5 million at the end of last year. We believe our current cash position provides us with significant runway to fund our operating activities advance our programs for the approval launch and continue to invest in truly portion growth, all while maintaining financial discipline we demonstrated to date.

With that, I'll turn the call back over to Chinmay.

Thank you, Neil, Matt and Tom. Operator, please open the line for questions now.

[Operator Instructions] Our first question comes from the line of Tyler Van Buren with TD Cowen.

Hello. This is Sam on for Tyler. And congrats on another strong quarter. I was just wondering, can you guys talk about what's driving the continued Attruby acceleration and specifically what you're seeing in those treatment-naive patients?

This is Matt. I'll take that one, and thanks for the question. We're definitely excited about the continued performance of Attruby. I think the acceleration you're referring to is being driven by a few things. The first is physicians' desire to use the only near-complete stabilizer on the market. Stabilization is the backbone therapy in ATTR-CM and near complete stabilization along with the truly speed and showing separation from placebo is attractive to patients and HCPs. They want something that's going to work quickly and it truly has shown that it can do that. And recently, as you heard from Neil in his original remarks, the real-world evidence has backed all of these points up for both the treatment naive patients and switch patients, and that's helping to drive our share upwards.

Yes. Maybe the only thing I'd add there is the serum TTR story, I think you saw a bevy of papers both from us, but then importantly from others, using the numbers that I put forth the projector increase associated with pretty remarkable decreases in mortality, downstream. And obviously, as a reminder, when we put patients on a Ramatis following administration of tafamidis coming out of our Phase III trial, you saw 3.4 per deciliter increase and everyone increased their serum TTR level. So it doesn't really matter how you measure it. You're just getting increases in serum TTR.

And the question outstanding was never, I don't know, Matt, if you'd agree with this, whether or not at amass a better stabilized or I think most people can understand that even if they can't understand a specific in vitro assay. And the bigger question was how much more is that buying me in terms of downstream results and these TTR work was just the first part of that you're going to see a lot more of that in the coming 12 to 24 months really just because we have enough patients now with not duration that we can start to ask and answer those questions.

Our next question comes from the line of Mani Foroohar Leerink Partners.

Congrats on the results. In the aftermath, the tafamidis IP evolution and some clarity on genericization of gas, not of acoramidis. Walk us through operationally how you think about the development and commercial strategy for revenue in the 2031, '32 and beyond.

Mani, thanks for the question. So the clarity on Redman's idea is clearly a meaningful positive for Bridge and Attruby. We now have at least 6 years of runway before generics, which is more than enough time to reach peak share. And obviously, this all materially reduces any tail risk we will have to the NPD program. I don't think the resolution really changes our commercial strategy. We've always been focused on establishing a true the treatment of choice in RCM, given its differentiated profile, and we're executing against that. I think you heard both Neil and Matt talk about the value of literature that we are producing as well as all the commercial activities which we are undertaking to really reinforce that differentiation and drive share. I guess what I'll say at the end is just -- we've shared our belief that Attruby will be a $4 billion drug last year in our Q1 25 earnings call, I don't think you've ever been more confident in that estimate. I actually think if anything, there might be some room for potential upside. I think as Neil mentioned in his prepared remarks, Attruby likely to keep growing even after 2032, given the ecosystem and channel dynamics that exist here with Part B. And so that's kind of what's driving our confidence. So yes, I think it's working for us. We've reduced the area on our valuation.

Yes, maybe I'll add to that. I mean, I personally did think Mani and we talked about it that it would be 2035. So obviously, I was wrong on that. That is a little bit of a discount, but not material, as I mentioned in my comments, and the bigger thing is like all of these differentiating studies that we're running, it is really starting to resonate with clinicians in addition to the fact that the access programs are superior. So I guess what your question is really alluding to is like will we run a double line head-to-head. We still might Were the option to do that. Certainly, we've been excited to do that in the context of either TTR levels or NT-proBNP. But how we size like a hospitalization study is difficult if you look at the number of events. We're going to have a strong look at the placebo arm of the upcoming poison trial to really understand what those event rates look like in the context of clinical trials to see if there are some double-blind headed opportunities. But there's nothing obvious right now. So let's continue on the real even studies, which I think are the best honestly, characterization of sort of differential competitive dynamics.

Our next question comes from the line of Biren Amin with Piper Sandler.

Can you walk us through the Board's decision to authorize the $500 million share repurchase program and how you're thinking about balancing that against your investment in new launches and pipeline? And I guess what, if any considerations are there for additional business strategic initiatives with this share repurchase program now being announced.

I'll tick that off. I mean I think right now, the focus is on focused execution against the pipeline that we have right now. We've got in discussions with investors ample growth that has not been valued in the context of this company to date. I mean the LGMD2I launch that I referred to, the AH launch, the AECOM launch even as totality, I think we're projecting market share numbers well in excess of what typically a third mover gets in that space. And then you think about the consequential additional indications, both in terms of hypo and importantly, in terms of chronic hyperthyroidism that we're kicking off. And then we've got the Canada program. So that constellation of activities is more than enough to drive long-term growth for any company, and that's kind of what we're focused on. Can we fully finance all of that comfortably, and we feel like we can. And therefore, beyond that, what all we do with excess capital and we think the best relative in terms of relative return way that we can deploy capital right now is into our own chairs just given the disconnect between intrinsic value and where we're trading. So that's really what the discussion came down to. It's hard to -- I know the normal way that biotech will grow and say, well, who carries share price is low, let's go ahead and dilute everyone and just keep going after science that we believe in. But that is not a reliable, sustainable long-term model in my belief, and nor is the 1 that we intend to employ here at BridgeBio.

Our next question comes from the line of Cory Kasimov with Evercore ISI.

Great to see all the ongoing progress. So I want to follow up on this real-world evidence that was referenced in both the press release and the prepared comments that reinforces Attruby's differentiation versus TAF. Can you kind of unpack what this real-world data that you're seeing, how it compares with what was demonstrated in the clinical trial setting? Is anything different now than it was or just more of it?

Yes, it's pretty different because recall that we had a significant less shift in our clinical trial, like those placebo outperformed the on-drug arm of ATTRACT. There's kind of no way for us to actually apple-apple go across like diuretic kind of case. Oh, and by the way, like even the use of diuresis and [indiscernible] and SGLT2s and so all of that stuff has changed pretty markedly. So it almost made it impossible accepting the in-trial comparisons we can make between tafamidis and acoramidis with all of the available caveats there, where, just as a reminder, acoramidis just outperformed examines in all aspects, which you did not see in HELIOS. But I think real will levies the right way to do this within systems or across a constellation of systems that we know have a lot of integrity in terms of clinical studies. And here, you're seeing things like what we mentioned in terms of diabetic intensification, we certainly didn't look at the downstream kidney effects like the Nevada system did, but it's all resident, I suppose with the advantages that we think Attruby has versus amis in terms of mortality and hospitalization. It's just nice to see actually play out in the real world.

Our next question comes from the line of Salim Syed with Mizuho.

Congrats on another great quarter. Just 1 from us maybe on infigratinib and PROPEL 3. So since you guys have had that read, I'm sure you must have done some market share work or at least spoken to additional folks in the Aecon community, both on the clinician side and family. So just curious what the feedback has been there? How the additional feedback informed your expectations for the commercial opportunity. I believe you said previously you sort of think about AECON being a $2.5 billion TAM and maybe hypocon, the same. Just curious if you have any other color there to offer on the commercial opportunity.

Yes. Good question, Syed. I think the feedback to the credit here hears me overall only positive. HCPs are telling us that they're constantly being a family when the oral is coming, both on families are on treatment today, but more importantly, those that stayed on the sidelines, which as a reminder, makes up out 70% to 80% of the U.S. market. The consistent best-in-class profile is continuing to resonate with the clinicians. They understand that AHP is best in class, the IT scores best in class. We have the most attractive safety profile and importantly, on proportionality right? Personality data point is the 1 that's resonating most the clinicians because this is the only product that has that day result in portionality, in a 3 to 8 age group population, and which is a demonstration of how directly targeting FGFR3 impacts more than just higher is about health. And on that note, we will be releasing more data on how infigratinib benefiting more than just hike in medical homes later this year, some of which has been seen before in 52 weeks geocontrolled pilots there. ultimately, all this is to show that it really reinforces our belief that we will have a peak market share actually more than 60% market share as valued by our market research here.

Our next question comes from the line of Ellie Merle with Barclays.

Two from me. First on limb-girdle. So you submitted the limb-girdle very quickly. So our math about 150 days from top line, which is a very fast compared to average. Can you walk us through where you stand on readiness and how you're preparing to get this drug into the hands of the limb-girdle community from day 1? And then a second question on the ATR space. How are you thinking about what we will see from cardio transform specifically prostate and the trial is very well powered, but what's the hazard ratio that you think could be competitive? And how are you thinking about that?

limb-girdle, this is Tom. So I'm going to pass, so I'm going to Anna Wade here and then [indiscernible] to be able, first of all, to say I'm really proud of our team for the quick turnaround on the NDA, and you expect that level of efficiency from the next 2 as well. But over to Anna, and [indiscernible].

Thanks for the question, Ellie, and thanks for the kind words, Tom. So yes, we're really excited. We have our commercial and sellership on board. We're getting ready to have the sale for higher at least this year. We also now have our medical leadership in place as well as the seasoned MSL team with neuromuscular and Reese experience. In Q1, our major catalyst is the NDA conference, as Neil mentioned, in March, where [indiscernible], a leading KOL and Cal presented our Phase III and term analysis data. And we have incredibly positive feedback at the meeting about the Impella package. Since NDA, we've heard about significant patient outreach to neuromuscul and intendedly we have received many inbound inquiries from both patients and physicians. Abacus right now is driving wins at the Phase III data as well as emphasizing the importance of genetic diagnostics leveraging responsive testing programs that are currently available. So that they want at lunch, we can be ready to get patient about the therapy.

I think let me address your second question there, he was on the cardio transform. Yes, we agree with you. It's a super well-powered trial. I mean, obviously, against the primary it was good and even in the subpopulation. Like if you take the same point estimate from Helios B on combo and you just think disease for and then you say how many more patients would you need like 2.5x more to hit a p-value 0.05 or less and they're pretty well powered for that. So I actually expect that they'll hit on almost everything that they're in carrying and so then it comes back to how do I cross [indiscernible]. how do I understand this? [indiscernible] technology, part of that will be how much knockdown they get and are they able to improve on the PK profile because I think the reason that Pat performed similarly to Ambua or in the HELIOS-B trial has to do with the timing it takes for good to get to me match knockdown. So take a lot longer than I would have expected. So we'll see if that's the case with their drug.

I think overall, obviously, cardio transform has more to do with the commercial dynamics without Mylan than it does with us, especially given the combo data that I just told you about it. I think people are going to reach for stabilizer first line anyway, number one.

Number two, I think when they're failing stabilizers, they're going to want a better stabilizer on board in combination. So if that come alarm does hit, I don't see it having a meaningful -- super meaningful effect for us. Again, I mean, from a biochemical standpoint, you always want to preserve the native tetramer. We're seeing more and more information about that. I'm surprised people haven't been looking at the publicly available fares database and what do things look like when you're knocking things down versus actually stabilizing and all consistent with the 2 25,000-plus patient studies that we've seen out there suggested a higher level of better for you, but I understand that in a short trial, those signals aren't necessarily resolvable. But I think over a longer period of time, stabilizers will continue to be frontline and in combination. I think we'll have a we'll have a pretty good start. But that's kind of -- that's how we're thinking about it. We do think Cardiopet will be positive, just given the patient numbers.

On your hazard ratio question, I mean, obviously, we think the bar is relative risk reduction of 42% and risk reduction of 50% upon hospitalization, which I suspect if this study is consistent with the rest of the modern studies are going to be a vast majority of the events will be hospitalization, not mortality. So I think that far 50% reduction in holding is kind of what I'll be looking for.

Our next question comes from the line of Anupam Rama with JPMorgan.

Congrats on the quarter. Quick on [indiscernible] 1 here. I know the NT NDA is on track here for the first half of this year. And then the press release highlighted nearly 2,000 now identified identifiable patients with ICD-10 code. Can you give us an update about further patient identification efforts? And how this sets up how we should all be thinking about the initial launch curve?

[indiscernible]. Yes. So I would say that the foundation of everything that we're doing around Visia identification is really awareness, awareness of the disease that's an important distinct subset within hypopara. And then, of course, awareness of our driving power and a wonderful effect can have for these patients. I think a major catalyst for awareness is going to be the upcoming presentation that you see next week followed by U.S. presentations later in the year and then hopefully a very high impact obligation as well. But in the background, I think there is some important tactics and strategy that we continue to employ. First, as you mentioned, IC 10 code is a huge advantage to us here. Many rare diseases don't have an ID in golf. They have 1 that's been in place for a couple of years already. So there's a good amount of data in that lets us take our analytics capabilities, put them on top of this and really deploy our field-based medical and commercial leadership in a more surgical way to go to the offices spread awareness and also make sure that the patients they think they have appropriately diagnosed with our sponsor genetic tests, whether commercially double genetic tests.

And then third, and I think this has been a bigger driver of identification that I would have thought is just family tracing, makes sense when you consider this isonomic conditions. So there's a 50% chance of passing on. So when we tend to find 1 person with this condition. If they look in good to a family event, we find out that many of them, in brothers, cousins, antidotal site conditions. So that's been a real valuable source of patient identification as well. So we'll continue all these efforts and accelerate them as we approach launch.

Our next question comes from the line of Derek Archila with Wells Fargo.

congrats on the progress. Just a follow-up on infigratinib. Some recent commentary on some of the early KPIs from the UV well launch seem positive and maybe early validation of kind of this market expansion pieces. So just curious how you think about infigratinib's profile versus the injectables and how this could further accelerate this market expansion potential?

Yes. Thanks, Derek. I think post not physicians and families are set about the total package of the grain, right, not just 1 thing. It starts with a 2.1-centimeter change of baseline HP, the largest effects shown across any of the I which was remarkable we use across the age groups. That, of course, has meant earlier, we always attempt on personality, a demonstration of the importance to directly engaging [indiscernible]. And then you have a differentiated safety profile, right, with no injection site reactions, no symptomatic extension, no hepatosis. And I think the safety differentiation is further playing out given the increasing and concerning signals of SKIPPY and demarcates which are both looking like potential Conplast. That go on top of this for us is being the daily oral. Based on historical benchmarks, we know that when oral enters a only injectables, it expands the market on average by 3 to 4x at [indiscernible] after launch. So ultimately, the pot here will have a choice of either 365 injections a year, but the 2 injections a year or 0, and I know which 1 not [indiscernible].

Our next question comes from the line of Paul Choi with Goldman Sachs.

Sticking with the infigratinib, I want to ask with regard to the PROPEL infant and toddler study in patients who are newborns are up to 2 years old. Can you comment on your updated thoughts on enrollment timing and when that might potentially be completed in the wake of your positive results from the PROPEL study and just how you think about timing for that potentially being completed and being added to the label?

Yes. Thanks for the question, Paul. Definitely, I think there's a lot of expansion from sites and proponents in the Phase III AI data just kind of -- what we know from the field showed that earlier intervening more likely your impact likely to impact clinical outlooks. I think we've seen that be averse there. So we'll provide an update on timing and probably later on once we have some more clarity on this program progresses.

Our next question comes from the line of Andrew Tsai with Jefferies.

Congrats on execution. I have a bigger extra question for you guys on your broader pipeline. Now that you have succeeded across 4 major programs all the way through Phase III. As investors think about the sustainability of your R&D engine, maybe talk about how you're currently thinking about the next wave of development beyond your portfolio? And how much you're open to adding more to the pipeline in the near term? And what indication areas you could be interested in?

Yes. Thanks for the question. I think right now, as I think a lot of our comments and actions have been consistent with, we're very focused on executing the opportunity in front of us. It's not often in a biotech will launch, 3 different products and 3 different indication setting alongside a pretty competitive market. at the same time. And that's going to take certainly against our lean back on all of the focus that we have I also mentioned earlier that we have pretty significant additional opportunities associated with leveraging 1 of our drug products, including some that we haven't talked about vis-a-vis Attruby. So I actually think that there's some pretty interesting stuff to do. We have an internal pipeline, obviously, prosecuting programs in ADPKD, leading cardiomyopathy and in delete antibody program in ATTR cardiomyopathy. So that's additionally programs that are very, very capitally efficient but programs that we have an eye on today. And then we bought back our programs against all of our current pipeline programs so that we can do what's right for the patient and physician community to continue to serve that as long as possible. So all those things put together, I would say, represent the menu of activities that we're interested in, in the near term. Obviously, we're students of the genetic disease space. BridgeBio has a significant stake in another company called Bandola Bio, which is really kind of 1 of our sister companies, and that has 17 programs. I think we've gone through ranging from Phase all the way back to the preclinical setting and a very, very exciting slate of small molecules, ASOs, antibodies, all targeting well-described genetic conditions at their source. And so I would say that we're happy for that to be sort of an off-balance sheet R&D exercise for now as is BridgeBio oncology therapeutics and really to focus on what we need to focus on here. which is continued prosecution of our pipeline programs and delivery of these important medicines to patients and ultimately, the capturing of the value that we have created for the investors and in fact just for many years.

Our next question comes from the line of Danielle Brill with Truist.

Congrats on the great quarter. Neil, I believe you mentioned in your prepared remarks that there were 6,100 new patient starts across the class in the quarter. As I recall, correctly, this represents a pretty meaningful step-up from prior quarters where I think it was more in the 4,000 new patients range. Just curious what's driving the step up here? And moving forward, how should we think about the size of the quarterly patient pool that you're actively competing for?

Yes, sure. I mean I think this market continues to grow somewhere between like, I think our internal numbers are somewhere between 5,000 and 6,000 in that range. a quarter in terms of the new patient starts or new patients to brands. So actually, I don't think we have 4,500 for the last quarter. I think it was about $5,000. But a little bit of this math has to do with like us guessing for our competitors, what the inventory hold that was or what the inventory buys were and things of that nature. So can never get it only [indiscernible] obviously, our own base number is fully right. But that does suggest continued growth. I mean will it continue to grow? I think so. Obviously, there's 250,000 patients with cardiomyopathy at the low end in the U.S., and I think we're doing a better job with 3 things. One is making sure that the algorithms are in EMR so that people think they look for these patients. there's all the tracer AI stuff that we've been doing, other algorithms that we make a little health care systems have been pointing for us to just get people that think maybe this is a TTR patients. That's one. Something that's driving genetic testing into variant heavy populations, that's been helpful as well. And there, probably the best is just broad traditional awareness and education through speaker bureaus really getting out into the capitated practices of the community practices to educate them more. So all of that is positive. I'd say on the negative side, we've heard quite a bit about this PYP shortage that technician can 1 of the ways that you can do the scans to get debt a definitive diagnosis or [indiscernible]. So that we have to keep an eye on. We've heard about that before. Like in 2025, we heard about that, I think, in the second or third quarter. So 1 of the new quarters and end market continue to grow. But what's keeping eye on that. That's resolvable. There's 3 major suppliers of that. And I think I expect in the years going forward, we shouldn't see much more of this sort of supply chain iteration around IP availability.

Yes, long story short, I believe that you should see -- like I think Evercore put out a nice analysis of this 3, 3 years ago or so was like you should see simple linear growth in identification given the number of patients that we believe have HTL cardiomyopathy coupled with the number of sponsors in the playing field and the availability of reasonable testing. I would expect that trend -- that positive trend can continue with some errors quarter-to-quarter.

Our next question comes from the line of Jason Zemansky with Bank of America.

Congrats on the great progress. Maybe 1 more on Encaleret if we may. As you look beyond the ADH1 opportunities, sort of the broader chronic hypoparathyroidism opportunity. How are you thinking about in encaleret positioning, I guess, relative to the parathyroid hormone replacement therapies. Is there a particularly attractive subgroup to target? Or are you looking at sort of the broader opportunity as a whole? And then maybe if you could talk about some of the pricing implications of pursuing a market that maybe looks a little bit like 25,000 patients in the U.S. and EU versus 200,000?

Jason, it's great to hear from you, and thank you for the question. We look forward to seeing you next week at the conference. So in terms of encaleret in chronic hypoparathyroidism, when we did our market research, it's really 3 things which drove our excitement about the opportunity. The first is that this will be the first oral option available in this chronic setting. And so the ability to give patients freedom from injection-type reactions and all the pain that comes with it, it's something that resonates very well, I would say.

The second thing is, if you look at the current options available, use an effect in terms of vortalcium normalization, but you don't really see that effect on during calcium normalization. And I think with encaleret, we have a very unique profile where we could normalize potentially both blood and calcium and we saw that in our all small Phase II trial, where we had around 80% of the patients modalizing both blood and urine calcium. And these are patients who are very sick and did not have the at our plan or any amount of the hormone.

And then really the third thing is that there is any potential safety risk in terms of board resorption from giving PDH at high levels for the word. And so I think we would completely avoid that. And I think actually, we get on read out significantly [indiscernible] profile for encaleret. And so I think that those 3 things or urine causing normalization and potential benefit on safety is really why we think we can compete and get a reasonable share even in the chronic agitate market, obviously, assuming that the trial works.

Our next question comes from the line of Sean Laaman with Morgan Stanley.

This is Morgan on for Sean. Can you just remind us specifically for infigratinib and achondroplasia, what kind of, if any, commercial preparations are taking place from BridgeBio?

Thanks for the question. I think we've done a lot to build strong commercial and medical leadership here, right, bringing on for both sides of the business experience in both set in the tire market with superior to data, especially with experience at [indiscernible]. We've also had a lot of experience with being groups with scale this play experience as well. Ultimately, I think right now, we're trying to make sure and we get the word out, not just leading in edited AMC, but also to a broader kind of new pediatric endocrinologists who are really excited about having an oral option, especially for validate if they're not seeing how the super specialized centers of care, more interested in happening, something that's easier for family minister as well. So a lot of exploration going on that front.

I think to remember we have a lot of the teams in place from the Attruby launch that can also help with the future launches for all of the indications. Think about market access with the payers, the pharmacies, these are all the same individuals, and we have relationships with all those people and are able to launch quickly, I think, as a result of that and get access and coverage.

Our next question comes from the line of John Boyle with William Blair.

Congrats on a strong quarter. So patient advocacy groups for achondroplasia seem to have a pretty big voice in the indication. So wondering if you had any interactions with them and if you could speak to how the integration profile is resonating there?

Yes, thanks for the question. I think that's been a core tenet of how we can develop the drug since ever. We've been working alongside acute groups, both United States and internationally on making sure that their input and voice is implemented in our development burden and how we think employs. And for us, being able to target FGFR3 directly, address the concerns of being able to look at not just height outcomes but health at as well, which is something we expect to play out in the longer strand of full extension program. And I think the really wonderful partners with us, and we anticipate that persisting through commercialization and launch as well.

Thank you. And ladies and gentlemen, that concludes our Q&A session. I will now turn the call back over to the BridgeBio team for closing remarks.

Thank you, everyone, for your questions today. We really appreciate your interest and look forward to updating you again next quarter.

Ladies and gentlemen, that concludes our conference call. You may now disconnect your lines. Have a pleasant day.

Hi, everyone. Good afternoon. I'm Ellie Merle, one of the biotech analysts here at Barclays. Very excited to have Neil Kumar here with us joining from BridgeBio, CEO. Thank you so much, Neil, for making the time.

Thanks for having me. Really appreciate it.

A lot to talk about across your 4 late-stage programs. Maybe just because it's topical now, let's talk about what we learned yesterday from the tafamidis IP Phase?

Sure. Let's get right into it. So just as a reminder, this is an IP situation that is related to a competitor's drug product. So I'll stay relatively high level in and around it. But effectively, there are 2 key battlegrounds that I think people are paying attention to in the context of this trial and the defense that Pfizer is conducting of its Vyndamax patent estate that should take it out to 2035.

The first has to do with infringement and the second has to do with validity. And really, what we learned about yesterday probably focuses more on infringement where we think the case is relatively clear, but I know that, that's been a key point of controversy throughout the course of the last couple of months. And there, if you just sort of think about Gibbs free energy in different crystalline forms, you have the low-free energy form, the low-free energy polymorph that is protected. It is the claim that Pfizer has asserted against all of the generic manufacturers in the context of this trial.

And the interesting thing that they've done very cleverly is -- or very astutely, I should say, scientifically is to use 3 orthogonal methods to effectively define what that low-free energy form is, obviously, solid-state NMR, XRD, those 2 technologies tend to do the heavy lifting typically on free energy form polymorphs.

But then the third one is Raman spectroscopy. And what we learned yesterday was one of the key experts associated with spectroscopy and I think just broadly will be allowed to testify, which I think is an important piece of what we're going to see. I also think it's reasonably apparent at least to us that Pfizer must have found this low-free energy form and most of the material that they have surveilled. Otherwise, they would not be applying the claim against these generic manufacturers.

And obviously, Dexcel has already said that they are infringing. So we believe that infringement piece for a wide variety of reasons, mostly scientific, is strong. But I think having the strength of Adam as an expert there will be critical as well. And obviously, their experts across both validity and infringement, I think, are a strong cast. They do have RA as well and [ Burnie Trout ] testifying in and around validity. So it should be a strong cast that we think will be congruent with their strong case.

And investor question we get is there's so much focus on Vyndamax, but a Vyndaqel generic, we could see end of 2028. Why does this not matter?

Well, everything matters. I would say the Vyndagel generic, Vyndagel as a brand has been discontinued, as you know, from the marketplace. It doesn't mean it can't be relaunched in some way, shape or form. It's also not substitutable. Obviously, there's different levels of API, and it's not what they're running current experiments with to continue to elaborate on the health benefits of this franchise.

It's sort of like are payers really controlling this category that astutely. I mean, in Europe, like Attruby is the leading brand, we're effectively generic as compared to Alnylam, and you don't see a whole lot of payer control. And I think when you think about the economics in the channel, given the fact that patient co-pays are all going to be the same because this is mostly a [ Medi D ] population, that the ISPs generally are going to want branded products and that brands are going to continue to do the research in this space.

And there's a lot of research to be done. You put all those together, I don't think Vyndaqel itself will be a competitive brand, maybe outside the VA or VA often will use 20 mg TAF. And then there are some institutions that use diflunisal as well as a generic that's generically a better stabilizer than 20 mg TAF. So there will be, I think, small pockets of usage, but it's -- I think Vyndamax is the big brand to pay attention to.

Okay. That's helpful. I'll probably have more questions if we have time on that. But I do want to focus on your portfolio outside of achondroplasia and ATTR since I think that gets so much airtime, I mean, as it deserves. But I think the pipeline beyond that is very valuable as well, and I think it's worth talking about. Maybe starting with ADH1, how should we think about the size of this opportunity and what drives your conviction here?

Yes. Well, I guess, first and foremost, what drives my conviction is this is a big unmet need with no therapies available today and the Phase III data were markedly compelling. I mean when you're talking about 75-plus percent normalization for patients, I mean, really, that's almost like a therapeutic cure, as I've said, 91% of people getting their PTH back into the normal realm as well. So that type of thing is super exciting for the patient population.

And then the question is, how do we find and activate that patient population. And so the second thing that excites me is this is a broadly prevalent disease from the statistical genetic standpoint, 10,000 to 12,000 people. It's not a pediatric condition that necessarily limits lifespan. So you can imagine that the population is large, but I would say a majority is unfound, not only TTR, and certainly not unlike TTR prior to the move from cardiac biopsy to technetium scan. And so how do we find it in this case? The good news is there's a subpopulation, nonsurgical hypopara where we can look. And pretty reliably, we're finding something like 20% to 25% of patients have hyperactivated mutations in the calcium-sensing receptor, which is what qualifies you -- what defines you effectively as an ADH1 patient.

So I think there's a reasonably large unmet need. I think this drug is really a beautiful product for those patients. And I think there's probably 3,000 to 4,000 already identified patients that we could launch into now. And it's a safe oral that has outstanding efficacy. So that's what gets us excited about that.

Should we expect a bolus for the launch?

I think -- I mean, there's a bolus on every launch, except for when you give drug away for free, I suppose. But yes, generally, there's going to be a bolus, I think, associated with the pent-up demand in this space. Yes. I mean that's kind of what was cool about -- I mean just generally, if you like model these launches, we have this revenue institute thing and it's like in rare disease, you typically see this -- there's basically a steep incline. And then there's a flattening in terms of the actual growth.

And then when the second derivative gets positive again, like you see in TTR, that's super exciting because it means there's new prescribers or there's a new dynamic available. I think it's for TTR, it's, by the way, just new prescribers and high-volume heart failure practices. So I imagine it will be a little bit like that here, too, in ADH1, like I think you'll see a relatively steep incline. And then you'll see a flattening in terms of growth. And then as we find new patients and find new prescribers outside of the severe endocrine population, and then we'll see more growth there.

What proportion of these patients are currently on [ Urispas ]?

Like 1%, I don't know if you...

Really.

Yes, it's not labeled for it. It's -- I mean there was that New England Journal piece, but we don't see a lot of patients on it, seeing many more patients actually on standard of care, which is ineffective and obviously exacerbates the urine figure and calcium, but I don't see a lot of patients on URV right now.

Okay. Let's talk about limb-girdle 2I, maybe the population there and how you see the opportunity?

Yes. So super exciting. I actually just flew up this morning from Orlando, where MDA is ongoing. And I think that, that data is going to be -- we have a late breaker that we got a press release coming out in an hour on some of the new data associated with it, but very privileged to have Dr. Kathy Matthews presenting our data in one of the keynotes there.

So again, I think my excitement in that space starts with the outstanding data that definitely surprised me to the upside in terms of the interim Phase III readout. Not only are we having really, really significant action on the causal biomarker of the condition, which is glycosylation of the alpha-dystroglycan complex, like 80% increases and in some cases, taking people back to normal levels of glycosylation.

We're also having that impact on CK where you'll see that a reasonable fraction of patients are actually back to normal CK levels, which is, as people know, a very sensitive measure of muscle damage. But most importantly, those functional improvements. And like to me, it's truly remarkable when you see a therapy that's not like slowing the condition, but actually improving it and it improves it on ambulation, all measures of ambulation as I think people will see from the keynote address plus FVC plus modified North Star test and you have that early action as early as 3 months.

So I think all of those things put together, it's like this is a really, really devastating condition, again, no available pharmaceutical therapies and probably something like 1,200 to 1,500 patients in the United States. This was a little better identified at the get-go. Actually, there's -- if you look at Iowa, you look at VCU, you look at some of these larger institutions, they have quite a few patients.

And there's 150, I think, MDA centers of excellence across America. And I think they all have reasonable numbers of LGMD2I patients or at least LGMD patients. And then the question is you just have to genotype them. Prior to probably not a huge deal to not genotype them because there weren't a lot of available pharmaceutical therapies, but now I think people will be doing that more.

Makes sense. And how should we think about the pathway to approval and the use of the sort of surrogate or biomarker?

Yes. I think given the fact that we had the statistically significant impacts on outcomes and inclusive of modest [indiscernible] North Star, our dialogue with the agency -- I should also say, one of the things the agency always looks at is what is the consistency of the data. You don't want a few outliers driving the signal. And here, it's been remarkably consistent, not only in terms of patient to patient, but also the subpopulations.

If you look at the compound H versus the L276i homozygous patient population, if you look old versus young, if you look at severely affected in terms of FVC, nonseverely infected, it's a very constant sort of gorgeous forest plot. We've shown some of that publicly, and I think the rest of it will be shown this afternoon. So I think given all of that, the agency's dialogue with us has been oriented toward full approval. And that's how we would expect to proceed.

That's exciting. And what about your conversations with ex-U.S. regulators?

Yes. So in Europe, we haven't had as detailed discussions yet, but we anticipate having those in about 2 months, where I think I'll have a better understanding of how they're thinking about the data set. But I don't imagine it would be highly discrepant to what has happened thus far. The data is the same data.

It's exciting. And this time next year, you could be launching 2 or 3 more drugs.

Yes. Super exciting.

How are you thinking about the commercial build-out, particularly ex-U.S. and what that might entail?

Yes, great question. I mean I would say, by and large, the commercial build starts with the decentralized model that we employ here in the U.S. So every affiliate is really going to be almost like if you think about big pharma, the global product leader or whatever, like, yes, every affiliate really owns the science, they own the medical affairs, et cetera. But then they get to hook up to the centralized commercial infrastructure that we have, at least in the United States, which does patient services, market access and distribution and design and sales force incentives and training and all of that stuff.

So I think it's -- they're going to be highly efficient launches from that standpoint. And we're never going to have to build the type of field force that we had to build for TTR for any of these, even including in achon. So I think that should be fairly efficient.

Ex-U.S., I mean, this will be the first time we're launching, obviously, since we're partnered with Bayer in Europe. And so we've got Hassan Jaroudi, who's done a lot of this work at Alexion, and we're excited for the opportunity to serve patients in Europe. Obviously, the one big advantage in Europe is that there's small numbers of centers of excellence that account for many more of these patients. And you can see some of these launch dynamics even in the achondroplasia ex U.S. launch versus the U.S. launch, it's easy to understand and find where those patients are. But I'm not negating the complexity of what we need to do, but that's one advantage.

The second advantage is for every single one of these trials that we run, they have been global trials. So just like with TTR actually, and I think you can see this from Attruby's leadership in Europe, in part, it's been a great job from Bayer. In part, that's been obviously the more marked focus on just looking at point estimates at 30 months and price points. But I think it's also been true that the goodwill you build up when you run these international trials, and we've run almost 30%, 35% of our population comes from Europe in all of these clinical trials, people have experience with these products and what they can do for their patients so.

Makes sense. Turning to Attruby. So we saw an acceleration in new patient starts in 4Q. What was the driver of this? And what should we expect throughout 2026?

Yes. I think, by and large, a big driver has been -- because you saw the uptick not only in scripts, but you also saw it in terms of number of prescribing physicians. So -- and this is not just us. I think this is all sponsors have been doing a great job of getting out to these high-volume heart failure practices and really educating on how you might find these patients.

I've probably not given enough credit to what these EMR flags and "AI algorithms" and things of that nature could do to help just physicians think about, "hey, this might be an ATTR cardiomyopathy patient. " So I think that's one thing that's really helped.

I think the second thing is the applicability, especially of small molecule stabilizers in those practices has helped us quite a bit. I mean I don't think Wall Street maybe gave as much attention to some of the subpopulation work that we had done over the course of the last year. But like the cardiac arrhythmic data was really, really interesting, I think, to physicians, especially in that "community" or JV setting because not only did it show impact on AF and obviously, hospitalization in the context of the cardiac arrhythmic population, which is like the majority of the patients, 50% to 60% of these patients have some sort of Afib involvement.

But most importantly, what it showed is the drug is active in non-Afib and Afib patients similarly. So you don't really have to worry about because Afib can be a complicated thing to manage. And so the simpler you can make the therapeutic choice and actually the way you manage patients, the better off physicians and patients are. And so I think a lot of that work that we've done has excited people and gotten us off to the right start in terms of naive share in that setting. So I'd say that's the second big driver of what we're seeing is just the continued prosecution of the data.

What are you seeing in terms of the types of prescribers or the types of centers where you're gaining the most share?

Yes. To be honest, I mean, we've heartenedly been able to gain across the board. I would say like we started at a slight disadvantage in the academic medical centers because they had experience with some of these other things through polyneuropathy.

And then obviously, the knockdown economics are a little bit different in academic medical centers where they might focus more. But again, I think for our prescriber base, it really comes down to the efficacy. And I think there's 2 stories that have really been, I think, winning the day there. One is the serum TTR story, where it's pretty clear that ever better levels of stabilization now. Pfizer did a solid in publishing their 2 papers on that as well, lead to ever better decreases in risk of mortality at 30 months. So I think that's been one thing.

And then the second thing, I think, is the early separation. Maybe haven't caught as much on in the community setting, but I think in community, I mean, the non-AMC setting. non-COE setting. But I think people are really paying attention to that, especially given some of the mechanistic work that we've been doing in collaboration with them on how is that occurring? How is that separation in morbidity occurring as early as 1 month. It's probably not the kinetics of monomeric deposition in the heart. It could be something else, and we believe it has to do with the cardiorenal access, which we continue to explore. So that will be the second thing.

And so like AMC, I see us picking up there. And then certainly, in these high-volume heart failure doctor practices, I think we've done a good job of educating on the benefits of a superior stabilizer. And it generally has been paying off for us in that setting as well. So I'd say in both settings, we've been picking up neither brand or naive share.

Anything that you would call out specifically around any 1Q dynamics you expect?

Not really. No, I can't think of anything interesting to say on that front.

That's encouraging. In terms of thinking about the price evolution long term, and I think that's really where a lot of the generic tafamidis conversation comes from. How are you thinking about this even say, over the course of 2026 with the evolution of gross net, but then, of course, longer term, when we see potential generics regardless of what year that may be?

Yes, it's a good question. I mean, obviously, the price has been going nothing, but up in the channel right now in part because of the -- that's only true in the U.S., and that's true because of the dynamics of the channel. And like I said, I mean, we're effectively -- I mean, we're the lowest priced drug in the marketplace, and I wouldn't say that necessarily helps us with some of the middle intermediaries. Ultimately, I believe it helps us with physicians and patients. But what helps us more is the hypergenous access programs that we have.

It's not -- this is not an easy category to manage, and that's why I don't think you're seeing it being managed in the United States all that effectively, mostly because there's not an obvious physical marker of nonresponse. And so like how are you going to like necessarily step one thing versus another. It really comes down to it's a devastating deleterious disease and a physician is going to feel like one product is better than another to put their patient on and they often will.

I mean I think there are some people who are very cost sensitive and might be using diflunisal, as I mentioned earlier, a 20 mg TAF. I don't think that's a very good thing for patients, to be honest. I mean I do think -- I don't know how many more times and how many more experiments need to be put out there to show that ever better levels of stabilization lead to better outcomes for patients. But I can't -- it's never going to be 100% answer there. But long story short, I don't see price dramatically changing in this category in the near term.

Okay. That's helpful context. Some exciting data from infigratinib in achondroplasia. As we head into the hypochondroplasia Phase II data in the second half, which I think was an interesting readout. What are you looking to see? And what are your expectations for what we'll get from an efficacy perspective in hypochon relative to achon?

Yes. So I think achon again, was -- I mean, I expected that trial to be materially positive, but I think that the 2.1, the third standard deviation for the Z score and certainly, the proportionality with the p-value probably slightly exceeded my expectations. So there again, that makes me excited about what's coming with hypochon.

Hypocon is a less well-described condition. Obviously, we don't have like the totality of the growth curves and all that, like we have the Hoover-Fong curves, et cetera, in achondroplasia. But I think in hypochon, first and foremost, we want to show some statistically significant impact on change from baseline in AHV. And I think really just get into the setting of hypochon, I think people will already given the mechanism and given the results in achondroplasia, I think people will be quite excited about that type of product.

And how are you thinking about the commercial opportunity in hypochon relative to achon?

I think -- actually, it's interesting. Someone was asking me about that earlier today, and I was thinking about it, like the enrollment rate for hypochon has been very high, which at first, I thought hypochon was a little less well diagnosed and could -- it probably is, to be honest. But the enrollment rate has been terrifically fast actually in our Phase II. So I would say the statistical genetic prevalence is pretty similar between hypochon and achon.

I don't think there's as many identified [ ketos ] right now in the space, but I think it could be very rapid because, again, these conditions are fairly obviously diagnosed. It's not necessarily a hidden condition like even an ADH1 might be.

As you think about the size, I mean, you have a large pipeline of these various indications between ADH1, limb-girdle, achondroplasia, hypochondroplasia, how would you order them in terms of when you do your internal modeling around peak sales?

Well, TTR is definitely the biggest. We think that's a $4 billion peak year product. And I think that's fairly consistent with the data that is being generated right now, commercial data, I mean. I'd say on the achon side, we believe probably $2 billion, and that's not including hypochon. So we haven't quite modeled -- we have to hit on our Phase II first to start including that in our PK models.

And I think for both ADH1 and LGMD2I, we have them at $1 billion peak. And I think some of what people are missing is the ability to price appropriately for the type of data that we have put forth in those 2 indications. So I think those are 2 meaningful marketplaces for us that are probably getting a bit of short shift. So that's how I would order them.

Obviously, the big thing that can move that is we're kicking off a Phase III in chronic hyperpara this year, this summer. And that's a monster market, and that could materially change the marketplace for encaleret. But again, we haven't hit on that yet. So that would be my ordering for the stuff that is post Phase III.

Okay. Great. That's helpful. And then taking a step back, I mean, you have a very unique business model and how you source assets and have a diversified portfolio. Beyond the programs that we talked about, can you speak a bit to your business strategy as well as some of the other earlier programs?

Yes, I would be delighted to. Obviously, right now, we're in the midst of a fairly heavy execution phase. We want to make sure that we get great labels and launch these drug products for the patients that we serve.

And then secondly, elaborate on all the opportunity associated with the existing medicines. Hypochon, we talked about, chronic hyperpara, I just touched on. There's some smaller skeletal dysplasias and other growth and other height-associated disorders that we might look at as well with infigratinib. And then we have a fifth program in Canavan disease, which I don't think will be super material commercially, but it's very, very important to the patient community that we serve.

Beyond that, we have obviously -- well, maybe not obviously, but we have a -- this is maybe one of the most exciting and also noncompetitive times in genetic medicine that I'd say it kind of reminds me of like when we started BridgeBio, there's so much substrate and no one cares because everyone is doing like obesity and I&I. So we've been able to accrue a very exciting pipeline at Gondola, which is kind of our off-balance sheet partner for doing R&D.

And we talked publicly about one of those compounds, which we believe is a best-in-class potential EPP product that has finished its Phase II, several more ideas like that across ADPKD and alpha-1 antitrypsin deficiency and TSC and I think with the potential for 8 development candidates in the next 6 months there.

And I think broadly, like outside of what we might do with our sister organization there, we're more focused on organic versus inorganic growth. Inorganic growth is very expensive. and the fact that we're getting to INDs and $15 million or less and all of these Phase IIs that we just talked about today, we're like $220 million or less all the way from front to back. So I feel like we can do that work for the patients that we serve pretty efficiently, and we have a lot of ideas. So our hope is that we're able to kind of correct -- capture the intrinsic value that we've generated for the investors that we're serving here and then turn around and do more of it.

Great. Well, I know we're out of time. But Neil, thank you so much for joining us, and appreciate all your insights.

Yes. Thank you. Appreciate you having me here.

Thank you.

Good afternoon. I'll be your conference operator today. [Operator Instructions] Thank you. Before we begin, I'd like to remind everyone that today's call may contain forward-looking statements within the meaning of the federal securities laws, including, but not limited to, statements about BridgeBio's future operating and financial performance, business plans and prospects and strategy. These statements are based on current expectations and assumptions that are subject to risks and uncertainties, which could cause actual results to differ materially from those expressed or implied in these forward-looking statements. For a discussion of these risks and uncertainties, please refer to the disclosure in today's earnings release and BridgeBio's periodic reports and SEC filings. All statements made here are based on information available to BridgeBio as of today, and the company undertakes no obligation to update any forward-looking statements made during this call, except as required by law. With that completed, BridgeBio, you may begin your conference.

Good afternoon, everyone, and thank you for joining BridgeBio Pharma's Fourth Quarter 2025 Earnings Call. My name is Chinmay Shukla. I'm the Senior Vice President of Strategic Finance at BridgeBio. With me today are Neil Kumar, our CEO, who will provide opening remarks and discuss overall corporate performance. Matt Outten, our Chief Commercial Officer, who will provide more details about our commercial performance, particularly the continued success of Attruby; and Tom Trimarchi, our President and CFO, who will review our financial results. During today's call, we will review our continued strong commercial execution in Attruby's fourth quarter and first full year on the market. More importantly, we will discuss what we believe is a transformative inflection point for BridgeBio, marked by positive top line Phase III results for encaleret in ADH1, BBP-418 in LGMD2I as well as positive top line data for infigratinib in achondroplasia.

With 3 successful late-stage readouts across our pipeline, we are entering a new phase of value creation and portfolio maturation. We will also review our robust financial position and how it supports our regulatory launch and life cycle expansion priorities across these programs. Following our prepared remarks, we will open the call for questions. For the Q&A session, we will also be joined by Ananth Sridhar, Anna Wade and Justin To, who lead encaleret, BBP-418 and infigratinib, respectively. With that, I'll turn it over to Neil.

Thanks, everyone, for taking the time today. This is our first earnings call since we reported the results of our Phase III study with infigratinib, which delivered a successful outcome for the community we serve in achondroplasia. Altogether with ATTR cardiomyopathy, this brings us to 4 large post-Phase III programs, and I want to begin my comments today by discussing what that portends in terms of the shape of the firm. In short order, this company will turn from a cash-consumptive business to one that generates significant cash flows. The shape of those cash flows connects to the clinical profiles that we will spend some time discussing today.

But before I get into that, though, I want to take a moment to paint the picture of what the overall economic productivity of our post-Phase III pipeline might look like over the coming 24 months. I do so because the immediacy of the transition from a cash-losing business to a cash flowing business is one that happens quickly and can open up new opportunities for a firm as successful at R&D as ours. Last year, we used $446 million for the year net of revenue. Cash burn declined in the fourth quarter relative to the third quarter and throughout 2025, driven by rising revenues and improving operating leverage. Similarly, while we are going to make significant investments for launch readiness against our next 3 products, we expect cash burn to roughly hold steady through this year and start declining by the end of next year, given expected increases in the Attruby revenue. That's less interesting to me, though, than the following fact.

Absent any strategic moves, our current pipeline will begin to generate cash in late '27 and will be a cash generation engine by 2028. The profile we anticipate having in 2028 would distinguish us in the field of genetic disease and more broadly would place us in the top 20 to 30 firms in the biopharmaceutical sector from the perspective of cash flow or EBITDA. This projected future is driven by growing and diversified revenue streams connected to our 4 post-Phase III assets, which we believe in 2028 will generate more than $600 million in profit. The value of any firm relates back to ROIC, revenue growth and cost of capital. And against all 3 metrics, we believe this firm has a rapidly improving profile over the next 3 years. Our anticipated profit is even more impressive when one considers that we've been able to advance programs from the preclinical stage through Phase III at under $300 million, in some cases, considerably under that and a higher probability of technical success than industry average, suggesting an engine that could drive repeatable organic growth. Of course, all of this now highly probable growth is underpinned by clinical data that we have already generated across our 4 Phase IIIs as well as data that we continue to generate and a commercial engine that continues to grow and grow share in the ATTR cardiomyopathy marketplace.

We intend to establish that commercial engine as best-in-class for both first-to-market and competitive market launches in genetic disease. Despite continued strong execution across our business, our recent share price performance does not reflect the progress we've made. We believe this disconnect is primarily driven by uncertainty surrounding the tafamidis IP situation, which I will address directly in a moment. Importantly, nothing about our fundamentals has deteriorated. If anything, our position has strengthened commercially, clinically and strategically. As we execute against our milestones, we believe the intrinsic value of BridgeBio continues to increase. We are keenly aware of the gap between intrinsic value and our current market valuation, and we are actively evaluating all appropriate options to ensure that shareholder value is properly recognized over time. More specifically, over the past 3 months, given the derisking of LGMD2i, our patient-finding progress in ADH1 and the clearly differentiated infigratinib readout in achondroplasia, we believe our intrinsic value has increased and its error bars have narrowed.

With over $1 billion of capital on our balance sheet and additional significant amounts of capital available away from the equity markets and with the base business fully financed, we believe we have retained optionality to capture the value you all have helped us to create. With that said, I want to spend some time today reiterating some of the important clinical data, especially as it pertains to the infigratinib readout. I want to highlight ongoing commercial readiness activities for LGMD2I in ADH1, and I want to talk about, and Matt will elaborate on this, our continued commercial progress in ATTR cardiomyopathy. On the data side, I'll begin with our recent Phase III readout in achondroplasia. As many of you know, we were privileged to generate data alongside the achondroplasia community that suggests a differentiated profile for infigratinib. The study successfully met the primary endpoint of change from baseline in average height velocity at week 52 with a p-value of less than 0.0001 with a mean treatment difference against placebo of 2.1 centimeters per year. In key secondary endpoints, infigratinib also demonstrated the first statistically significant improvement in body proportionality in achondroplasia with a least squares mean difference of minus 0.05 with a p-value of less than 0.05 against placebo in children younger than 8 years old, which were more than 50% of our participants and in a prespecified analysis.

It succeeded on change from baseline in height Z score at week 52 with a lease squares mean increase on the treatment arm of 0.41 standard deviations at week 52 associated with a p-value of less than 0.0001. All of these numbers, as a reminder, are best-in-class and unique to infigratinib. Infigratinib was also well tolerated with no discontinuations or serious adverse events related to study drug. 3 cases or 4% on active of hyperphosphatemia considered a mild and transient with no cases requiring either dose reduction or discontinuation and no adverse events associated with the inhibition of FGFR1 or 2, for example, retinal or corneal adverse events. As a reminder, infigratinib's differentiated oral route of administration and its mechanism, which uniquely targets this well-described condition at its source, produced Phase II efficacy and safety results that were highly differentiated. Our Phase III data have confirmed those efficacy and safety profiles. And interestingly, as we have begun to test this product profile since the readout, we have heartenedly found that our base case achievable market share has risen from the 52% I mentioned in my JPMorgan talk to in excess of 65% peak year share. In addition, that preliminary market research suggests not only differentiated peak year share, but also significant market expansion, similar to what we've seen when orals enter markets as diverse as Fabry, migraine, hereditary angioedema and in many other categories.

In fact, a recent analysis done at our Revenue Institute in partnership with MIT suggests that across indications, the launch of an oral product increased the sales in the category by about 170% over 5 years from launch of the first oral product. With regards to our efforts in LGMD2I, we're excited to be presenting the full data set from our study at the upcoming Muscular Dystrophy Association Conference, where Dr. Catherine Matthews from the University of Iowa will give the keynote. We have built and onboarded a dedicated commercial leadership team to ensure we are fully prepared to serve the LGMD2I community from day 1. This is a population with profound unmet need, and we are ready to execute. At the same time, we are not limiting our focus to the patients already identified. We are actively working to expand awareness, accelerate diagnosis and help uncover individuals who may be unidentified within the broader LGMD or Becker muscular dystrophy populations. Our goal is simple: to find every patient who can benefit and to ensure we are ready to reach them the moment we are able to.

Moving to ADH1, our other first-in-class product, encaleret, -- we continue our patient finding efforts, which have already identified in excess of 1,700 unique patients in claims data. We also recently had pre-NDA communications with the agency, which were supportive of our expectations. And we continue to anticipate the launch of both encaleret and BBP-418 in late 2026 or early '27. Finally, and most importantly, I want to talk about our ATTR cardiomyopathy franchise, where as I suggested recently, we continue to elaborate not only on the fullness of the best-in-class stabilizer hypothesis, but also on our differentiation in the real-world setting and our ability to impact patient health as early as 1 month, by far, the earliest impact we see from any medicine in this space. We already preannounced the fourth quarter Attruby net product revenue of $146 million, which corresponded to greater than 25% NBRx share as of December 31, 2025. Over the last few weeks, Attruby's commercial momentum has continued. As of February 20, we have seen 7,804 unique patient prescriptions written by 1,856 unique prescribers. You'll hear more from Matt about what this means in terms of competitive differentiation. And as I alluded to as well in my JPM talk, we are continuing to interrogate the importance of the cardiorenal access, which seems to be uniquely involved in our early onset of action.

We have also noted with great interest the recent PNAS paper that I only had a bit of time to talk about at JPMorgan. which suggests that binding enthalpy best predicts the confirmational stabilization imparted by kinetic stabilizers as opposed to binding affinity, KD or Gibbs-free energy. As we have shown through ITC experiments and as we published in Miller at all, we have a vastly superior enthalpic binding mode than does tafamidis, which in concert with superior binding kinetics continues to reinforce Attruby's better stabilization profile. A recent bevy of literature further supports that increases in serum TTR are associated reliably with decreases in the relative risk of mortality. These papers suggest that for every mg per deciliter increase in serum TTR, you decrease the risk of mortality at 30 months by approximately 5%. As a reminder, we observed in our Phase III study that patients increased their serum TTR by 3 mg per deciliter when moving from tafamidis to acoramidis. This suggests a whopping 15% relative risk reduction in mortality when moving from tafamidis to acoramidis. Let me also address the recent stock volatility, which is largely centered on questions regarding VYNDAMAX IP and the potential for generic entry. First, it's important to separate 2 things: the legal process around tafamidis and the fundamental strength of Attruby. Our confidence in Attruby is rooted in its clinical profile and market positioning, not a particular IP outcome.

On the IP front, the Pfizer decision to withdraw one of its EU patents defending the VYNDAMAX equivalent product was unexpected. That said, it did not materially change how we view the EU market given VYNDAMAX's orphan drug exclusivity in wild-type ATTR cardiomyopathy through 2030, which is now and how we have always consistently modeled that geography. In the U.S., which is the market of greatest importance to us, we believe the IP position is stronger. The patent claims at issue are narrower than those in Europe, including specific XRPD peak limitations for Form 1 that were not part of the EU case. In addition, U.S. law applies a higher legal threshold for invalidity requiring that challengers prove by clear and convincing evidence that a prior art process necessarily and inevitably produces the claim form, not merely that it could or likely would. That said, IP trials are inherently uncertain, and we will reassess as more information comes available following the U.S. proceedings in April.

Stepping back, however, our strategy does not depend on tafamidis IP. Attruby has demonstrated near complete stabilization, rapid clinical benefit and meaningful differentiation in ATTR cardiomyopathy. It is already priced at a discount to VYNDAMAX and is less than half the price of the knockdown technologies. We believe physicians are making decisions based on clinical performance, not simply price and prescribing trends we are seeing are reflecting that. Even in a hypothetical scenario involving generic tafamidis, we do not believe a less efficacious product would undermine the role of a clinically differentiated therapy in a serious progressive disease like ATTR-CM. In short, we remain confident in Attruby's positioning today and in the years ahead. And with that, I'll turn it over to Matt to speak more specifically about the commercial momentum we're seeing.

Thank you, Neil. Consistent with what we highlighted at JPMorgan in January, we believe 2025 reflected strong commercial momentum for Attruby, and it represented an important step forward in advancing 3 additional product candidates towards potential commercialization. In the fourth quarter, we delivered 35% quarter-over-quarter growth in net product revenue, ending the year with $502.1 million in total revenue and $154.2 million in quarter 4. Of this, the net product revenue for Attruby was $362.4 million and $146 million, respectively, while new patient growth accelerated in the latest quarter to reach 7,804 new patient starts. When viewed in conjunction with the IQVIA data, it becomes clear that Attruby is accelerating growth at a significantly faster rate versus previous quarters, while the competition lags behind. This is particularly obvious in first-line patients where the exceptional data for Attruby, along with our experienced field teams have driven sales to the highest levels since launch, surpassing all expectations. We have historically given out the new patient start number each quarter and have done so again despite the competition not offering similar numbers.

Moving forward, we will not be offering new patient start data because of this lack of transparency by others. Continuing to do so would put us in a competitive disadvantage, but our expectations are that Attruby will continue to grow as it has done since launch and as exemplified with today's update. As adoption grows, particularly in the first-line setting, we remain focused on ensuring patients and health care professionals have clear, balanced information when evaluating therapy options. That focus is especially relevant given recent updates we've seen in competitor direct-to-consumer communications. After receiving a letter from the FDA several months ago and pulling their television ad from the airwaves, Alnylam has returned to TV advertising. But of note, the safety section has been updated.

Besides adding the warning about the risk of vutrisiran lowering vitamin A and potentially affecting vision, the ad now points out the risk for several additional concerns, namely joint pain, pain in the arms and legs and shortness of breath. In a population already often suffering from these issues, the possibilities of amplifying, compounding or causing shortness of breath and/or pain in the joints and/or pain in the arms and/or pain in the legs should be highlighted to any patient considering treatment with vutrisiran. The fact that these risks had been omitted but are now stated at the end of each commercial and hopefully all promotional materials and messaging will correct and highlight for patients and health care professionals some things to consider with vutrisiran treatment, especially if they are a newly diagnosed patient versus someone who has tried all other options.

If we shift back to the reasons for the growth of Attruby, there are several driving factors. First, the number of prescribing HCPs continues to grow, but of equal importance, HCPs who start using Attruby continue using Attruby. We are seeing repeat use and stable patient persistence, which tells us physicians are comfortable with what they are seeing in their practice. We believe the success we have seen in 2025 is driven by Attruby's differentiated profile as the only near complete stabilizer on the market in contrast to therapies that rely on partial stabilization or partial knockdown mechanisms of action. Attruby has also demonstrated the fastest time to separation to date, an attribute that matters as physicians seek therapies that can deliver meaningful benefit quickly.

Importantly, persistency and adherence for Attruby continue to exceed our original expectations, which were based on historical ATTR treatment patterns, reinforcing our confidence in the durability of the franchise. We believe we have the strongest commercial teams in the industry, spanning sales, marketing, strategy, analytics and market access. Many team members have worked together for years, and we've continued to build on that foundation with targeted hiring of top talent, including the recent expansion of the Attruby sales team. Overall, Q4 reflects continued progress across key metrics, including growth in patients on therapy and ongoing use by prescribers, and we are excited to see continued growth in quarter 1 as we head into 2026.

Turning to the pipeline. We are focused on the next wave of potential launches. We are excited by the recent clinical results for BBP-418 in encaleret and infigratinib, all of which exceeded expectations across their primary and secondary endpoints. Based on the strength of these data, we believe each program will be the leader in its respective market and bring much needed therapies to families and patients in need of care. Building on the successful launch of Attruby, we have established a proven commercial foundation and are well positioned to extend this model as we prepare for future launches across our pipeline. We look forward to going into more detail as we get closer to approval for each. I will now turn the call over to Tom.

Thank you, Matt, and good afternoon, everyone. I'll now discuss our financial results for the fourth quarter and full year 2025. Please note that our commentary on today's call will focus on GAAP financials unless otherwise indicated. Total revenues were $154.2 million in 4Q 2025, consisting of $146 million of Attruby net product revenue, $5.3 million of royalty revenue and $2.9 million of license and service revenue compared to total revenues of $5.9 million for the same period last year. The $148.3 million increase in total revenues was primarily driven by a $143.1 million increase in net product revenue from Attruby, reflecting broad-based growth across market segments, including accelerating first-line adoption, increasing new patient starts, expanding prescriber depth and strong persistency and adherence supporting durable revenue growth.

We also recorded an increase of $5.1 million in royalty revenue from ex U.S. net sales of BEYONTTTRA in Europe and Japan. For the full year 2025, total revenues were $502.1 million compared to $221.9 million for the full year 2024. The $280.2 million increase in total revenues for the full year was primarily due to a $359.5 million increase in net product revenue from Attruby and an $11.2 million increase in royalty revenue from sales of BEYONTTTRA, partially offset by a $90.5 million decrease in license and service revenues versus the prior year. Total operating costs and expenses for the fourth quarter of 2025 were $293.7 million compared to $231.9 million in the same period in the prior year. The $61.8 million increase in operating costs and expenses was primarily driven by a $63.3 million increase in SG&A expenses, partially offset by a $13.9 million decrease in R&D expenses, primarily due to decreased R&D activities related to Attruby and BEYONTTTRA following regulatory approval.

For the full year 2025, total operating costs and expenses were $1 billion compared to $814.9 million in the prior year. The $210.6 million increase was primarily driven by a $242.3 million increase in SG&A, largely reflecting the company's investments to support the commercial launch and ongoing activities for Attruby. This increase was partially offset by a $54.9 million decrease in R&D expenses, primarily due to decreased R&D activities related to Attruby and BEYONTTTRA following regulatory approval. Turning to our balance sheet. We ended the year with a cash position of $587.5 million in cash, cash equivalents and marketable securities. We completed the issuance of $632.5 million aggregate principal amount of 2033 convertible notes in January 2026, which provides significant cash runway to continue supporting our transition into a diversified late-stage multiproduct business. With that, I'll turn the call back over to Chinmay.

Thank you, Neil, Matt and Tom. We will now turn the call over to the operator, who will open the line for questions.

[Operator Instructions] Thank you. Your first question comes from the line of Salim Syed from Mizuho.

This is Bennett for Salim. Congrats on another quarter of continued patient growth. If I may, could you comment on why Attruby continues to show consistent growth even as competitors growth seems to be slowing down? I mean, can you comment what are the key drivers behind it? And what is the feedback that you feel is resonating more with docs and patients now that we are several quarters in?

Yes. Thanks, Bennett. Maybe I'll turn it to Matt to answer that question.

Sure. Thanks. So I think it's multifaceted, but a big part is the field team that we have at BridgeBio. The right team makes or breaks a launch, and that's across both commercial and medical. And then, of course, there's the data. No one's been able to show better data or near complete stabilization only at Attruby. I think the time to separation is a big factor, and you heard some of that in the earlier comments. And I think finally, we've stayed disciplined and focused on what's important for patients and HCPs. We have category-leading efficacy and safety with consistent results across all patient types. So a great team and a great medicine, I think, is hard to slow down.

Yes. Maybe I'll just build on that. You can see in the new patient script numbers, something kind of interesting where we had that rapid acceleration at first sort of plateaued and now we have a second wave of acceleration. That's sort of rare if you look and model most launches where you see kind of a burst of activity and then typically, you see a slowing. And so that really portends 1 of 2 things. One is obviously rapid patient identification, which I think we are seeing in the field. And secondly, it's really a second wave of prescribers that are starting to wake up to some of the messages that we're putting forth. So that, I think, is an exciting profile generally for a launch this early in. And couple that with nearly 1,200 new scripts since I gave my JPM talk, that's a very, very exciting trajectory right now.

Your next question comes from the line of Mani Foroohar from Leerink Partners.

On continuing to show volume growth in the face of competitors who are seeing slowdowns. You've talked a lot about the commercial differentiation and differences in your growth trajectory versus competitors, lots of different pieces of data go into that. But I want to look past out into just what the time line is into whenever tafamidis gets generic and beyond about clinical differentiation, which you've identified as core to your strategy to driving continued growth and durability in the face of a generic whenever that happens. Can you tell us when we'll have significant incremental real-world data, longer-term data from acoramidis to establish that difference in clinical benefit that you guys are hanging that growth tail on?

Yes. Great question, Mani. Thanks for it. I think first, the key is for us to really start to get some of the data that we presented in the last year out into the field and understood. Maybe just a couple of pieces that I think have been overlooked or are just starting to really make their way into the field. First and foremost is the early impact, that impact as early as 1 month that I talked about at JPM, we continue to interrogate the precise mechanism behind it. But as you know from these clinical trials and a lot of the real-world evidence, early CVH is extremely common. So you want to get patients on the drug that can take action as early as possible, not only for that reason, but obviously, this is an ongoing mass action and deleterious disease. So you want to be on the drug that has the earliest impact. The second is the AF data that we put forth. Nearly 60% of patients in this space suffer from AF or cardiac arrhythmic events. And I think the most important piece of the data that we put forth when we showed the 70% reduction as published last year is that we're having an equivalent effect on or off in the AF subpopulation. And so when you think about AF patients being slightly harder to manage in the context of ATTR cardiomyopathy, here, you have a drug that has consistent and high impact. In fact, the highest point estimate we've seen in terms of both reduction in downstream outcomes of 43% and reduction in AF itself of 17%. So that, I think, is the second piece that we need to do a better job of educating on, and I think physicians will find it exciting. And then finally, it's the variant population, right, the sickest by far of the subpopulations, they do deserve a better drug and that 0.41 hazard ratio that we presented on with statistical significance, even more impressive given the fact that less than 10% of our patients on ATTRibute were ovarian patients. I think that is the best point estimate again with the best statistical significance in the space and extremely consistent with the binding mode that we've articulated, which is differentiated against tafamidis. So those would be, I think, the things that we need to do a better job of driving into the marketplace right now. On a go-forward basis, the 2 big areas that we're interrogating, number one, are real-world evidence, which you should see by the end of this year, this calendar year. And the second is the cardiorenal access work that we're doing, where we think we have a unique signal that connects interestingly to the early onset of activity and could really, I think, change the shape of this marketplace going forward. So that's what I'd say on that front.

I have a quick follow-up, more on firm-wide strategy. You guys have talked about the transition towards cash flow generation over the course of a couple of years. Obviously, that happens when you have multiple high-margin small molecule assets. Can you talk about how you guys think strategically longer term about use of cash and where -- and how to put that incremental free cash flow to work? I'm not saying call for a dividend buyback, et cetera, BD, but just how you guys think about your strategy and where that capital should go in a '28, '29, '30, et cetera, free cash flow generating BridgeBio?

Yes, totally. Well, I would say at the very highest level, and as we've been talking about, I think, a little bit more over the last couple of months, we're very pleased with the efficiency of our R&D engine, efficiency both in terms of time and cost and obviously, the validity of it as it pertains to probably a technical success. And as we talked a little bit about a few months ago, Mani, I know you and I have connected on this, the pipeline that is attended at Gondola is a wonderful example of the ample substrate available to help patients with genetic disease. And our objective function is to serve as broadly as possible. So given all of those things, with cash flow, we would intend as long as we can beat our cost of capital to continue to reinvest into R&D and in some cases, bring in partially owned assets that we have access to through Gondola and bring those forward into the, again, highly efficient operating model that we've established in mid- to late-stage development and ultimately in the commercial setting. Obviously, the stock is not trading where we would like it to trade and it's trading quite a ways off intrinsic value. There are opportunities to do other things with cash flows, namely share buybacks and dividends if indeed, we don't feel we can capture the NPV of fully financed assets as they move into the marketplace. So a bit of this will be just to see whether or not we can do a better job of helping investors avail of the value that we create and getting the stock price and cost of capital back up into a normal realm. And then that, I hope, would under sort of get us going in terms of growth in the R&D sector. Does that answer your question?

Absolutely. Congrats again a good quarter...

Your next question comes from the line of Tyler Van Buren from TD Cowen.

So following the 3 successful Phase IIIs in recent months, can you elaborate on your launch readiness and expected field footprint in the context of your burn commentary and the expected cadence of regulatory and commercial catalysts over the next 12 to 18 months?

Yes. Thanks, Tyler. Maybe I'll ask Matt and Tom to comment on that.

Sure. Tyler, so I think we're going to follow the same rigor as what we did for the Attruby launch. I think one of the big differences is this time, we'll be launching on a global basis. And as a part of that, we're building in the U.S., but also ex U.S. as well. We'll have more on that towards the end of the year in terms of both additional revenue for Attruby that will be coming rest of world, but also our prep and build-out for the 3 additional launches in the U.S. and the rest of the geographies as well. And I think what's important, you've seen the recent data readouts. We're setting or resetting the standard of care for each and every one. For LGMD2i and ADH1, it's going to be a first and best-in-class story. And for achondroplasia, it's going to be resetting the standard with best-in-class data.

And I'll take the question on burn. So as we've discussed, we've seen over the last several quarters, our cash burn has been on a downward trajectory. That's driven, first and foremost, by the strong ramp of Attruby and gross profit that it provides. But I will also say that it's been due to our disciplined OpEx profile here. As we look to ramp the next 3 launches, we do expect a gradual increase in OpEx throughout the year. However, we expect burn to hold steady throughout most of the year and drop off again towards the end of the year as we continue to see an expanding operating margin provided by the Attruby brand. Thanks for the question, Tyler.

Your next question comes from the line of Biren Amin from Piper Sandler.

Congrats on the quarter. I have a high-level question. As you've demonstrated impressive productivity and outlined BridgeBio way as a sustainable development model, which was highlighted in the drug discovery today manuscript recently in January. With that in mind and as we look beyond 2025, what are the key drivers of momentum for the company? And when should investors expect new assets to enter the pipeline?

Yes. Thanks, Biren. Thanks for the question. A little bit overlapping with some of my comments that I gave against Mani's question as well. But maybe I'll just say like near term, our focus continues to be obviously making sure that these drug products that we just registered successful Phase IIIs on are approved and ultimately launched correctly. That's the highest and best use of our time right now. The second best use of our time are the additional indications associated with medicines that we know are safe and effective, such as obviously chronic hypopara in the context of encaleret and hypochondroplasia and some of the other height disorders that Justin has talked about in the past associated with infigratinib. So that would be the sort of second category of growth. But I think you're asking the right question. Look, at the end of the day, as I mentioned earlier, the scientific substrate available to us to target well-described genetic conditions at their source continues to grow. And we're finding starting points all the way from the clinic back to early-stage discovery where we're probably most adept. And that's highlighted in the ever-growing pipeline at Gondola, which obviously BridgeBio shareholders partially own. So I would think over the course of time, if indeed we're able to correct our cost of capital and trade closer to intrinsic value, number one. And number two, we're able to really stick the landing and effectively get these drugs approved and launched. There will be a moment where we can bring some of those other assets in and prosecute them with the great infrastructure that we've already set up here, namely mid- and late-stage development, regulatory, the ability to put it in the hands of a great commercial team and to do all of that efficiently in terms of time and cost. So that's kind of the high-level answer. I don't have anything specific on a specific asset that we would bring in anything like that. I do think you should look for us generally to rely on organic, not inorganic growth, organic meaning from the ecosystem of BridgeBio activities and BridgeBio companies and not looking for big M&A or anything like that. We tend to look at that as a rather expensive mode of growth and one that we probably don't need to take on given the fact that we're getting to INDs in less than $10 million or $15 million and through Phase I/IIs in less than $100 million. So unless we run out of ideas internally, I don't think we would be aggressively moving toward M&A for growth in the next 3 to 5 years.

Your next question comes from the line of Cory Kasimov from Evercore ISI.

This is Adi on for Cory. I wanted to ask on infigratinib. Now with the Phase III data in hand, how are you thinking about the competitive landscape across not just CNP pathway therapies, but also other FGFR-targeted programs, which are more specific to FGFR...

Thanks for the question. Yes, Justin, do you want to take that?

Yes. Again, thanks for the question. So really, we believe the balance of efficacy and safety shown PROPEL 3 proved that infigratinib is not just best-in-class, but potentially last-in-class in achondroplasia. On the efficacy side, we had a plus 2.1 center per year change from baseline HV and the first and only static improvement in proportionality. Most importantly, we normalized absolute HV, bringing back kids with achondroplasia to wild-type growth levels of 6 centers per year. Across every single measure of efficacy, whether it be in animal models or in the clinic, we have set a new bar here. On the safety data side, we had a home run outcome, right, with basically no change in mean phosphate levels between the placebo and treatment arms and no signs of FGFR1 or 2 associated toxicity. And really, I think the other molecules being developed in this space, whether it be CMPs or FGFR3 inhibitors have 2 issues. One, on the efficacy side, you actually don't want to overshoot 6 centimeters per year too much. We've heard from clinicians that the skeletons and bones in achondroplasia aren't built for too much growth given preexisting low bone mineral density, and we really hit the sweet spot there. On the safety side, we obviously avoid all the well-known issues associated with the CMP class, such as on vasodilation. Now the other FGFR3 inhibitors in development trade off selectivity for FGFR1 and 2 for significant VEGFR3 liabilities. And there's 2 issues related to that, and they're not just theoretical risk. The first is on sermatogenesis. And because of this, enrollment in trials are restricted to pre-puberil mails for these other programs. And the second and potentially even more of a looked issue is the effect on angiogenesis. Many molecules that have in vitro potency findings for VEGFR3, even without clinical findings, end up with a box warning on their labels for impaired wound healing. And a great example of this is RETEVMO. So net-net, we're really happy with where we've landed on data and our safety profile obviates the need for other FGFR3 inhibitors. We absolutely could go up further in dose given our safety data, but really think that there's no need to in achondroplasia given that we have gone back to wild-type levels of growth. So I hope that answers your question.

Your next question comes from the line of Elena Merlefrom Barclays.

But if you could go over your views in a little bit more depth on the TAF IP and some color there and specifically your base case for when tafamidis goes generic in the U.S., how you're thinking about it? And can you elaborate on why this doesn't matter for Attruby in your view? And then I have a follow-up question.

Elena, thanks for the question. Yes, I mean, broadly, we tend not to comment on the IP situation for our competitors, but obviously, it's been a big story for the stock here. So let me turn it over to Chinmay to take a crack, and I'm happy to elaborate on it.

Yes, happy to take that. Elena, thanks for the question. Maybe I'll talk about it in 2 ways. I think we -- as Neil mentioned, we try not to talk about our competitors' IP, especially when the competitor is not as -- we believe not as potent as our molecule. But I think let's talk a little bit about what we think will happen on the trial and maybe a little bit on our strategy for why this doesn't really matter. So I think maybe I'll start quickly on Europe since I know you had some questions there. I think it's important to note that Pfizer withdrew its patent there. And so that's going to limit the precedential value of this ruling for related parties and other jurisdictions. I think as Neil highlighted in his prepared remarks, our base case for Europe has always been entry and -- generic entry in 2030, and that's based on 4D for wild-type ATTR-CM. That's still our assumption. There are 2 more patents in Europe, which protect Pfizer. So there may be some potential upside there. It's also important to note on that front, the really strong treatment naive share that Bayer has been achieving, which talks a little bit about how physicians, not just in the U.S. but globally are recognizing the differentiation of acoramidis. Turning to the U.S., which I think is the market which probably matters a little more. I think Neil had a bunch of comments in his prepared remarks on how we think about it. But based on publicly available information, I think that a couple of things are interesting to note there in addition to what Neil said. One is that Dexcel, which is, I think, the lead filer has conceded infringement of the 441 polymorph patent. And the other interesting thing to note is also that the bar for validity is much more innovator-friendly under U.S. law. So as Neil mentioned in his remarks, IP is always uncertain. So we'll keep monitoring it and seeing what happens in Europe in April in the U.S. trial. But I think that we feel good about where we are right now. And I think that we do feel like VYNDAMAX should have protection into the 2030s, potentially up to 2035. I think it's important to note, though, that we feel like the tafamidis IP debate is a little bit of a side show. It doesn't really matter for Attruby's uptake. You guys heard today from Neil and Matt and everyone else about the tremendous momentum which we are seeing for Attruby. The patient weeks -- number of patients per week continues to increase as we go forward in our launch and continues to accelerate. And I think that's driven by the differentiated clinical data, which we have for Attruby. And so even in a scenario where a generic tafamidis enters the market, we just don't believe that a less efficacious product will displace a clinically superior therapy in a serious progressive disease. We've seen this pattern, by the way, play out in multiple therapeutic areas such as PAH, statins, prostate cancer, where differentiated second-to-market molecules continue to grow even after the first to market goes generic. So we feel good about the long-term value of Attruby, and I think that we look forward to continuing to execute against that.

Great. And just a quick follow-up. How do you see the use of serum TTR in clinical practice in the real world evolving and your perspective there and how that could potentially show differentiation for physicians?

Yes. Great question, Elena. So I'd say, first and foremost, you probably saw the recent 2 JAK papers that came out looking at serum TTR elevation and correlating it with downstream relative risk of mortality reduction. Both of those were associated with tafamidis, but they reiterated the point that our publication last year made, which is that ever higher levels of serum TTR are associated with ever lower levels of downstream mortality. And that roughly, you could imagine every 1 mg per deciliter increase leading to about a 5% relative risk reduction in downstream mortality. So that's exciting. Obviously, the studies that Pfizer did had significantly higher levels of variant patients in them. So you're going to see similar serum TTR rise as you saw in our studies, but that's just basically rigged up so that you can see a higher increase because you've got many more variant patients. If you normalize for variant to wild-type patients, even in cross-trial studies or cross-study comparisons, you can see that we have a significantly higher serum TTR elevation. But I think that the most interesting data from that standpoint were literally the same patients going from tafamidis on to acoramidis in the context of our OLE and ATTRibute, where you saw, as I mentioned earlier, that 3 mg per deciliter increase when going from a partial stabilizer to a full stabilizer. And I think now we can say -- and I remember Elena having this debate with you a long time ago, even it's like what is the shape of that response curve in terms of ever higher levels of stabilization leading to ever better outcomes. And I think here, at least we can say it's roughly 5% per mg per deciliter. So it's about a 15% relative risk reduction in terms of mortality going from tafamidis to acoramidis, putting aside the earlier onset of action and some of the other advantages. So I think serum TTR will become ever more important based on these publications. Let's see. It's not broadly used. I don't know, Matt, if you disagree right now. But I think our hope is on a go-forward basis, it will become an ever more important marker of drug action and also therapeutic choice.

For the question...

And your next question comes from the line of Andrew Tsai from Jefferies.

Just wanted to stick on the theme of cash burn and near-term profitability. What are your guys' expectations on priority review vouchers for nondilutive capital? I think they're going for $200 million to $300 million a piece right now. So which of your pipeline drugs or even which indication per drug could be eligible for PRV? And when do you expect to receive them?

Yes. Good question. I didn't factor that into my earlier comments. But Tom, do you want to take that?

Yes, sure, I'll take that. So first, absolutely thrilled to see that program has been reauthorized. It's been a hugely successful incentive for BridgeBio companies like us in being able to responsibly invest in diseases that affect very few patients. and otherwise would be at risk of being left behind. So really happy that, that's been extended. We actually have 3 programs that have already received rare pediatric disease designation, and we expect to be eligible to receive a PRV upon approval. So those are BBP-418 for limb-girdle, infigratinib for achondroplasia and then our BBP-812 program. And as you rightly pointed out, the pricing of these has not only held in, but risen over the last few months. So there's significant asset value there already within our portfolio. Looking out more broadly to the Bridge ecosystem, many of the programs we work on over at Gondola Bio affect children. And so there will -- I would expect there to be many more PRV-eligible programs in the ecosystem around Bridge. So a great day for patients and biotech companies like us that are focused on rare disease communities.

That concludes our question-and-answer session for today. I'll now hand it back over to the company.

Thank you, investors, for joining us on our call today and for the analysts to ask the questions. We look forward to updating you on our next quarterly call in a few months. Thank you.

That concludes today's meeting. You may now disconnect.

Good day. I will be your conference operator today. [Operator Instructions]

Before we begin, I would like to remind everyone that today's call may contain forward-looking statements within the meaning of the federal securities laws, including, but not limited to, the statements about BridgeBio's future operating and financial performance, business plans and prospects and strategy. These statements are based on current expectations and assumptions that are subject to risks and uncertainties which could cause actual results to differ materially from those expressed or implied in these forward-looking statements. For a discussion of these risks and uncertainties, please refer to the disclosure in today's earnings release and BridgeBio's periodic reports and SEC filings. All statements made here are based on information available to BridgeBio as of today, and the company undertakes no obligation to update any forward-looking statements made during this call, except as required by law.

With that completed, BridgeBio, you may begin your conference.

Thank you, operator, and thanks to everyone for joining this call. Together with our incredible team, I'm grateful to be able to share with you, on behalf of the extraordinary physicians, participants, families and caregivers involved, the positive Phase III results of our PROPEL 3 clinical trial. The strongly positive and consistent data the community worked tirelessly to generate come together at this moment to portend a new and better day for the families we serve, and we are excited to continue our partnership with the achondroplasia community to ensure we meet their needs as we move our medicine into the commercial setting. As a reminder, the slide deck associated with this call is publicly available, and we will refer to specific slide numbers as we progress the discussion.

Before I briefly set the corporate context in today's readout, I want to begin with the most important slide in this document, Slide 5. A thank you to the amazing and inspiring children and families, advocates, physicians, clinical research staff and collaborating research partners that made this study possible. As we have hopefully demonstrated in the past across conditions as disparate as MoCD Type A and ATTR cardiomyopathy, we recognize our responsibility to you now and therefore, plan to continue studying this medicine in additional settings and to provide it as broadly as possible for those who may want it.

Turning to Slide 6. I'll take a brief moment to provide some corporate context for today's data. As many of you know, BridgeBio was founded 10 years ago to target well-described genetic diseases at their source. With this positive Phase III result, we extend our ability to serve communities with unmet need and build on our team's remarkable track record. Our 4 most recent Phase IIIs in ATTR cardiomyopathy, LGMD2I, ADH1 and achondroplasia have all been markedly successful and together lay the groundwork for a diversified and differentiated genetic disease company in the years to come.

We do this work knowing that every minute matters for the communities we serve. As shown on Slide 7, we seek to minimize time and expense per program so that we are able to do and serve both large and small genetic marketplaces in economically responsible ways. We do this in part by employing small teams to run each of our programs forward, our belief being that at least in the R&D setting, smaller teams work harder, faster, sweat the details more and have more fun doing it. This style of work is particularly well suited for advancing programs in the Mendelian disease space, where we start with a strong understanding of patho mechanism and what is required of a medicine to matter. Selecting the right problems to work on, not just the right platform, is an underrated and hard-to-explain skill. A team's prowess in this regard can only be understood retrospectively.

On Slide 8, we suggest that our strong scientific substrate and decision-making processes are yielding today, a high probability of technical success from our portfolio. Over time, we hope we can approach the engineering life success rates that Genzyme and Shire demonstrated when pioneering the ERT and PRT spaces. Finally, as suggested on Slide 9, there is no better time than now to be applying the principles of efficient operating and high-quality problem selection to the field of genetic disease. As our ability improves to resolve more clearly mechanism of disease, employing many of the advances referenced on this slide, so in turn does our opportunity to help greater numbers of individuals. That's where we're headed. But the floor today belongs to our efforts in achondroplasia and the remarkable results of PROPEL 3.

With that, I'll turn it over to Justin, Daniela and team to tell you more.

Thanks, Neil. Our belief in infigratinib, just like with any BridgeBio program, is rooted in the foundational belief that the status quo is not good enough for families and individuals living with genetic conditions. It's a belief that we can and that we should do better than current options by targeting the cause of biology, which for achondroplasia is directly inhibiting FGFR3 gain-of-function.

PROPEL 3 is a culmination of a scientific journey that started back in 1994 when gain-of-function mutations in FGFR3 were first identified as the cause of achondroplasia. This discovery led to the [ SAML ] paper at JCI in 2016 by our scientific collaborators at INSERM, led by Dr. Laurence Legeai-Mallet, who used infigratinib to demonstrate for the first time, profound improvements in achondroplastic mice. 8 years later, we published our seminal results from our Phase II data in the New England Journal of Medicine, demonstrating proof of concept that directly targeting FGFR3 can lead to more types of efficacy and deeper efficacy in the clinic. And that brings us to today's top line readout for PROPEL 3, where the totality and consistency of evidence clearly demonstrates a best-in-class product profile that is able to do more and to do better than the status quo.

Now moving to Slide 12. I'm pleased to announce that across every single key measure of efficacy, infigratinib sets a new bar while also being a safe daily oral. On the primary endpoint of change from baseline in annualized height velocity, where the bar has been stuck at plus 0.15 centimeters per year, infigratinib was able to demonstrate a mean difference against placebo of plus 0.21 centimeters per year and LS mean difference of plus 1.74 centimeters per year, with both Ps being less than 0.0001. This is the largest change ever observed in RCT for achondroplasia, which is all the more impressive given that we studied the broadest age range across any trial.

On change in height Z-score, a secondary endpoint, where no treatment arm has been able to show more than an improvement of plus 0.3 standard deviations, we broke plus 0.4 for the first time on the treatment arm with an LS mean of plus 0.41 on the infigratinib arm and an LS mean difference against placebo plus 0.32 with a P of also less than 0.0001.

Impact on upper to lower body proportionality has been the endpoint that has been most difficult for any 52-week placebo-controlled trial to show real impact on. We're excited to announce today that for the first time, a statistically significant result has been achieved against placebo. In a pre-specified exploratory analysis described in the [ set ], we demonstrated an LS mean difference of minus 0.05 against placebo with a p-value of less than 0.05 in children younger than 8 years of age. This was a subgroup that was nearly 50% of our trial population. In the overall population, we demonstrated a favorable trend with also a very strong treatment arm effect of minus 0.05.

Finally, on safety, we're thrilled to repeat the results that we saw in Cohort 5 of PROPEL 2. We had a well-tolerated safety profile that was consistent with the lack of inhibition of FGFR1 or 2. There were no SAEs related to study drug or discontinuations related to study drug. There were only 3 cases of hyperphosphatemia. All 3 cases were mild, asymptomatic, transient and resolved without the need for either dose reduction or discontinuation. There were no AEs associated with inhibition of FGFR1 or 2, such as corneal or retinal. And importantly, we avoided the AEs associated with CNP analogs such as symptomatic hypotension, ISRs and hypertrichosis. Given the totality and consistency of this data, we believe that the future of treatment options for achondroplasia does not involve a needle, whether it be daily or weekly.

I'll now hand it over to Dr. Daniela Rogoff, our Chief Medical Officer who has been with this program since day 1, to go over these results in detail. Keep in mind that these are just the top line data, and that more detailed results will be forthcoming in future conferences.

Thank you, Justin. Let's start on Slide 14 with the overall Phase III study design. This was a double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral infigratinib in children 3 to less than 18 years of age with potential to grow.

As you can see, PROPEL 3 covered the largest age range of any randomized controlled trial ever conducted in achondroplasia. Children had to have completed at least 6 months in our observational study, PROPEL, before being randomized in a 2:1 ratio to receive either infigratinib or placebo. Children received treatment for 52 weeks and then were offered the possibility to roll over to the long-term extension study, PROPEL OLE. The primary endpoint was the change from baseline in annualized height velocity compared to placebo, and the key secondary endpoints were the change from baseline in height Z-score in relation to reference data in achondroplasia and change from baseline in body proportions also compared to placebo.

On Slide 15, we have the demographics and baseline characteristics of the participants. 74 children were randomized to the infigratinib arm and 39 to the placebo arm. As you can see, the age and sex distribution were very similar in both treatment arms. And likewise, the baseline annualized height velocity and height Z-score were also very similar, showing how comparable both treatment arms were.

Now let's talk about the exciting efficacy results. We are starting on Slide 16 with the primary endpoint of change from baseline to week 52 in annualized height velocity compared to placebo. As Justin mentioned, the study's primary endpoint was met. On this table, we can see the mean AHV at baseline and at week 52 for both treatment arms. The mean difference in the change from baseline in the annualized height velocity between oral infigratinib and placebo was 2.1 centimeters per year, which was highly statistically significant with a p-value of less than 0.0001. The difference in the least square mean change from baseline in the annualized height velocity between oral infigratinib and placebo was 1.74 centimeters per year, which was as well highly statistically significant with a p-value of less than 0.0001. Both the differences in the mean change and the least square mean change are the largest difference seen in any randomized controlled trial in achondroplasia.

On Slide 17, we have the results at the different age groups. We can see that the robust increase in annualized height velocity can be seen consistently across all age groups. To our knowledge, these increases are the highest reported in each subgroup.

Slide 18 beautifully shows the absolute annualized height velocity. We can see that children that received oral infigratinib quickly increased the AHV to around 6 centimeters per year that is the mean for the average height pediatric population and continue to grow at that rate, whereas children in the placebo arm continued to grow at the average annualized height velocity of children with achondroplasia. The least square mean annualized height velocity on the treatment arm was 5.96 centimeters per year, the highest reported to date.

Moving on to Slide 19. On this slide, we have the results on the key secondary endpoint of change from baseline in the height Z-score compared to placebo. These height Z-scores are calculated using reference data in achondroplasia. We can see that the increase in the growth rate with infigratinib translated in a continuous increase in the height Z-score, while the height Z-score persisted unchanged in the children that received placebo. The least square mean change from baseline compared to placebo was 0.32 standard deviation score, also the largest observed in 52 weeks in a randomized controlled trial. The increase in the treatment arm of 0.4 SDS, or standard deviation score, is also by far the largest seen to date.

On Slide 20, we have the results of the other key secondary endpoint of change from baseline in upper to lower body segment ratio compared to placebo. When evaluating all the children, treatment with infigratinib resulted in a favorable trend to improvement in body proportions, showed by a decrease in the upper to lower body segment ratio compared to placebo with a least square mean difference of minus 0.02.

However, and what we are most excited about are the results in the subgroup of children 3 to 8 years old. That is the baseline age window where changes in body proportions are more likely to be evident given the natural change in the upper to lower body segment ratios throughout childhood. In this age group, infigratinib demonstrated a statistically significant decrease in the upper to lower body segment ratio compared to placebo with a least square mean difference of negative 0.05 and a p-value less than 0.5. This age group made up nearly 50% of our trial. Oral infigratinib is the first drug to demonstrate a statistically significant difference in body proportions in a 1-year treatment trial.

Now let's move to safety on Slide 21. Infigratinib was well tolerated with no safety concerns and no safety signal indicating inhibition of FGFR1 or 2. Most adverse events were Grade 1 or 2 in severity and typical for children of these ages. Treatment-emergent adverse events were well balanced between the treatment arm and the placebo arm. We did not have any Grade 3 or higher, any SAE or any adverse event leading to study discontinuation that were deemed related to infigratinib. Focusing on areas of interest, we had only 3 cases of hyperphosphatemia, all of which were mild, asymptomatic, transient and did not require dose reduction or discontinuation. We did not have any adverse event associated with inhibition of FGFR1 or 2, such as retinal or corneal adverse event.

On Slide 22, we can see the phosphorus levels throughout the study. The darker blue line shows the mean and standard deviation of the phosphorus levels in the infigratinib arm, and the lighter gray line in the placebo arm. The colored area reflects the reference range. As you can see, the mean phosphorus levels were very comparable between both treatment arms at all time points and within normal ranges. There was no change in the mean phosphorus levels at week 52 compared to baseline in either of the treatment arms. Furthermore, the maximal change of phosphate levels observed for any child at any time point was within the typical intra-subject variability in the pediatric population.

So in summary, these results show that oral infigratinib works and has a very favorable safety profile with no evidence of inhibition of FGFR1 or 2. The exciting results about body proportions suggest that infigratinib has the potential to improve clinically meaningful outcomes like functionality and activities of daily living.

So what comes next? We are working on regulatory submissions to hopefully bring oral infigratinib to children with achondroplasia as soon as possible. We are planning to submit the New Drug Application to FDA and Marketing Authorization Application for EMA in the second half of 2026. And of course, we will be presenting the results from PROPEL 3 at medical and patient advocacy group conferences.

Before I hand it over to Justin, I wanted to express our deepest gratitude to the study participants, their families, our principal investigators and their study team, advocates and collaborating research partners. None of these could have been possible without you.

So now back to Justin.

Thank you for the overview of the data, Daniela. On Slide 26, we would be remiss if we didn't acknowledge that the results of PROPEL 3 are just the beginning of our commitment to families and individuals living with achondroplasia. We hear the feedback that it's not just about changes in height, but more importantly, longer-term improvements on health and function. Today's results on proportionality are a promising start, but there is still a lot of work to be done. We will continue to study the longer-term impact of infigratinib on important measures such as body proportionality, spine parameters, physical functioning and other factors that may meaningfully impact quality of life. We look forward to sharing these results as they are available over time with the community.

On Slide 27, I'd like to highlight that today's results are just the beginning of what's possible for a safe oral FGFR3 inhibitor. Within FGFR3-driven gain-of-function conditions, we have an active ongoing trial for infants and toddlers with achondroplasia, which we believe will be registration-enabling for that age group. In hypochondroplasia, the strength and consistency of the results today give us the confidence to significantly accelerate that program, which is also driven by FGFR3 gain-of-function mutations. We are now enrolling the observational run-in for our Phase III trial.

Finally, within the category of FGFR3-driven conditions, we know much of the attention to date on therapeutic options for achondroplasia have been focused on individuals with growth potential. Given the mechanistic role of FGFR3 in spinal tissue, we believe that an oral FGFR3 inhibitor may uniquely be able to impact aspects of spinal health in an adult achondroplasia population, and we are planning for further exploration in this area.

We also believe that outside of FGFR3 gain-of-function conditions, inhibition of FGFR3 may be able to increase growth in some other growth conditions. There is a growing body of evidence that there is FGFR3 overactivity in conditions like Turner syndrome and SHOX deficiency, and we have initiated planning for clinical studies in these conditions. Given the safety results seen today, it's clear that we will have the ability to explore higher doses in these conditions, if needed.

I'd now like to hand it over to Matt Outten, our Chief Commercial Officer, to go over our commercial plans for infigratinib in achondroplasia.

Thank you, Justin. 6 for 6 has a nice ring to it, and I'm excited to share our commercial plans for infigratinib, the sixth rare disease medicine BridgeBio will potentially bring to the market. This matters because it means we have real experience planning and launching medicines, and we've built and proven a repeatable commercial engine in rare disease. This is a team that knows each other well and knows how to perform together. Many of us have worked side-by-side for years, and our playbook has delivered across multiple therapeutic areas.

So what does that mean for infigratinib in achondroplasia? It means that we know how to reach the right health care professionals quickly and efficiently. We've listened carefully to the community, and we won't let them down with the subpar and lackluster support programs that are far too common in rare disease. Consistent with our program in ATTR-CM, we will offer the most generous and comprehensive programs in the space. And we know how to recruit and deploy top-tier commercial talent to build the strategy and execute the tactics required to win in a competitive market.

In that spirit, I'm pleased to announce that Aaron McIlwain has joined BridgeBio from Ionis Pharmaceuticals as the Senior Vice President of Sales and Marketing to help us bring infigratinib to the market. Aaron has a strong track record across multiple product launches, and we are thrilled to have him join us in this next phase of commercial preparation. He will be joining many of the same individuals who drove the successful launch of Attruby and who will also be central to the launch of infigratinib.

If we move to the next slide, you can see just how large the opportunity is in achondroplasia, both in the U.S. and globally. Of note, treatment is concentrated, allowing a reasonably sized sales team to effectively cover the entire U.S. market. We also plan to launch infigratinib in the rest of the world ourselves with the exception of Japan, where we have a partnership established.

So why are we so confident in this launch? It starts with the data. The data discussed today represents the highest efficacy rates shown to date in a clinical trial across average height velocity, Z-score and stat sig improvements in proportionality. In addition, infigratinib was well tolerated, with no SAEs related to the medication. That combination, compelling efficacy and safety is going to translate to exceptional launch performance and set a new standard of care in achondroplasia. We will be updating our market research with this new and exceptional data, and we'll come back to you with updated market results soon.

And let's not forget that on top of the efficacy and safety data, infigratinib will also be the first and only oral therapeutic option, providing freedom from injections, hypotension and injection site reactions, making infi the first and only disease-modifying oral medication and the new standard of care for achondroplasia. We're highly confident in our ability to launch successfully in achondroplasia not only because of the compelling data announced today, but because of the team, the platform and a proven track record that puts us in a strong position to deliver 6 for 6.

Thank you, and I will now turn the call back over to Justin.

Thank you, and we will now take questions.

[Operator Instructions] Our first question comes from the line of Biren Amin with Piper Sandler.

Maybe just to start off, as you think about how this data translates to a commercial opportunity, how are you thinking about peak year sales opportunity for infigratinib and overall market share based on the strength of the data that you presented today? And can you maybe share more on the commercial opportunity across both U.S. as well as ex-U.S. geographies?

Thanks for the question, Biren. Now this data set really represents the best case scenario for commercial TPP, superior AHV, superior changes in height Z-score, [ clean safety win ] and the surprise upside of show an impact proportionality, especially when it's commercially important in the [ 38 ] group. Now with clinicians that we've spoken with so far, they've used phrases like game changer or transformative. Now Matt, you can probably comment more on the market sizing?

Sure. Thanks, Justin. So I guess I would just call out the skeletal dysplasia market is already about $5 billion, including achondroplasia. And remember, the market research that we were using before -- it did and continues to show that injection burden is a significant concern, and families are eagerly awaiting an oral option.

And in the research we've done before, we were using our old TPP. Even with that, we saw over half of the market being captured with infigratinib. And as I mentioned earlier, we're refreshing that data now and changing up our target profile with the new data announced today. And that has a significant improvement in terms of what we were testing before, especially in proportionality, and we'll report back to you all on what we see post that market research.

Our next question comes from the line of Cory Kasimov with Evercore ISI.

Look, these are super exciting results. And maybe the most surprising part, at least to me, are the data around body proportionality in the 3- to 8-year olds. So I want to ask how you believe or what you're hearing from like how regulators view proportionality, whether it's kind of supportive only versus potentially label relevant? And then separately, but related, from a treatment point of view, what's the ultimate clinical implication here of this proportionality benefit?

Yes. Thanks so much for the question. So let me hand it over first to Daniela to talk about the clinical implications, and then we can talk about the label.

Yes. Thank you. And thank you for the question. And the reason why we are very, very excited about body proportions is because the potential -- the great potential for improvement in a very clinically meaningful outcome. Particularly, improvement in this outcome in body proportion is -- will reflect or has or suggest the potential benefit of infigratinib in functionality and activities of daily living. So the implication is great. It is big on the community and on the children because this is something that really were the key points for them to expect a meaningful outcome in a clinical trial.

Yes. And Cory, given the totality and the consistency of the data on every single key metric of interest, given the size of the subgroup here on the proportionality endpoint making up more than half the trial, I think we're optimistic of our odds that language around that in the label, but still a little bit too early to comment.

Our next question comes from the line of Tyler Van Buren with TD Cowen.

This is Nick on for Tyler. Congrats on these results in the third positive Phase III in nearly as many months. So from us, safety has obviously been a common topic among investors, but the 4% Grade 1 hyperphos is impressive. What happened with these 3 children? And were these the only patients that had phosphate values above the normal range?

Also for a quick follow-up, the value proposition in treatment-naive patients is pretty straightforward. But how about the prevalent switch patients? Is there anything to do or to explain to physicians to support this switch?

Yes. Thanks for the question. So I'll hand it over to Daniela first to talk about the hyperphos cases.

Yes. Thank you. Let me start by reiterating that infigratinib had a very favorable safety profile with no safety signals indicating inhibition of FGFR1 or 2. Regarding the 3 cases of hyperphosphatemia, we were very careful and used stringent criteria in our clinical trial. These 3 children had a very mild elevation of phosphorus. And even though their phosphorus values were above the reference range, they reflected an increase from their baseline of no more of 0.4 milligrams per deciliter that is absolutely within the expected variability in the phosphorus levels. Again, but it's important to reiterate that these elevations were transient and did not require dose reduction or treatment discontinuation.

And to give a little bit more detail on these 3 cases, all these were boys around 13 years of age, that is an age where the reference range for phosphorus changes. The values in all 3 cases were mildly elevated for the strict reference range used in the study. And -- however, these values would not have even been considered as above of normal ranges had we used a less strict range, for example, the clinically accepted reference range of [ CALIBRATE ]. So this, in addition to the data showed earlier where the mean phosphorus was within normal ranges at all time points, it shows that there is no signal of infigratinib inhibiting FGFR1.

Yes. And to your question around the switch marketplace, I think there's still definitely a very significant opportunity there for us uniquely. Now going back to kind of the investor webinar we did a few weeks ago, when we did a lot of clinician research, the #1 reason why physicians today and families today aren't interested in therapy in the United States, in particular, is around the want to avoid daily or weekly injections. So we think we're uniquely set up for the treatment-naive population and for the switch population as well. There's already a lot of interest from families and clinicians on having kind of the needle-free option.

Our next question comes from the line of Mani Foroohar with Leerink.

A number of the key ones have been asked, so I want to dive into a little bit of commercial strategy and market segmentation, if all right. Obviously, this has for VOXZOGO been an OUS growth story more recently. Can you give us a sense of to what extent you think proportionality and better AHV for you can potentially expand penetration into the TAM? Are there subpopulations of patients who are specifically less compelled by height itself as an endpoint that might be brought into the market? And to what extent is that playing out in the U.S. versus OUS markets in terms of patient segments, achondroplastic children with achondroplastic parents as opposed to normal stature parents, et cetera?

Yes. Thanks for the question, Mani. So we actually did some interesting work kind of looking at different oral analogs, seeing that when they first enter the marketplace, how they change the dynamics and the total addressable marketplace when it's been previously only been injectables. And on average, I think within the first 5 years, the total marketplace grew, I think, by an average of three- to fivefold. I think that's really kind of just like speaks to how important it is to have an oral alternative for these chronic conditions, I think, regardless of geography.

And again, I think that's consistent with the research that we've done in the United States, where we've heard that the #1 reason why families aren't on a therapy today is around not wanting to deal with the burden of injection. And I think having the very strong signal on proportionality at week 52, especially in the 38-year-old subpopulation, which again, I think could be one of the most commercially important populations, is just kind of even more reason for people to consider looking at the FGFR inhibitor.

Question comes from the line of Salim Syed with Mizuho.

Congrats on the data. It looks really good. Neil, Justin, maybe just a couple from us. One, just on the 5.96 centimeters per year absolute AHV. Could you just clarify, what was like the upper end of what you saw in the individual patients? Like were there any cases of hyper growth? Or are we still all talking about patients being under any -- like still within normal, but at the very, very top end of that range?

And then the second, just -- I think I missed a comment on the p-value of less than 0.05 for body proportion, is the base case that, that will get into the label with that p-value? Or will you need to combine it with PROPEL 2 or -- or what's exactly the status there and the body proportion into the label with that p-value?

Yes. No, I think thanks for the question. So why don't we first talk about the 5.96, right? I think that's actually -- thanks for picking up on that. That's actually one of the numbers we're most excited about. When we've looked at historical literature across multiple different [ payers ] and natural history studies, the average AHV for the population of average [indiscernible] is 6 centimeters per year, right?

So I think the fact that we are essentially at that level just kind of goes to show, one, that really being able to inhibit FGFR3 at the source is able to kind of restore levels of growth back to kind of the wild-type level. And two, there's really not much kind of room for further improvement. We really didn't see any concerns around [ hyper growth ] or anything like that. And I think, again, it is a really nice data holistically.

Now with regards to your question on proportionality. Again, just kind of given the consistency of the data that we've seen in all the different measures, right, across AHV, Z-score, the strong proportionality signal that we saw in this large sub population and the totality of the data, again, it's always too early to comment on kind of the regulatory discussions. But given the fact that we have breakthrough therapy designation with the FDA and a very collaborative relationship with the FDA to date, I think we're optimistic that I think this will be a really differentiated label.

Our next question comes from the line of Danielle Brill with Truist Securities.

Congrats on a great outcome here. So I've been getting some questions on the 2 different change from baseline scores in AHV, the 2.10 centimeters per year and the 1.74. I guess, what does the LS mean actually adjust for? And which of these is the most appropriate for comparison versus CNP and your Phase II signal?

Thanks for the question. Now first, I want to comment that infigratinib's efficacy was remarkably consistent between the Phase II and the Phase III data. 2.1 centimeters per year is the unadjusted mean between treatment and placebo, which is also the way it was measured in the Phase II.

The 1.74 number is a statistically adjusted number. We actually wanted to include both numbers because it can be opaque at times, what statistical models different companies use to adjust the observed meaning. And so we thought it was actually probably the best way to allow for apples-to-apples comparison. No matter which number you will choose to focus on, though, we have the highest AHV seen in this area to date. And really, I think this effect size, the magnitude of this effect size is further supported by the consistency and the totality of the magnitude effect that we've seen in all the other endpoints, whether it be absolute HV, change in Z-score and especially proportionality. And again, this is especially noteworthy given that we studied the broadest age range enrolled across any trial in the States to date.

The next question comes from the line of Paul Choi with Goldman Sachs.

Congratulations on what is very impressive data. There's been some questions and debate in the investment community with regard to the role of FGFR inhibition on the CNS, both centrally and peripherally. Can you comment on if you saw any observations or any measurable effects there? And second, just given the data and the fact that there isn't an oral option available currently on the market, do you think you can get a priority review with your infigratinib filing?

Yes. Thanks for the question, Paul. I'm going to turn it over to Daniela first talk on the CNS side of things.

Thank you. The results of the study clearly demonstrated that infigratinib was well tolerated, with no safety signals indicating inhibition of FGFR1 or 2. We just discussed, for example, the phosphorus, where we showed that phosphorus values were comparable to the placebo arm, and the 3 cases of hyperphosphatemia would not have even been considered hyperphosphatemia should we have used less strict reference range.

So regarding the claims of CNS safety issue, these are unfounded claims based on neonatal knockout mouse model experiments, which are certainly not relevant for the treatment with infigratinib of children with achondroplasia, the doses used here. This is supported by clinical data not only from the PROPEL 3, as we just showed, but data up to 5 years in nearly 200 kids in our study. Furthermore, in human PBMCs, at this exposure level, there were no inhibition of FGFR2. So again, infratinib showed a very favorable safety profile and with no signal of FGFR1 or 2 inhibition like hyperphosphatemia or corneal or retinal disorder. So the claims of CNS safety issues are not really scientifically or clinically substantiated.

Yes. And just to add a final point on that. It's actually remarkable, some of the outright lies one of our competitors in the space are saying. All they can do is make stuff up about other players in the space because they're not happy with the results. I think we stand firmly and proudly behind our safety profile. We're going to let our science [ stake ], and we're not going to stoop to their level.

Now Paul, going back to your question about prior review. So given the fact that we have Breakthrough Therapy Designation in space, I think there was a recent study shown that there's like a 90% correlation between breakthrough therapy status and priority review. So kind of given the totality of the data that we're seeing today, I think we have a good shot at priority review.

Our next question comes from the line of Andrew Tsai with Jefferies.

Congrats on all the success so far. Hopefully, more to come. I distinctly remember you guys mentioning to look at Z-scores when you hosted the webinar last month. Really, your height Z-score seems to outperform your peers. So what do you guys think this finding precisely means for the community?

And then secondly, these scores do increase over time when we look at the kinetics in your slides, which then raises a question to me, how much more improvement we can get on even more dosing past 52 weeks. So can we expect you to share another cut from the open-label follow-up data maybe this year? Or does that come later?

Yes. Thanks for the question. So let me hand it over to Daniela first on the Z-score.

Yes. So to address the significance of Z-score, it normalizes the height for the agents across the reference population that in this case is the achondroplasia reference population. This is the highest improvement in Z-score with an LS mean value of 0.41 in the treatment arm from -- as a change from baseline and a placebo-adjusted value of 0.32, which is also the highest across the trial. So this contextualizes the change in the height in its relation to the population. Justin?

Yes. I think something I'll also add, what's remarkable about the height Z-score other than the magnitude is actually kind of the speed of the separation too. I think we were able to reach kind of like a milestone like plus 0.2 and plus 0.3 faster than any other [ therapy ] in the space, and we're the first to ever get anywhere close to plus 0.4 in the treatment arm.

Now what does this actually mean, especially in terms of AHV, to your question around AHV as well. We have basically effectively normalized AHV to the group of the average stature population at this highest value seen across any trial at almost 6 centimeters per year. And really, it kind of leaves, based on that simple math, like a 0.04 center per year room for improvement to kind of get back to that wild-type level of growth. So especially given the safety profile today, I think there's really not much room for improvement here.

Your next question comes from the line of Ellie Merle with Barclays.

Congratulations on the data. You mentioned that there were some other indications beyond hypochondroplasia and achon that you were thinking about. Can you maybe elaborate on the biology and some of those indications and which you think might make more sense for an FGFR inhibitor versus which diseases the biology might make more sense for CNP?

And then a second question, just for hypochondroplasia. How are you thinking about the increase in AHEV that we should expect to see there relative to what we would see in achondroplasia? And any differences from a dosing perspective around how the dose response might compare between achon and hypochon?

No. Thanks for the question here, Ellie. So yes, we're really excited about some of the work we're doing in other indications outside of hypochondroplasia and achondroplasia, such as Turner syndrome and SHOX deficiency. And I think, again, in that -- in those cases, there's actually a kind of developing body of literature kind of showing high between those conditions and gain-of-function and activity in FGFR3. And so actually, there's actually a mechanistic rationale for exploration [ that's been for granted ] in those indications.

And if you think about how the CMPs are kind of trying to play up that type of angle there, it's actually really through inhibition of the MAPK pathway, which obviously, if you kind of target upstream of the FGFR3 pathway, you would actually expect the same results and actually with the benefits of having the oral form factor as well. So kind of more to come there.

With regards to your question around hypochondroplasia, I think we published a few months ago really, the consistency of the in vitro data between the mutations in the hypochondroplasia setting compared to achondroplasia. So we really kind of don't expect any differences in dose or efficacy between achondroplasia and hypochondroplasia population. But more to come there, and something really we're really excited about.

Our next question comes from the line of Anupam Rama with JPMorgan.

Congrats on the data. Just a quick broader question here. Like maybe for Matt, how do you think about the size and scope of the sales force here in the U.S.? And can you comment on synergies with ADH1? And then comment on how you think about a European build-out here?

Yes. Thanks for the question. I mean, I think the nice thing is it's a fairly concentrated market, but it is a large market. I mean I mentioned in some of my earlier comments, right now, it's $5 billion globally. These kids are all over the world, and we are planning to launch this ourselves outside of Japan. So we're in the process of building all of that out now. I don't think you would expect to see like an ATTR-CM size sales force for something like this. I think that's also similar to ADH1. I think you can cover the centers and the doctors very effectively with a small, really good sales force.

I think the nice thing, too, is the messaging is fairly simple. It's the best data that's been shown to date, and no more shots ever. So this is not a complicated sell. It's not a lot of physicians and health care providers that you have to hit. And the data is very clean and very easy to comprehend and looks amazing. So I would expect that this will be a fairly straightforward launch.

All right. And that concludes our call. Thank you, everyone.

All right. That concludes the Q&A session and today's conference call. We would like to thank you for your participation.

All right. Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my squad, Priyanka Grover, Joyce Zhou and Rati Pinge.

Kicking off the conference, we have BridgeBio. And then presenting on behalf of the company, we have CEO, Neil Kumar. Neil?

Well, thanks, everyone, for taking the time this morning. I'd like to thank Mike, Ben and the entire JPMorgan team for having us here again this year.

This morning, I was reminded that BridgeBio turns 10 this year. And for a vast majority of those years, we've had the absolute privilege of being pajooled, challenged, and sometimes supported by the man to the left at me here, Anupam. So thank you for the partnership through the years, Anup.

Maybe I'll continue in that vein of thinking and thank all of the investors, both in the room and on the line for the support over the last decade. Together, we have created the second, or third most efficient R&D engine for patients suffering with genetic diseases. Three approved products to date with hopefully three more to come in the next 12 months. Almost 20 INDs generated and most importantly, nearly 10,000 patient lives affected, with hopefully many tens of thousands of more to come in the coming years and decade.

But you didn't come here this morning to hear me talk about the past. You came to hear me talk about where we're going and where we're headed over the coming weeks, months and years. And for that, we continue to believe that it is day 1 in this era of genetic medicine. And I'll give you updates today, all new information across the 3 different stages of our business.

First and importantly, our commercial franchise in ATTR cardiomyopathy. Second, updates both on the data front and regulatory front for our late-stage franchises in achondroplasia, LGMB2I, ADH1 and Canavan disease. And then finally, I'll touch on some of that early-stage research substrate that's exciting us so much, and give you a good example of some of the early-stage research we're doing with our EPP, potentially best-in-class asset, that just cleared its Phase IIa.

But let me start with the most important slide in this document. We are preannouncing today our Q4 revenue number of $146 million. And the reason we get excited about this number is that it suggests we are helping ever higher numbers of patients with ever more numbers of physician partners. $146 million of revenue is a 35% growth over our last quarter, and suggest about a 60% CAGR. And just as another reminder, this is actually more revenue generated in the fourth quarter of launch than tafamidis generated as it came out of the gates. This brings our total in our first 4 quarters of revenue to $362 million.

And even more heartening than this number are the numbers that lie underneath it. Some 6,629 unique U.S. patients that we've been able to serve with Attruby in partnership with over 1,600 physicians. And as you all know, we focus greatly on NBRx share. NBRx share, given the dynamics in this commercial marketplace, we believe, is suggestive of ultimate TRx, our goal being 30% to 35% peak year share by volume. We're well on our way with greater than 25% NBRx already just 1 year into our launch.

Altogether with our partner, Bayer's efforts in Europe, we believe that the Attruby/Beyonttra franchise in 2026 will generate over $1 billion of revenue. Of course, all of this is possible given the unique biochemical and clinical characteristics of the molecule. As you all know in this room, it is the first and only near complete stabilizer as labeled by the FDA, and has provided what we call [ 3-42-50 ].

At 3 months, statistically significant separation from placebo, at 30 months, a 42% relative risk reduction against those same characteristics of all-cause mortality and cardiovascular hospitalization, and at 30 months, a whopping 50% reduction in hospitalization, suggesting we're able to help patients live longer and healthier lives out of the hospital setting.

Over the course of the last 12 months, you've seen from us over 50 publications and abstracts delving into various aspects of this overall value proposition, as well as trying to better understand where our drug best performs for patient populations like the variant population, or patient populations like the AFib population.

Today, I want to focus a little bit on one of the aspects that I think has been -- that has been underappreciated, which is the assets early separation from placebo. Some data that we published at HFSA, that I think honestly was missed by most investors and actually a lot of physicians, was that we had indeed observed a numeric separation in cumulative morbidity as early as 1 month with our drug. Now that's a bit of a head scratcher because obviously, if you think about the kinetics within the heart, it's probably not the impact of turning down of the amount of toxic monomer that's depositing in the heart that's actually driving this impact.

And so we sort of scratch our heads and asked the question, what might be driving this? And it took us to analyzing some of the very unique hemodynamic and cardiorenal properties of this asset. And I won't spoil, nor do I have time to go through the whole story here, but you will see a series of publications over the next 12 months, suggesting that Attruby actually has renal protective attributes, analogous to the SGLT2 and ARB class, and totally unique to this compound.

Now why might that be? Obviously, it is because Attruby is delivering the highest known kinetic and overall levels of stabilization in this space. I've said it before, and I'll say it again, Attruby simply sees more of the target TTR. It binds it more effectively with a superior KD2 binding as compared to tafamidis, and ultimately does a better job of gluing the tetramer together over time.

For those of you that have been following the preclinical work in this space, you'll have seen the PNAS, or Proceedings of National Academy of Sciences paper that came out about a month ago, with some really beautiful mass spec work. And I'll read the conclusion from the authors just briefly. Our thermodynamic analysis further supports the notion that binding enthalpy, not affinity KD or change in goods to free energy, better predicts the confirmational stabilization imparted by these kinetic stabilizers.

As many of you know, and as we published in [indiscernible], using an ITC approach, we have a vastly superior enthalpic binding mode as compared to tafamidis. Now the good news is we don't even need it because we also have a superior binding approach. And it wouldn't be a talk from me unless I trotted out a new quote from Jeff Kelly, as many of you know, the inventor of tafamidis, and the founder of FoldRx. This is an e-mail that he sent to our founders, Isabella and Mamoun some time ago, and he says, given the variability in soschiometry in the experiments between tafamidis and AG10, which is acoramidis, or Attruby, and TTR, the data will always tell the same story. That AG10 is better than tafamidis as would be expected from the determined binding constant. We wholeheartedly agree and we'll continue to interrogate the advantages of this ever better stabilization for the patients that we serve.

Today, we're announcing something in tandem to those efforts. We've long sought the ability to pair upstream turning down of the toxic monomer that deposits in the heart because recall, both knockdowns and stabilizers are trying to turn off the faucet of toxic monomeric deposition in the heart with an agent that helps clear the already deposited plaque because, by and large, we are diagnosing patients too late, and at a point where there is already pathogenic deposition of amyloidotic plaque in their hearts. And the right way to do this is to establish a depleter or antibody-associated program that promotes the clearance of that already deposited plaque.

We've been greatly privileged to be working with Dr. Richard Scheller, our Chairman of R&D, who, as many of you know, ran R&D at Genentech for a very long period of time, and was associated with Herceptin amongst many other great antibodies, and he's been leading this project for the last couple of years alongside our colleague, Christine Zhang. And what we wanted to do within this space was to build on prior efforts and really optimize an antibody against 4 key dimensions.

First, obviously, we wanted to bind more target. We wanted to find, and in this case, a cryptic previously described but not employed binding site within the fibril to go after. Secondly, we wanted to clear more target by better recruiting macrophages to our antibodies upon binding. And then third and fourth, we wanted to improve antibody half-life by optimizing pH sensitivity within the endosome and then ultimately taking advantage of some of the novel literature on FcRn binding that many of you are familiar with to improve antibody half-life, therefore, making it more effective, and hopefully more convenient over time. And we are heartened to say that we've been able to create an antibody to date that actually checks off all those boxes, very close to development candidate, and we anticipate moving this program into the clinic in the coming 18 months.

Okay. So I'd like to turn now from ATTR cardiomyopathy to our development franchise, and I'll start with our profound results that we published just a few months ago in the context of limb-girdle muscular dystrophy Type 2I. As a reminder, this is a deleterious condition with no available pharmacologic therapy that affects almost 7,000 patients between the United States and the EU.

2.5 months ago, we published the interim Phase III results from our trial that sought to look initially at biochemical impact against the causal biochemical damage associated with this condition. The bad news around this condition is that there are no available therapies. The good news is it's remarkably well described biochemically, owing uniformly to loss of function mutations in an enzyme called FKRP, which leads to a lack of glycosylation of what's called the alpha-dystroglycan complex in the muscle, and we sought to turn up that glycosylation level so that we could go forward and help patients.

We powered the trial so that we could look at biochemical glycosylation of the ADG complex in tandem with a measure of muscle damage called CK. And sure enough, after 1 year, as we looked at the trial, we found a 1.8x increase, even more profound than we observed in Phase II in ADG glycosylation, and an 82% decrease concomitant in a measure of muscle damage called CK. So those were very heartening. But what we saw next, we didn't expect.

We saw statistically significant improvements against measures of both ambulation and breathing. This is the first data set that looks like this as far as I know, in the muscular dystrophy space. And what was even more encouraging was for each of those two measures, both ambulation and breathing, we saw a decline in the placebo arm, and an incline or improvement in the therapeutic arm, suggesting that we are improving patients and in some cases, on breathing, and on ADG, returning a few patients back to normal within a year. That is a profound advance. When we talk about therapeutic cure in the context of what we do, we don't often think about small molecules. But this is truly therapeutic cure for a few of the patients that we have treated here.

I want to elaborate on that data that we announced at top line with a bit more detail. These are data that we shared with the agency in mid-December, and these are the forest plots against all of the primary and key secondary endpoints that I just mentioned. And I don't have time to go through each single one of these plots, but I think you will see that the consistency of the plots, and the statistical robustness are encouraging.

Furthermore, what you can see from this drug is treatment and effective treatment across a number of different subcategories, suggesting either early stage or late-stage disease. So for instance, for compound heterozygotes that tend to be more severe in this disease, we see marked efficacy consistent with what we see in the "milder condition", which is the L276I homozygous population.

Additionally, we see consistent efficacy from young to old people who have had the disease for a long time, versus people who have just been diagnosed, and at different baselines of FVC. So beautifully consistent data that we were able to share with the agency. And perhaps the most important data pertains to the modified North Star test. As many of you know, this division of the FDA likes to look at North Star, or modified North Star, a very difficult endpoint against which to achieve statistical significance.

We designed our trial to do so after almost 3 years. But after looking at the interim data 1 year in, what we showed was a 2.6 delta, again, with a decline in placebo and an improvement in what we saw on active with robust statistical significance. This was certainly -- our trial was certainly not powered to show this, and we were extremely encouraged to see this data, coupled with the data I just shared with you.

We took all of that data into a presentation to the agency in mid-December, and they quote, we're very pleased that we had demonstrated consistent treatment effects on multiple efficacy endpoints and upon seeing the data, asked us to file our NDA toward traditional and full approval versus accelerated approval, knowing that leaving kids on placebo arm for the entirety of the design trial would likely be unethical. We anticipate filing this NDA sometime mid this year.

I'll turn now to our efforts in ADH1. As many of you know, ADH1 is a condition that affects almost 12,000 Americans alone, making it one of the larger markets and certainly one of the more underdiagnosed conditions that we go after. Again, the good news here is that this condition is remarkably well described, owing uniformly to gain-of-function mutations in the calcium sensing receptor, and we are going after this condition having designed a negative allosteric modulator of the calcium sensing receptor. Again, just about a couple of months ago, we were privileged to announce our Phase III results in this category, where we demonstrated a 76% responder rate following encaleret treatment.

Now response here is actually normalization of urine and serum calcium, which are the two things that drive all of the conditions in this disease. So low serum calcium levels is what drives tetany, brain fog and ultimately seizures and high urine calcium levels drive downstream nephrolithiasis, CKD, kidney stones and the like. Recall also that standard of care, which only had a 4% response in our clinical trial, is simply calcium supplementation. So even when patients can get back to normal levels of serum calcium, they're actually downstream harming themselves by loading up their kidneys with calcium.

A 76% full normalization of patients once again applies to this concept that I talked about during my comments on LGMD2I. This is therapeutic cure for these patients. They are back to normal levels of calcium and could undergo and live a relatively normal life on a go-forward basis. Hearteningly, we also showed in 90-plus percent of patients response to the drug. So there's normalization and then there's response. 90-plus percent of patients were normalized as you look at their PTH, and they moved in the right directions when we thought about urine and serum calcium levels. So very few segment of this patient population would not be served with encaleret on a go-forward basis.

So how do we find these patients? As I mentioned at the outset, this is a relatively underdiagnosed disease. How do we go about starting to find patients that would find this therapy useful? And the team has done a really nice job of providing really three angles to this.

The first is to improve genetic testing and to partner with prevention, and other local providers so that we might offer a panel to identify pathogenic variants associated with the calcium sensing receptor. And as many of you know, we've also published some literature on what those variants are, and really drilled into the constellation of known pathogenic variants as opposed to the buses in this gene.

Second, our commercial team created an ICD-10 code so that we might better codify and identify patients with frank ADH1 as opposed to chronic hypercalciuria throughout the course of time. And then finally, actually, the guidelines were updated to suggest genetic testing for those with nonsurgical hypercalciuria, so that they might see whether or not their ADH1 patients actually hiding within the context of that broader HP community. It's not unlike actually ATTR cardiomyopathy, or even hypertrophic cardiomyopathy, when I got started. These patients are hiding within the context of HFpEF, we needed to find them. Here again, we need to establish the algorithm to find the patients that would best benefit from this drug product.

And extremely excitingly, what the results of these efforts have been to date is the identification of 1,700 unique patients based on, again, the efforts of these alone, plus the medical education that we've been doing. This underlies our projection there are about 3,000 to 5,000 identified patients associated with ADH1 today, but more importantly, in my mind, suggests that we have the right approach to continue to find new patients over time, especially after the therapy launches. This is pretty robust growth given the fact that the therapy is not even approved, or in the commercial marketplace today.

Okay. Turning finally to an update on the encaleret program as it applies to an additional indication, chronic hypoparathyroidism. As you all know, for every medicine that we interrogate, our responsibility is to figure out all of the different ways it could be applicable to human health. In this case, the phenotype of restoration of urine and serum calcium suggested to us that this may be a useful and the first oral product in the context of CHP. And indeed, in a very small but robust in terms of its signal clinical trial in about 10 patients, what we showed was 80% normalization of urine and serum calcium in the context of chronic hyperparathyroidism.

We took that data, coupled with the mechanism, coupled with what we've learned from our ADH1 trial to the FDA, and we aligned on an extremely exciting trial that we intend to prosecute starting midyear. We call it the RECLAIM-HP trial. What you can see from this trial design are really two salient characteristics.

One, this is a 6-month trial. We intend to relatively quickly interrogate this compound to better understand whether or not as an oral agent, it can provide the types of efficacy we see with PTH replacement therapy or even better. Secondly, the primary endpoint, the proportion of participants achieving albumin-corrected blood and urine calcium within the target range. Now recall, our Phase II data, this suggests a very high probability of technical success associated with this clinical trial. So we are excited not only to launch an ADH1, but also to serve patients with chronic hypoparathyroidism on an ongoing basis.

I'd like to turn now to our achondroplasia and hypochondroplasia franchise associated with our small molecule, infigratinib. As a reminder, this affects some 55,000 individuals between the U.S. and EU, and represents a significant unmet need. For those of you interested in this program, I would suggest that you listen in to the webinar that was recently published on Friday. Our colleagues, Justin To, Daniella Ragoff and Dr. Lager, we were very privileged to have her on the line, both talk about the architecture of this condition, as well as how meaningful infigratinib could potentially be to the folks we're trying to serve within this population.

On that webinar, Justin mentioned that we have achieved last patient, last visit against our Phase III in achondroplasia and anticipate reading out that data to everyone sometime in Q1 of this year. Importantly, we also have first patient enrolled in our pediatric and toddler study. Recall, PROPEL 3 already is interrogating the broadest set of ages within the achondroplastic trial setting from 3 to 18, but we'd like to go all the way down to as low an age as possible, and therefore, PROPEL I&T is important. And then really excitingly, we have full enrollment completed for our Phase II portion of our hypochondroplasia study, again, a related condition arising from a different, but still activating mutation in FGFR3.

As Justin mentioned during the webinar, and I think it's important to reinforce, this is the best and most advantaged approach within the context of achondroplasia. First, it is the only approach mechanistically to target this condition at its source, FGFR3 overactivation. Secondly, in the definitive animal model, it provides not only quantitative advantages as compared to the CMP class of medicines, but also qualitatively is able to deliver results against things like foramen magnum, surface area and things outside of long bone growth that ultimately are important to the community that we serve.

Third, and most importantly, in the New England Journal of Medicine last year, we published quantitative outperformance of this agent in the context of achondroplasia, both when looking at change from baseline in AHV, as well as absolute AHV, and then coupling that with maybe perhaps the best endpoint given the variance associated with AHV, which is the Z-score where we showed a 0.36 plus standard deviation at month 12.

The community was incredibly excited about these results in addition to the fact that we were able to the first -- for the first time to provide a statistically significant result against proportionality, a decrease of 0.12. We're the only agent in this space that's received breakthrough designation, suggesting that the FDA sees this as a marked leap against standard of care. And finally, and importantly, as we've done our market research, this is a convenient, safe and oral medicine, that allows all kidos that might want to try this agent to be able to try it in a convenient manner.

And just so I can elaborate on that a little bit here. You can see a picture of the capsules on your left-hand side, again, 17 millimeters long, very easy to swallow. And if you have trouble swallowing that, you can break this up into the granules, which are 2 millimeters long and easily mixable with soft foods.

Okay. So what does this look like in terms of the marketplace? We obviously have to start thinking about our commercial efforts. And for those of you that were here a couple of years ago, you'll remember that as we were getting set to launch in ATTR, we had done quite a bit of market research using a couple of different tools to better estimate what our share would be, and how to size our sales force. And I think actually, those projections have been fairly accurate. And we marry those now with a third tool that I'll talk about in a moment.

So the first way that we try to understand how this agent might perform is by taking a variety of TPPs and using it in the context of market research, where we're able to go out to 80% of the physicians by volume that are prescribing today's currently available CMPs.

The second is that we look at analogs and 3,500 molecules, many of them that are oral versus injections, et cetera. So we were able to look at the appropriate analogs to estimate what PKM market share might look like in this space. And then finally, in collaboration with MIT, Andrew Lowe and his QLS group, we have launched a Revenue Institute where we will be publishing on in the next few months, a brand-new algorithm that helps us better predict how our molecules will launch over time and indeed, how other molecules hopefully will launch in a future state.

So I won't talk about all of the research here. You can expect to hear updates from us in the months to come, especially as we get a glimpse of our Phase III data. But here's the TPP that we actually tested in market research most robustly. And you can see, again, an indication that's the broadest indication in terms of age range being interrogated in our trial, an MOA that's a selective FGFR1/2/3 inhibitor, the dosing and administration that's a real mark step forward, a daily oral as opposed to a daily or a weekly injection. We put our delta in AHV change from baseline at the tippy top of what CMPs have been able to achieve 1.5 centimeters per year. And we put a well-tolerated AE profile into the TPP, which is effectively all of the safety that you've seen from this compound to date, less than 10% hyperphos, and importantly, avoidance of injection site reactions, hypotension because recall, that's really where the CMP category comes from and the excessive hairiness that has been otherwise observed with some of the CMP products.

And what we found based on that TPP was a stubbornly consistent 52% market share. We believe that we will take a vast majority of this market, but we will at least, given the market research, take a majority of the market given the profile shown on the left. So again, we anticipate data so we can fill this in for real and go and take somewhere between a majority and vast majority of the market based on data to come.

Last but certainly not least, are our efforts in Canavan disease. As many of you know, Canavan is an extraordinarily rare, extremely deleterious neurodevelopmental disease, and we've been taking a gene therapy approach to see what we can do to serve children affected with this condition. I don't have time to walk through many slides on this, but what I will show you in this single slide associated with Canavan is the evolution of the data that I presented last year, where you can see at our eve of 14 high dose, robust and profound decreases in the causal biomarker associated with this disease, which is urine NAA and mirrored by CSF NAA.

And very hearteningly, you see a dose-responsive improvement in the behavior of these children, improvements such as sitting, head control, reaching and grasping and in certain cases, ambulation where you would certainly not expect to see it. We continue to dose children and assess the safety and efficacy of this product, and we anticipate filing its BLA sometime in 2027.

Okay. So hopefully, three launches upcoming. How are we going to do it? That's a lot for a small biotech, and we think we can employ this decentralized model that we have to continue to scale launches, those three launches, hopefully, if we're lucky with the achondroplasia top line, and hopefully launches to come with some of these additional indications that I talked about. And what we've done here is we've preserved the affiliate structure so that we have the teams that are close to the physicians in any given therapeutic area, that are close to the patient and patient advocacy groups, and that are close to the data, really running the launches, but they're doing so in partnership with the wonderful team that Matt Outten and our commercial colleagues have put together, therefore, making it such that we don't have to respend the money to set up the infrastructure.

As many of you know, in rare disease, the preponderance of spend is not against FTEs or the field force every time, but rather against the back end of market access, patient services, analytics, et cetera. So we can use that already established expertise and apply it to launch after launch in tandem with the affiliates. And so that's what we intend to do over these next 3 launches and hopefully, maybe 5 launches associated with the comments I've made to date. But the question is where else do we want to take this platform in the years to come?

And that takes me to the final points maybe I'll make on why we believe it is still day 1 in this area of genetic disease. And I won't belabor it because I think many of you in the room know this. But about 3 years ago, I was up here chatting with Anup about this concept of missing heritability. And why is it that so much of what we see in terms of phenotype is not well captured by genetic information.

And it turns out, as many of you know, who have been following the literature that just an increase in whole genome sequences versus exome sequences, coupled with the higher density of data has allowed us to really fill in the gaps around missing heritability, and to begin to really tamp that down. But maybe most excitingly, we're able to start to identify these new variants and then connect them with mechanism, and then connect that mechanism with phenotype. What's allowing us to do that?

Obviously, advances in long-read sequencing, allowing us to identify things like structural variants. Obviously, advances in things like having a pan-genome, a better reference against which we can understand variants, the pre and aforementioned increase in data density associated with these databases like UK Biobank and the like. And then really importantly, the ability to interrogate the function of these variants in cell and tissue-specific experiments so that we can tease out their function and better design therapeutics that target well-described conditions at their source.

A fingerprint of all of these advances is simply the pipeline that we see at GondolaBio, a company, as you know, that is a sister company to BridgeBio, and a company that you collectively own as investors in BridgeBio. Here, you can see 17 different programs in a span of just a year, all pretty early stage, advancing all the way from early-stage research to Phase II, but in important areas of high unmet need. Investors will be familiar with areas like EPP, ADPKD, alpha-1 antitrypsin, CMT1A, neurofibromatosis type 1 and the like.

I don't have time to go through all of these programs, obviously, but I'd like to touch on one example of, again, the well-described process that we put forward at BridgeBio, which is to take generally small molecules and target these well-described conditions at their source.

So I want to talk a little bit about our EPP program. Most of you in the room, I think, and on the line are familiar with EPP, but for those of you that are not, it is unfortunately a very large unmet need, affecting some 20,000 to 25,000 people between the United States and the EU. So that makes it one of the larger disease states that we work on. And when it does affect people, unfortunately, it affects them with deleterious morbidity associated with skin damage and excruciating pain, as well as downstream liver disease. That's the bad news.

The good news is that the path of mechanism of this condition has been very well described over the years. So what we can see here from the cartoon on the left-hand side of this slide is that this condition uniformly arises from mutations in the heme synthesis pathway, most commonly through mutations in ferrochelatase. And what that does is it promotes the production of a compound called PP IX, which then is present in the plasma, the skin and the bile at too high a concentration. And because PP IX is photosensitive, it drives the phototoxicity and pain that I just mentioned.

Now there are many different ways to go after this condition. There are noncausal ways to go after it like using canning agents that has been the approach of Clinuvel, Mitsubishi Tanabe. And then there are different ways to target this causal pathway. Certainly, this medicines has one where they try to inhibit the intake of glycine. And we looked at that product, and we started to ask ourselves, how do we improve upon it?

The intake of glycine and its inhibition takes a very long time to provide PP IX reduction. It's not able to provide PP IX reduction to the marked levels that would be required to take people back down to, let's say, "a normal range of PP IX". And you can't do it safely. As you know, GlyT1 inhibition, which is associated with glycine intake comes from the schizophrenia field and is associated in EPP trials alone with high levels, almost 50% of dizziness and other AEs.

So we asked ourselves, how else might we target this [indiscernible] at its source, but do so avoiding some of those handicaps? And what we decided on, in collaboration with Dr. Ma at University of Pittsburgh, was to inhibit the egress of PP IX from the red blood cell by inhibiting potently its solitary transporter, which is entitled ABCG2. And so we have designed a compound by the name of PORT-77, which is an orally bioavailable, highly potent inhibitor of ABCG2 that in cellular models, animal models and the like has provided best-in-class efficacy and a beautifully safe profile that allows us to turn down levels of PP IX in the plasma and importantly and uniquely, PP IX levels in the bile, saving off both the phototoxicity and pain that patients suffer from, but also the downstream liver disease.

So I'll just go right to the point here, which are the results of our Phase IIa trial, which we recently just generated about a month ago. And here, you can see the design of our GATEWAY trial effectively to interrogate 2 different doses of PORT-77, and to look at the change in plasma PP IX as compared to baseline and running placebo. We also obviously wanted to interrogate PK, safety and tolerability.

So what did we find? Firstly, and hearteningly, we found a profound impact in terms of the diminishment of PP IX in the plasma. This has not been seen before, 75% reduction in PP IX levels. And even more importantly, because every minute matters for the patients that we serve, we were able to take action in a matter of hours as opposed to weeks from this medicine's drug. And within days, we reached steady state at 75% reduction. So the marked efficacy associated with this compound is unique in this space.

But perhaps even more encouraging to me was the next slide. I have sat on many clinical trials, and I rarely get this level of consistency from a Phase IIa. Here, you can see all 12 patients, and I'll just take your eye to the dark blue lines here. Every single patient dosed with a high dose PORT-77 experienced a reduction in PP IX levels. Maybe the smallest reduction observed was 57%. And again, the mean was 75%. So not only do we see profound reductions in PP IX levels, not only do we see relatively quick reductions in PP IX levels, we see very consistent action from this drug across the patient population. And importantly, we are doing it safely. You can see a numeric imbalance in actually favor of the treatment as compared to placebo in most of these rows. This is importantly different than the other molecules in this space.

Okay. So what I hope I've convinced you of in a few brief slides, and we will certainly be elaborating on this more in talks to come is that we have an ABCG2 inhibitor that it applied in its application to EPP allows for potential best-in-class PP IX reduction. It has a dual mechanism that targets all aspects of the condition, has a clean safety profile, and that we're able to see it and that reduction within hours, not days to weeks.

This is just one snapshot of all of the progress that you as investors own across the ecosystem of BridgeBio. We've got BridgeBio and its late-stage franchises. We certainly have early-stage research ongoing, as I highlighted with the depleter program, and there are other programs in that same vein at Bridge. We have all of what's happening at GondolaBio. And indeed, you are substantial owners of BridgeBio Oncology Therapeutics, where the CEO of that effort, Eli Wallace, will be talking a bit later today about some of the exciting updates against its franchises as well.

So lots going on, lots to do for the patients that we serve. And this is just a summary of all of the issues that I've covered today. Commercial momentum, late-stage development momentum, early-stage research and development momentum, all portending, I hope, in partnership with you all in this room, the ability to serve many more patients in the years to come.

And it wouldn't be a JPM slide if I didn't end on the comment that we are well financed to undertake all of these activities in the coming years, and that all collectively, these activities will create a steady drumbeat -- hopefully, drumbeat, hopefully, of advances for both the patients that we serve and investors in and around the stock.

And so with that, I will thank you all for your attention. And if we have time, I'll take a question or two.

Neil, your presentation was so robust. I do not have any questions.

Thank you Anup.

Thank you for standing by. At this time, I would like to welcome everyone to the BridgeBio Pharma Achondroplasia Investor Webinar. [Operator Instructions]

I would now like to turn the call over to Justin To. You may begin.

Good morning, and welcome to the BridgeBio webcast for the infigratinib program for achondroplasia. Before we begin today, I'd like to remind our audience that we will be making forward-looking statements today. For a discussion of these risks, please see BridgeBio's most recent financial statements. This is an exciting time for a program as we have recently achieved last participant's last visit for PROPEL 3, our Phase III clinical trial in achondroplasia, and we expect to announce top line results by the end of the first quarter.

Today, we are excited to be joined by Dr. Janet Legare, Professor in Genetics in the Department of Pediatrics at the University of Wisconsin School of Medicine and Public Health. She is also an investigator in the PROPEL 3 trial, and she is the Director of the Midwest Regional Bone Dysplasia Clinic, one of the largest of its kind in the United States. She will be providing an overview of achondroplasia, its genetic pathophysiology and unmet medical need.

We will then have Dr. Daniela Rogoff, who is the Chief Medical Officer of Skeletal Dysplasias at BridgeBio, go through the PROPEL clinical development program and design of PROPEL 3. Finally, I'll be then walking through the commercial opportunity for an oral treatment option in achondroplasia and what the preponderance of mechanistic nonclinical and clinical data suggests for our Phase III. We will then conclude today with Q&A.

With that, I'd like to hand it off to Dr. Legare.

Thank you for that kind introduction. Again, my name is Dr. Janet Legare, and I run the Midwest Regional Bone Dysplasia Clinic. Our clinic is 45 years old, and it was started in 1981, and we see patients throughout the lifespan, which gives us a unique perspective in seeing how growth in childhood can affect the long-term outcomes and function of people with achondroplasia. Achondroplasia is the most common form of disproportionate short stature or dwarfism. In fact, more than 90% of patients we see with skeletal dysplasia have achondroplasia. It is a rare diagnosis of approximately 1 in 25,000, but that means that about 15,000 people are affected in North America.

Achondroplasia is much more than just short stature. There are many health consequences of having decreased bone growth. And this is because how those bones grow affects the underlying structures. If a patient has achondroplasia, they have a 50% chance of having a child with achondroplasia. But by far, the majority of people with achondroplasia are born to average stature parents. What that means is that they are the first person in their family to have achondroplasia.

Diagnosis of people with achondroplasia usually occurs in the first 1 to 2 days of life. It can occur prenatally and about 33% of the time, it does occur prenatally, but we only see it on ultrasound after approximately 26 weeks of gestational age. We can diagnose it prenatally via genetic testing in which we find an FGFR3 pathogenic variant. We can diagnose achondroplasia earlier in pregnancy if one of the parents has achondroplasia, and we are doing surveillance for the diagnosis.

To understand achondroplasia, we need to understand types of bone growth. And then we're going to go down to the growth plate level and then ultimately, the cellular level. So we have 2 types of bone growth in our body. By far, the majority of bones grow through cartilage growth plates. These are called endochondral bones. We also have bones that don't grow through cartilage growth plates, and these are called intramembranous bones, and this is the top of the skull, the collar bones and the lower jaw.

So what you will see in this picture is that all of those dark blue bones are bones that grow through cartilage. The orange areas are the growth plates. So that is the area where achondroplasia is really doing its work. So any intervention that we hope to have is going to also work at those same areas. You'll see that almost all bones in the body grow through cartilage growth plates.

So let's go down to the growth plate level. Again, bones grow through cartilage growth plates. So on the left, you will see a typical growth plate in an average stature individual. And this resting zone is where you have cartilage cells kind of hanging out until they are stimulated to grow. Then they start dividing or proliferating. And you'll see that they are lining up in columns as they enter the hypertrophic zone. This is where those cells are getting bigger and differentiating and secreting compounds that are going to ultimately help the bone cells come in and form bone.

Let's look at the achondroplasia growth plate. You'll see that there are less cartilage cells hanging out in that resting zone, and they're more disorganized in the proliferation zone and the hypertrophic zone. There are less cells and they're not lining up into columns. They're also not getting as big. And ultimately, this results in less bone being laid down.

Now let's go one level deeper and go to the cellular level. So we have fibroblast growth factor receptor 3, which is a receptor that sits across the surface of cartilage cells or chondrocytes. And when fibroblast growth factor is bound to it, there is an activation of 3 important cellular pathways that ultimately decrease bone growth. These decrease the cartilage cell proliferation, another pathway decreases the differentiation and hypertrophy, and one more pathway increases cell death.

So ultimately, activation of FGFR3 decreases bone growth through the activation of these intracellular pathways. So by blocking the activation of FGFR3, we can directly target the overactive FGFR3. And this is done through inhibiting the tyrosine kinases. So again, this is active inhibition of the FGFR3. And it doesn't just affect one pathway in the cell, it affects all 3 pathways, ultimately decreasing the effects of that FGFR3 gain of function variant.

So how does this affect the clinical picture? So let's look at the clinical picture of somebody with achondroplasia a little bit more closely. What you'll see on the left is a typical girl with achondroplasia. She has a larger head, a flatter face, a little bit of frontal bossing, a narrower chest, short arms and short legs with some lower leg bowing and a fairly normal length trunk. She has short fingers with what we call a trident configuration and a flatter mid-face. We see these clinical features because of how the bones are affected, and we see the medical sequelae because of how the decreased bone growth affects underlying structures.

So people with achondroplasia are born shorter than average stature individuals. And this is a typical growth chart from ages 4 years old up to age 20. And what you'll see on this blue line is the mean general population height per year of age. What you'll see on the lower curve is the typical growth curve for achondroplasia. Children are born shorter than their average stature peers, but they grow further and further away from the curve as they grow through childhood because they grow less per year than children who are average stature.

So we want to use the correct growth chart. We want to use an achondroplasia growth chart. Z-scores are standard deviation from the mean. So we use the achondroplasia growth chart. And if that z-score is increasing, that tells us that a child is growing more than typical for a child with achondroplasia.

It's not just short stature though. We need to look at proportionality. So in an average stature individual, your wing span equals your height by about age 11. Your upper segment ratio, which is the top of your head to your lower pelvis and your lower segment, the bottom of your feet to your lower pelvis are also equal to 1 at about age 11. What you can see from these pictures that, that is not the case in somebody with achondroplasia. Their sitting height is really almost normal, but their overall height is low. So this affects not only their height, but it affects their function. It affects how you can wash your hair, how you can wipe yourself after toileting, how you can reach things in a supermarket. So what we know is that this proportionality affects function significantly and contributes to the short stature. Ideally, if we can increase proportionality, that is going to improve function.

So achondroplasia is associated with many medical issues. And again, this is because of the bone growth affecting the underlying structures as well as how differential bone growth affects other bones. So we are overall looking for improved health and decreased medical sequelae in all of these areas, but the easiest way to measure that is to measure height. And by measuring height and how much a patient grows in 1 year, which is called the annual growth velocity, that tells us if interventions are affecting the growth plate, which then subsequently affects the bone growth.

Our overall goal is to improve health and decrease medical sequelae, but height is the metric. We also know that as height increases, mobility, function and quality of life are shown to be increasing. So it's important to remember that height is the metric, but improved health is the goal. Thank you.

Thank you, Dr. Legare, for the great presentation. In this part, I will be sharing about infigratinib and the clinical development program in achondroplasia. Let's start on Slide 18. Infigratinib is an oral, first-in-class FGFR1-3 tyrosine kinase inhibitor that is being developed as a treatment option in achondroplasia. Dr. Legare already discussed how infigratinib can work, so I will not go into too many details. Briefly, the FGFR3 is a negative regulator of the growth plate. In achondroplasia, the gain-of-function pathogenic variance in the FGFR3 leads to the receptor to be on an on status even in the absence of ligand. This leads to improper chondrocyte proliferation and hypertrophy, which caused the bone to grow slowly.

We like to use the analogy of a car brake. The FGFR3 acts by pressing a brake on the bone growth. In achondroplasia, this brake is stuck, and it does not allow the bones to grow in a typical way. Infigratinib inhibits the kinase activity of the FGFR3 and with that decreases all the downstream signaling pathway, as a difference from CNP, which only targets one of the signaling pathways. This means that infigratinib targets the condition at its precise source.

So going back to the analogy of the car brake, infigratinib releases that brake, allowing the chondrocytes to resume activities, restoring a more typical bone growth. One important point is that even when infigratinib is an FGFR1-3 tyrosine kinase inhibitor, at the doses we are using in achondroplasia, it is expected that only the receptor that is only overactivated gets modulated by infigratinib without getting to inhibit FGFR1 or 2. This is supported by the safety data from our Phase II study that I will be presented in a few slides.

On Slide 19, we can see a picture of infigratinib. Infigratinib is being studied as a sprinkle capsule to be administered orally. Capsules, which are 1.1 centimeter in length can be swallowed whole or the content, meaning the granules sprinkled on soft food or taken directly. As you can see, the granules are very small of approximately 2 millimeters in diameter, which makes it very easy to take by children. The strength of each capsule depends on how many granules are inside and each child's dose is based on their weight.

Moving on to Slide 20. On this slide, we have the summary of the development program of infigratinib in achondroplasia, which comprises of 5 studies evaluating the safety and efficacy in approximately 300 children ages 0 to 18. The first study is the observational study, PROPEL, that has the objective to collect baseline data on children that would participate in a clinical trial with infigratinib. In this study, data not only on growth are being collected, but medical complications, quality of life are also evaluated, among others.

The second study was the Phase II PROPEL 2, which was defined as dose finding and as proof of concept to provide preliminary evidence of safety and efficacy. This study enrolled children 3 to 11 years of age. In the dose escalation portion, 5 ascending doses were evaluated. Cohort 5 dose level of 0.25 milligram per kilo per day was selected to be explored in the Phase III as it was the dose that resulted in the most effect while being safe. I will review the results of this study later in the presentation.

Once we have the dose identified, the Phase III study started. Again, I will share a little bit more details later in the presentation as well. The next study is the PROPEL OLE that is our long-term open-label extension study where children received treatment with infigratinib until completing growth. All the children that participated in PROPEL 2 and PROPEL 3 and a group of treatment-naive children directly from PROPEL are offered the opportunity to participate in this study, which will provide information about the effect of infigratinib beyond 1 year and most importantly, the effect of infigratinib beyond growth.

To complete our development program in achondroplasia, we have initiated an infant and toddler study, PROPEL I&T, where we will identify the dose and collect safety data and efficacy data in infants and young children 0 to 3 years of age. We are very excited that this study is already underway. As I mentioned before, our Phase II provided a preliminary evidence of efficacy and safety. Results from this study were published in the New England Journal of Medicine. In the next couple of slides, I will go over the results of Cohort 5.

On Slide 21, we have the summary of the safety in Cohort 5. Infigratinib was well tolerated with no safety concerns identified. There were no adverse events that led to treatment discontinuations. Most of the adverse events were mild in severity and assessed as not related to study drug. No hyperphosphatemia was observed and not corneal or retinal adverse events were reported.

Moving on to efficacy now on Slide 22, we have represented the change from baseline in the annualized height velocity at month 6, 12 and month 18. We can see that treatment with infigratinib in Cohort 5 resulted in a robust increase in the annualized height velocity, which is sustained throughout the study. The change from baseline at month 12 and month 18 was 2.5 centimeters per year, which is highly statistically significant with a p-value of 0.0015 at month 18. At all time points, this response was greater than any other treatment approved or in development for this indication.

Moving on to Slide 23. This slide is showing the height z-score and the change from baseline during the 18 months of treatment. As Dr. Legare explained, z-score is a way to standardize a measure, which in this case is height. A z-score of 0 indicates that the height is exactly at the mean of the population. A positive z-score indicates that the height is abide above the mean and a negative z-score indicates that the height is below the mean of the population. The mean plus/minus 2 standard deviation is where the majority of the population is. Height z-score is a widely used way to display and interpret growth measurements.

Here, we can see the height z-score and the change from baseline in Cohort 5. An increase in the height z-score indicates that the average height is increasing in relation to the reference population, which in this case is children with achondroplasia. We can see that the height z-score is continuously increasing with a change of over half a standard deviation score at month 18. So when we put the change in annualized height velocity and the change in height z-score together, we can say that the cumulative increase in the growth rate observed during treatment translated into a statistically significant increase in the height in relation to the population of children with achondroplasia.

Slide 24 shows the effect of infigratinib on body proportions represented by the upper to lower body segment ratio. At month 6, we had already seen a trend towards improvement in body proportion, which continued to show persistent decrease with longer duration of treatment, reaching statistical significance at month 18 with a p-value of 0.001. This improvement in the upper to lower body segment ratio after only 18 months demonstrates strong potential for a meaningful effect on body proportionality. In summary, results from the Phase II study were very promising and allowed us to start a Phase III pivotal study.

On Slide 25, we have the study design of our pivotal Phase III study, PROPEL 3. This is a double-blind, placebo-controlled trial to evaluate the efficacy and safety of infigratinib in children 3 to 18 years of age with potential to grow. As you can see, PROPEL 3 covers the largest age range of any randomized controlled trial ever conducted in achondroplasia. Children had to have completed at least 6 months in PROPEL before enrolling in a 2:1 randomization ratio to receive either infigratinib or placebo. Children received treatment for 52 weeks and then are offered to the possibility to roll over to the long-term extension study PROPEL OLE.

The primary endpoint is the change from baseline in annualized height velocity compared to placebo and the key secondary endpoints are the change from baseline in height z-score and in body proportions also compared to placebo. Other secondary endpoints are safety, change in quality of life, participant and caregiver evaluation of treatment benefit, which is done by qualitative interviews, among others. We are expecting top line results later in Q1, as Justin indicated in the introduction.

So now I will pass it over to Justin. Thank you.

Thank you, Daniela, and thank you, Dr. Legare. Ahead of the PROPEL 3 readout, I wanted to summarize the holistic totality of evidence that makes infigratinib potentially the best-in-class treatment option for achondroplasia. As Daniela and Dr. Legare mentioned, it is the first treatment option in development for achondroplasia that is a true precision therapy, targeting not just MAPK, but STAT1 and all other important pathways downstream of FGFR3.

In the definitive mouse model, we saw some of the most profound efficacy to date on long bones and most importantly, for the first time, efficacy in the foramen magnum and spine. In PROPEL 2 across multiple dimensions, we saw the largest degree of efficacy in any clinical trial. the largest change from baseline in annualized height velocity, the highest absolute AHV, the largest change in height z-score and most notably, a statistically significant improvement in upper to lower body proportionality. These results were all published in the New England Journal of Medicine.

We are the first and only recipients of the breakthrough therapy designation from the FDA in this space, having met the regulatory requirement of showing evidence of substantial improvement over standard of care. And most importantly, if approved, we will be the first oral treatment option in this space, avoiding the significant challenges associated with the CNPs and repeated injections from hypotension and injection site reactions and the psychosocial burden for both caregivers and children. Given the totality of this evidence, we believe infigratinib, if approved, can be the market leader in this space. We will be sharing some of the market research that supports this hypothesis in the next few slides.

Now before we get into what the market research tells us, it's important to highlight the forecasting capabilities we have built at BridgeBio. By incorporating comprehensive physician surveys, analogs and the multiplicity of proprietary databases and models, we are able to better predict physician behavior and preferences. This has been proven with our earlier market research on Attruby, which has predicted our strong commercial uptake to a remarkable degree of accuracy. We've applied this rigor and methodology to conduct extensive research on infigratinib, which I'll be going over in the next few slides.

Now we conducted an extensive physician survey with nearly 100 HCPs who together see approximately 40% of children with achondroplasia in the United States. Above all, one message was loud and clear from this research that the value proposition for an oral FGFR3 inhibitor is incredibly compelling to physicians and families. Across almost every TPP we tested, we are projected to win over 50% market share in a 3-way market.

Notably, this market share number was consistent regardless of the point estimate on AHV that we tested. This finding is consistent with analog research that we've done in spaces like rheumatoid arthritis and PAH, where stakeholders place a premium on the holistic benefit for families across convenience and quality of life. It's clear that as long as there is a safe oral option available, physicians will want to use it.

On the next slide, to better understand these market dynamics, clinicians were asked to rank on 1 to 9 scale, the attributes most likely to drive switching from current therapies. The strongest driver by far was oral administration with 94% of respondents citing the ability to avoid injections as a compelling reason to switch. This was closely followed by targeting FGFR3 to address the causal biology. Both of these factors ranked well ahead of incremental gains in efficacy.

Now moving on to the next slide. We wanted to place this all in the context of the overall market opportunity and the remaining white space. Globally, there are over 55,000 individuals living with achondroplasia with open growth plates, which implies a market opportunity of over $5 billion. Only about 10% of these individuals are on a treatment option today. We believe an oral therapeutic option is not only helpful but necessary to unlock the full market opportunity in achondroplasia.

On the next slide, we try to better understand this treatment-naive population. By far and away, reasons relating to the burden or tolerability of injections are described as some of the most significant barriers to uptake today in the United States. 94% of physicians surveyed included in their top 3 reasons and 45% of clinicians had this as their #1 ranked reason for not prescribing today. This is backed up by what we've heard from caregivers and family members.

There are many families who are on the fence about trying treatment and having to go through daily or even weekly injections makes this discussion a nonstarter. We hear constantly from families about the psychological stress of giving their children with repeated injections with concerns about how it impacts the relationship with their kids. We can and we should do better for families of children with achondroplasia.

Now moving to the next slide and bringing this together. We see PROPEL 3 as the culmination of a scientific story that started in 1994, when gain-of-function mutations in FGFR3 were first identified as the cause of achondroplasia. This led to the seminal paper in JCI in 2016 by our collaborators at [ Inserm ] that demonstrated profound improvements in achondroplastic mice for the first time with infigratinib.

Eight years later, we published our seminal results from PROPEL 2 in the New England Journal of Medicine, demonstrating proof of concept that directly targeting FGFR3 can lead to more and deeper efficacy in the clinic. And that brings us to the PROPEL 3 top line in Q1, where the totality of evidence we've discussed today leads us to believe that we can and should be doing more and be doing better for families of children with achondroplasia.

Now with regards to the PROPEL 3 readout, what does doing more and what is doing better look like? First, on safety, it will be important to not have symptomatic hypotension or injection site reactions. And we would want to see a low-grade hyperphos (sic) [ hyperphosphatemia ] rate of less than 10%, which, by the way, is far below the rate seen on the labels of other growth-promoting agents that were commonly used like weekly growth hormone.

On growth, there's 2 dimensions that matter. The first is that we want to be able to see a change from baseline in annualized height velocity of more than 1.5 centimeters per year against placebo. Second, and just as importantly, we want to be seeing an improvement of more than 0.3 standard deviations on height z-score on the treatment arm, which is the upper limit of what was seen by the CNPs. As mentioned by Dr. Legare, change in height z-score helps contextualize the child's height against the achondroplasia age and gender match population.

On proportionality, we want to see a decrease of 0.05 or more from baseline on treatment arm, which would be the largest effect seen at 52 weeks in any trial. A home run scenario would be if we see statistical significance, which would be unprecedented in a 52-week trial. Either of these outcomes could potentially lead to a significantly differentiated label. We are doing all this in the backdrop of running the most ambitious pivotal trial in achondroplasia spanning ages 3 to 18. While we know that this may impact our primary endpoint, given that in other trials, the youngest and the oldest kids showed the least treatment effect, we think it is important to aim for the broadest possible label at launch.

Finally, in terms of doing more for families, I would be remiss without mentioning our commitment and our interest in looking at measures beyond height in our longer-term open-label extension trial, particularly impact on skeletal changes, quality of life and continued impact on proportionality.

To conclude, we are excited for infigratinib to not only just be a potential first-in-class oral, but the potential best-in-class treatment option for children and individuals living with achondroplasia, and we expect top line results for PROPEL 3 by the end of Q1. We are building the capabilities required to support a global launch and are actively interrogating opportunities to deliver on the full potential of the molecule, first starting with hypochondroplasia and potentially other FGFR3 implicated conditions like Turner syndrome and SHOX deficiency.

With this, I'll turn it over to the moderator to begin the Q&A portion of today's call.

[Operator Instructions] And your first question comes from the line of Salim Syed with Mizuho.

Just one for maybe the physicians on the line around hyperphos (sic) [ hyperphosphatemia ]. Can you just maybe clarify -- I know you kind of -- I know, Justin, you referenced this less than 10% number here. But for the physicians on the line, just maybe could you put it into context for us, just how do you think about hyperphosphatemia as a safety consideration in the space for FGFR inhibitors for this disease? And just related to that, Justin, can you just remind us if the BridgeBio team has access to blinded safety data for this PROPEL 3 study?

Thanks so much for the question, Salim, and thanks for everyone for joining the call today. So I'll take this first, and I'll kind of bring it over to Dr. Legare to give her clinical perspective. So again, as we mentioned earlier, we've done a lot of research with clinicians and low-grade hyperphosphatemia isn't really something that concerns them, especially if it's less than 10%. Now it's quite common with other growth-promoting agents. And again, to contextualize this, the hyperphos (sic) [ hyperphosphatemia ] rate on the various daily and weekly growth hormones are like 20% to 40%, and they don't require any special monitoring.

And now I'd like to pass it over to Dr. Legare to give her clinical perspective.

Thank you for the question. This is a really good question. And I thought about it a lot when I joined the trial, to be quite honest. And I also spoke with my nephrology colleagues to make sure that this wasn't getting brushed over.

Let's talk about hyperphosphatemia first. Levels are higher in younger children, and they stay high as they grow. And over 2 decades, they eventually decrease to levels that are seen in adulthood. So I am specifically not worried about any level that's 7 or under. But with decades, and again, decades, like 30, 40 years, hyperphosphatemia levels in like 8.5 to 9 range, you might see a little bit of vessel calcification. But chronic low-grade hyperphosphatemia is extremely well tolerated. So I am specifically not concerned, and we really can't use a blanket statement on hyperphosphatemia because it, again, varies throughout childhood.

Another thing to put out there is that if you are a late bloomer, for example, you go through puberty at a later age, your fast -- first level is going to be higher. And so this really needs to be looked at in the context of the whole child. So again, I'm not worried about it. Chronic low-grade hyperphosphatemia is extremely well tolerated. And as Justin mentioned, these are -- this is seen in human growth hormone as well. And that's, again, any time you're stimulating growth, you might see some increase in phosphorus levels.

Okay. And just, Justin, can you just answer the other part of the question here? Do you guys have access to blinded safety data here? I mean are you flying in blind? Just give us some context.

Yes. I mean recently, we just achieved last participant's last visit. So the study is still kind of undergoing the data cleaning before database lock. So again, I don't really see that.

Your next question comes from the line of Biren Amin with Piper Sandler.

Maybe to start off with a question for Dr. Legare. In your practice, roughly, what proportion of patients remain untreated today? And what are the most common reasons why they're not choosing to go on treatment? And how do you think families and patients would view the possibility of an oral therapy?

Biren, thanks for the question. I'll hand it over to Dr. Legare for this one. I think she's going to be the best one to talk about it.

Thank you for the question. I think it's a really good one. Approximately 40% of the patients I see with achondroplasia who would technically qualify for a treatment modality are not on treatment. And the reasons vary. One is the shots. There's no question that the primary reason is the injections.

The second reason is that people are in puberty. And they are like, do I really want to do a shot every day for 2 more years to maybe get another inch. So I think it's really important that we start treatments early. I think it's important that we show disproportion. They don't want to just be taller. They want to have improved function.

But primarily, it's that they don't want the shots. There's no question. And I think as we're showing more data and specifically, if we can show proportionality, if we can show improved height, then that's going to be a game changer. I think there's a lot of room for people to be on treatment. And again, my hope is that as we're improving height and we're improving annualized growth velocity, that's going to tell us that these bones are growing and ultimately transition to decreased medical sequelae.

And I'll be honest, I have quite a few people on injections, and they are all asking when is the oral going to be available. It is very rare. I might have 1 or 2 people or 1 or 2 families who have not asked me that question. They are all just buying their time until the oral is available. And so I feel like more than half of my patients on injections are going to be switching if or when this is approved by the FDA, if the results are promising, which I anticipate. Does that help?

Yes.

Your next question comes from the line of Tyler Van Buren with TD Cowen.

Another one for Dr. Legare. From a Phase III and real-world decision-making perspective, what minimum magnitude of improvement in annualized height velocity would you view as clinically meaningful for families considering a daily oral therapy that would lead to broad uptake or at least half, if not a majority of patients going on an oral compared to the injectables?

Thanks so much for the question again. I'll take this first, and then I'll hand it over to Dr. Legare to chime in. It's interesting, again, from our research and discussions with physicians and more importantly, caregivers. Many already view this as like a best-in-class therapeutic option given the totality of evidence from the mechanism and us having like a route of administration that fits into life with children, right? Would you rather have over 4,000 injections, over 600 injections or 0, right? And so on efficacy, given what we see on the Phase II, we also expect to outperform on efficacy across multiple dimensions.

And I'll hand it over to Dr. Legare to talk about what's kind of the bar she would expect or want to see for families to think about switching.

So this is another great question. The -- for patients to want to switch, we only need to see the same efficacy as with the daily injection. So we need to see an extra 1.57 centimeters per year that they are on the treatment. So really, a home run would be seeing more than that. But I think that at least 50% of my patients that are on treatment would be changing if it was at least as -- if it was even just as efficacious as the current injections.

Now again, I believe having seen some of the Phase II data that came out and just looking at the class that this is inhibiting all 3 cellular pathways instead of just that MAPK pathway. I believe that this is going to be more effective. But again, it only has to be the same for it to be meaningful and for it to have a significant market share, I believe.

Your next question comes from the line of Andrew Tsai with Jefferies.

There are obviously these -- a few programs out there for ACH. Ascendis just reported some combination data this week. So I wanted to gauge your guys' thoughts on those findings specifically. And then broadly speaking, maybe talk about the potential for infigratinib to be a combination treatment. Is this a truly winner take-all for infigratinib? Or can it be actually combined with the CNP analog since its mechanism is pretty unique?

Yes. No, thanks so much for the question. I'll take this first, and again, we would welcome Dr. Legare's thoughts on this as well, given her experience. So again, we weren't really surprised by the combination therapy data that was released yesterday. So again, numerically, it looks really impressive.

But if you look closely, the data -- all data, whether it's change of baseline AHV or absolute AHV that was released yesterday is remarkably consistent with what's been shown in the literature for nearly 30 years now of the fact that human growth hormone monotherapy in achondroplasia and other growth conditions where there isn't growth hormone deficiency like Turner and other conditions.

So what you see in those conditions with growth hormone alone and in achondroplasia is you see like absolute AHV in the 8s and 9s for about 18 to 24 months before it falls off significantly, which is why it's never been approved by the FDA, nor is it why -- nor why it's not used by clinicians in the United States today. So it's very unclear if anything, what CNP is doing on top of that, which is probably why they didn't really show a CNP -- sorry, a human growth hormone-alone control arm. The analogy I like to use is if you're going like a fast car going 100 miles per hour and you throw a ball out of the window, the ball is technically going 100 miles per hour as well, right, but car that's doing all the work.

Dr. Legare, I would welcome your thoughts on kind of combo with human growth hormone as well.

So I'm going to answer 2 parts of that question because I think there were 2 questions. One was, what do I think of the human growth hormone and TransCon CNP combination data. But then if I'm correct, your second question was, would we ever use a tyrosine kinase inhibitor like infigratinib combined with the CNP analog. Is that correct?

Yes.

Okay. So let me answer the first question, which is the human growth hormone and TransCon CNP. This came out of the COACH trial through Ascendis. And this is using the weekly human growth hormone combined with the weekly CNP, which is navepegritide. I think this was -- it's obviously very impressive data. What we know, like Justin was saying, is from all of the previous studies, you get a really good response with growth hormone really in anybody for the first 6 to 9 months you are on there, but then -- on it, but then it peters out.

And so I don't think that using human growth hormone and CNP together is ever going to be a long-term option. I do think that it may be one of those options where if a child isn't responding really well, maybe you use a boost of that for 6 months. But it is never going to be a long-term option where they are on this for their life. So that's kind of for that first question.

We know from a hormone standpoint that achondroplasia arises because of a difference in the growth plate. It does not arise because there is less growth hormone. So you can stimulate this pathway all you want, but then ultimately, it will equilibrate and it will become less effective to the human growth hormone, whereas these specific medicines, they work at the cellular level and the cell and the growth plate are not going to become tolerant of them, if that makes sense, whereas they will become tolerant to the growth hormone.

An answer to the second question, which is, do I ever see a role for combination therapy of using the FGFR3 inhibitors compared with the CNP analogs. Gosh, in an ideal world, I would love to see that maybe in the infant population so we can decrease foramen magnum stenosis, which one works better or if we use both together, can we really prevent these infants needing cervical medullary decompression. So I could see a time when maybe there's a combination, but the question is really going to be in the American market, will an insurance company pay for both? And I would love to see it, especially in those first few years of life when we could really make a big impact.

But as a physician, I am going to choose whichever medicine is going to block the most of -- the most pathway in an infant because I want the biggest efficacy. And I want to work -- I really want to get the most bang for my buck. And at this point, I think you're looking at the FGFR3 inhibitors a little bit more than the CNP analogs for blocking more of those cellular pathways. Does that help?

Helps a lot.

Your next question comes from the line of Mani Foroohar with Leerink Partners.

Thanks for taking the question and for taking the opportunity to give us a little bit of table setting ahead in the data here and some perspective. I've got a couple of follow-up questions on colleagues that have asked previously, but we'll start with the age range of the Phase III study. Can you give us a sense of what kind of the advantages and the strategy is behind studying a broader age range? And how we should think about efficacy in terms of AHV for each age group, the younger patients below 11, the very youngest, the oldest above 11, et cetera.

Yes. Thanks much for the question, Mani, and happy to take that. So again, just as a reminder, this is the broadest age range that's been studied in a Phase III trial, again, looking at 3 years to 18 years old. And the reason is we want to look for the broadest possible label. Obviously, there's a trade-off here where there is less of a treatment effect that's been seen in the previous trials in the space in a 3- to 5-year-old population and those above 11 years old. I think it was like [ 0.77 ] per year in the BioMarin Phase III when you look at the 11 population. And when you look at the various populations like less than 5, it's like about plus 0.1.

Again, given what we saw in our Phase II data, we thought it was really important to be ambitious here, right, because it's really important to -- based on all our market research, what everything is indicating that as long as there's an approved option in a given age range, physicians are really interested in using it. So that really kind of drove our strategy of why we wanted to go so broad with the Phase III to kind of get the broadest possible indication here so we can kind of get access to as many as possible.

Now I think with regards to kind of the different ages that we would expect in these populations, it's going to be tough to tell, right? Because obviously, there's only been a few trials run in this space. So again, I think overall, it's going to be, for us, a win here, honestly, is what Dr. Legare mentioned that at least looking around parity would be really important here.

Great. When you talk about being ambitious here, should we think about a need to reformulate for newborns to less than 2-year olds? Is that same formulation, but it's a different study? And how should we think about the time line?

Yes. No, great question here. So we are running a separate study for infants and toddlers with achondroplasia basically from birth to 3 years of age. And so -- that's actively ongoing right now. And what's interesting is basically for almost all kids, but the very youngest, they can actually take kind of the same formulation, which is like mini tablets -- the mini-tablet formulation that we have. It's really only for those that are the youngest, but basically those who are less than 6 months, we're looking at a slightly different formulation, but there's past precedents of different oral formulations that are suitable for kids younger than 6 months of age. Does that help answer your question?

That's helpful. And one sort of second question, which I've gotten a couple of inbounds about. You guys have talked quite transparently about your market research. There's been a lot of very transparent investor communication. One of the conversations I've had with [indiscernible] the market recent you guys are testing are hyperphosphatemia at the less than 10% ratio sort of being a sweet spot. Should we take that to be your expectation on this study in terms of proportion of patients showing hyperphosphatemia? Is that the wrong expectation? Like how -- what should we be looking for and expecting?

Yes. No, I think, again, the less than 10% number is something that we've extensively tested and have thought about. And again, just kind of really given the totality of what we've seen in the Phase II would be something that I think would be kind of an appropriate bogey for us to be thinking about here. Again, I think that's also -- as Dr. Legare mentioned early in the presentation, it's really far below the rates that have been seen on other growth promoting agents as well. So I think less than 10% would be a huge win.

Your next question comes from the line of Danielle Brill with Truist.

I guess one for Dr. Legare. Are there any advantages in your view of infigratinib's profile versus other emerging FGFR3 selective assets in the pipeline? And then based on the data that had been generated so far, what is your view of infigratinib's profile versus these other emerging approaches? And maybe quickly, just a quick reminder from Justin. Can you remind us what the latest thinking on plans for ex-U.S commercialization are?

Yes. I'll take both questions. So on the ex-U.S. commercialization piece, I think we are very interested in looking to commercialize outside the United States, given that this condition is really seen at a few concentrated centers of excellence in other countries. And so we're actively looking to build our footprint in those geographies and think between the profile of the drug, the data that we hope to see and our relationships with these kind of key sites that we can really be set up for success here with a kind of thoughtful build.

Now with regards to the other FGFR3 inhibitors in development, I think there is kind of fundamental issue with their key hypothesis, right, which is they think they can do better by sparing FGFR1 and 2 and therefore, which could lead to a higher therapeutic index. And I think there's 2 kind of fundamental flaws with that. The first is around the actual benefit of sparing FGFR1 and FGFR2.

From the data to date with infigratinib and from what we expect to see in FL3, I think it's clear that we're far from the doses where we're really inhibiting FGFR1 and FGFR2 compared to FGFR3. And I think we have a significantly broader therapeutic index than what's being portrayed. And so if there's, for some reason, ever a need for more efficacy for a subset of individuals, I wouldn't see any challenges with exploring a higher dose of infigratinib in that subset. And so that, in my opinion, really obviates the need for other FGFR3 inhibitors, which would be significantly behind.

I think the second issue with that is what this trade-off with FGFR3 selectivity actually entails. So what happens is when you're trading off selectivity for FGFR1 and FGFR2, they actually trade off for more selectivity on off-target effects like FGFR3, which we know is closely linked to spermatogenesis and angiogenesis. And so as a result, some of the other programs that have this liability have been required by the FDA to kind of essentially discontinue males once they get close to puberty. And we also know from genetics that there are conditions caused by loss of function in FGFR3 like Milroy disease and other conditions as well. So hopefully, that answers your question.

Due to time constraints, that concludes our question-and-answer session for today. I will now turn the call back over to Justin To for closing remarks.

Yes. Again, I really appreciate everyone being able to join the call today, and we'll talk to you all on the other side of the top line. So thanks so much.

Ladies and gentlemen, that concludes today's call. Thank you all for joining. You may now disconnect.

Good day, everybody. My name is Ash Verma. I cover SMID-Cap biotech and Spec Pharma and welcome to UBS Healthcare Conference. Our next company here BridgeBio Pharma, and I'd just like to quickly introduce our panelists. So Ananth Sridhar; and Anna Wade; and then Chinmay Shukla.

So thank you, everybody, for joining us. A lot of different things going on with your story. So maybe I'll just like give an open-ended question and then we can sort of going from there. And just for the audience who are in the room, if you want to submit a question through the QR code, like that will pop up here at this iPad hopefully, and I can bring that in towards the end of the discussion.

But with that, yes, maybe just if you can get it started on like the recent 3Q update, and you've had a few different like pipeline readouts come out in the last few weeks, essentially...

Yes. Happy to talk about that. So first of all Ash, thank you for hosting us, and thank you to the entire UBS team for giving us an opportunity to participate in the conference and thank you to the investors who have shown a lot of interest in our story.

So 3Q last couple of weeks was really a transformational period for the company. I think we have shown this year that we can really distribute our product commercially in a very competitive market, and we continue to show that in the third quarter earnings call. Our volume accelerated, our price is stable. So our sales have really started to accelerate. So we feel great about that engine.

And then we further buttress that engine by reading out 2 Phase III trials, both in very large $1 billion-plus opportunities, ADH1, Encaleret in ADH1 with an expansion opportunity in chronic HP. And then BBP-418 in LGMD2i with an expansion opportunity in LGMD2M, 2U and also Fukuyama disease. So we feel we are very well positioned to transition into becoming a diversified rare disease company.

And on top of all of that, we also have an exciting Phase III update coming up in early '26 for infigratinib in achondroplasia. And then later in '26, we'll read out our proof-of-concept study for infigratinib in hypochondroplasia. So a lot happening. I'm happy to dive into all of that.

But I think the takeaway is that the company is now transforming itself into being a diversified genetic disease company with multiple big products.

Great. Good start. So maybe just if we talk about Attruby, the launch has been very successful so far. And the update that you provided in terms of the patient adds in 3Q and seems to be pretty broad-based as well. What I'm trying to understand is where -- like what are the sources of the revenue? Like which type of patients are starting to get on the treatment?

Yes. It's a great question. So like you said, the uptake has been really broad both in terms of patients, but also in terms of physicians who are prescribing -- regions in the U.S., which are prescribing. So that gives us a lot of confidence that this is quite robust and it's going to continue in the future.

Having said that, we've always focused most on the treatment naive section of the market or the first-line section of the market. We continue to see every single month more treatment-naive patients start Attruby than the previous month. Every time we've reported our quarterly number, we have said that our treatment-naive patients have been a majority of them.

And I think in the last update, we said that our share is well in the 20s now there, and they comprise of a vast majority of our patients now. So we feel very good about how Attruby is being used by all patients and all physicians. And we are particularly thrilled with the momentum we are seeing in the treatment-naive section of the market.

Yes. I hear this from some of the other competitors as well, just like treatment-naive adoption has been very strong. I mean I'm just curious like what is essentially driving behind that? Is it like a lot of disease awareness and just the availability of the therapy or is there any -- what are some of the pushes that you're doing from a commercial standpoint to get more patients activated?

Yes. Yes, it's a good question. So the market has definitely expanded. If you look year-over-year, the market has expanded meaningfully. We used to say that there are about 2,000 to 3,000 treatment naive patients who would start therapy every quarter last year. Today, we are seeing it's at least 3,000 patients, but there are probably more than 3,000 patients.

So number one, the size of the pie has expanded for everyone. That's mainly because of more players coming on the market and more awareness of the disease. That's also activated different types of physicians who are finding these patients, which has really benefited Attruby, especially in the high-volume heart failure clinics section of the market.

Beyond that, I think that for Attruby, specifically, we've had very strong clinical data. And really, our commercial strategy has been to lead with our clinical data. So whether that's in the AFib population, which is about half of these patients where we have shown the best point estimate, whether it's in the variant subpopulation where again, we have shown a profound benefit, including a static benefit on mortality and hospitalization where we continue to publish, including at AHA, more data I think that those kinds of real-world evidence generation, showcasing Attruby's unique profile, coupled with the market growing, has helped us to really accelerate this launch, I would say.

Got it. And just as you look towards like 2026, do you think that the focus will continue to be on the naive patients or does that start to diversify a little bit?

Yes. So we've had a very broad and balanced sort of uptake across all sort of sections of the market. But treatment-naive has been the focus. It will continue to be the focus. I expect that our switch share has now stabilized. So I think that I don't -- I expect that in '26 and beyond, we're going to continue to see a lot of growth from the treatment-naive section, and I think we continue to get our fair share of switches.

Got it. Yes. I mean one of the things that like I've started to hear from investors just on the impact to VYNDAQEL. So I mean, you might have seen like they missed the VYNDAQEL number a couple of weeks ago when they announced the earnings, which has again kind of stood this controversy, is the market finite? And -- is it like a zero-sum game between the 3 players? So just curious like what -- like when you see that happening, like what does that tell you? Is that a good or a bad sign, I guess?

Yes. I think that maybe there are 2 aspects of this. Maybe I'll break it down into the volume and the price. I think if you look at the commentary from Pfizer, they very clearly talked about double-digit demand growth, right? And I think that if you -- again, if you look year-over-year, given that tafamidis has to have an IRA impact this year, right? So that means that their volume has to go up by 25% year-over-year just to match the sales number, given the 20% rebate to Medicare.

I think that, that continues to say that given they're annualizing at about $4 billion in the U.S. continues to say that the market is very large, and it continues to grow. I think that stabilizers remain the backbone of care.

Having said that, yes, it is true that we have taken -- again, the company commented on their own earnings call that Attruby has taken share. And we continue to position ourselves as the best stabilizer, the best first-line option for these patients.

So I do think that this is a market where all players are going to do extremely well. But I also think that Attruby is going to be -- we have certainly said that our goal is to be 30% to 40% of the overall market. And internally, given the strong start that they are our partners had in Europe where they're at a majority share, internally, we do try to push ourselves to see that, hey, can we go beyond the 30% to 40% and get a majority share in this market.

Right. And then I guess just the piece about the Pfizer competitive dynamics. So they have been saying that there would be more pricing pressure on them going forward. Does that -- can that translate to more sort of a broader impact on the overall market? Or is it something that is singled out just to VYNDAQEL?

Yes. So so far, we haven't seen any pricing pressures for us. I think that Attruby is in a very, very privileged position, right? So one, we were quite responsible in how we priced and Neil, our CEO has commented on this in all of our earnings calls that we do expect long-term prices in the category have to come down, which is why we started at a 10% discount to tafamidis, despite having, what I would say, really strong data on hospitalization, fastest time to separation on hard outcomes, both strong data points that payers care about.

So I think given that, coupled with the fact that our strategy remains parity access, we're not looking to pay for preferred access. I think if you rewind a few minutes ago, I was saying that the main driver for us has been our clinical data. We want to do that. We think that if we are all in the physician's office and the physician is making the choice based on data that we will win a lot of patients and so I do think that we don't expect to see any sort of pressure here. We expect our gross to net to be stable over the next few quarters.

So that's kind of what I would say on that topic.

Got it. Got it. Okay. All right. And then just staying on the same theme. So as tafamidis goes generic, yes, I'm trying to understand what is your base case assumption? Are you seeing any kind of a combo use right now? And can that like trigger more of a combo use after generic.

So let me first take the combo use questions. Yes, there is combo use in this market. I think it's pretty well known that folks are using 2 agents in combination right now. Very little combo use with Attruby though.

Now what is interesting to note is that there were guidelines which were published by the ACC a week or 2 ago, which clearly said that there is no discernible benefit of combination therapy. When you couple that with the fact that a combination therapy is about $750,000 a year, and you take your previous question about payers, right? I do think that, that segment of the market is at pretty big risk of just going away.

Thankfully, we don't play in that segment, so we worry about it less. As it pertains to your question on TAF IP, I think that our position on this is very clear, right? We've said that, we think that tafamidis is protected well into the 2030s potentially up to 2035 given their polymorph patent. I think that when we look at the fact that physicians and payers -- physicians and patients are already reaching for a Attruby first, right? Well into the 20% range, treatment-naive share means that there's a very big section of the market, which prefers to use Attruby, which I think further insulates us from whenever TAF goes generic.

You couple that with the product hub strategy that they have going on for VYNDAQEL right now. All signs point to the fact that this is going to be a very durable market.

And then lastly, you can look at any kind of commercial analog right, whether you look at the statin place or whether you look at the PH marketplace, when the first-to-market molecule, less potent molecule goes generic, the second to market, more potent, differentiated molecule, right? We have a differentiated label, the sales of that product don't really go down. The growth just maybe slows down a little bit, but the sales definitely don't go down in any way.

Is that because of the volume dynamic or like pricing pressure or any step edit type of...

Yes. So normally, what we have seen is that volume continues to grow in those categories because ultimately, physicians want to prescribe the most potent molecule. And the drugs are not different in cost for the patients. So they don't really -- they also want to be on the most potent molecule. So your volume continues to increase.

And I think when it comes to payers, given you have a large installed base of patients, I think at that time, if we give a small rebate, they're not going to require a step edit or something like that. And that's certainly what we've seen in other categories, too. So if your volume continues to accelerate and maybe your price takes a small onetime adjustment, you're going to be able to continue growing through it. And so that's kind of what gives us a lot of confidence here.

Got it. And then you had some data that you presented at AHA this past weekend. Maybe if you can just kind of highlight what are the key takeaways from that?

Yes, happy to do that. So we had a lot of data which came out at AHA. And we had, I would say, a very robust engagement with HCPs. Our commercial team was there. They were able to meet with a lot of customers, educate folks on Attruby and really get the word out.

And I do think that awareness increasing has driven more diagnosis in the space. So that's one macro comment. The specific data that I would highlight is actually our variant data. So the variant population here is one which has significant unmet need, right? They have a high risk of mortality. Currently, it's a severely underdiagnosed piece of the market, right? So it's a place which the market is going to grow in.

If you see what we presented there, we've said that we have -- we're the only agent which has shown a statistically significant difference in mortality and cardiovascular hospitalizations. And I think that at AHA, we continue to expand on that story with a 59% reduction in ECM and a 69% reduction in ACM and first CV event at 30 months. Both of which were stat sig.

And I think that what was really profound to me as a scientist is, sometimes you'll see these poster presentations and then you don't see a peer-reviewed publication. Maybe it's because I went to grad school and suffered through a lot of peer review. And I think your smile tells me, you did, too. I think that what was very exciting to me is we had a simultaneous publication also. And so the data is now out in a peer-reviewed published manuscript. So very excited about that, I would say.

Great. Awesome. So maybe just like switching gears a little bit, like talk about the pipeline. So you had this -- a few updates, like you said, ADH1 and limb-girdle. Maybe like I'll start with ADH1. So this Phase III update, like can you comment on just the kind of the durability and long-term safety of the normalization effects that happened?

Sure. I'll pass it on to Ananth to talk more about ADH1.

Yes, it's a great question. So just to remind folks, we presented top line results from our study of encaleret in patients with autosomal dominant hypocalcemia type 1 ADH1. There's a cohort of about 67 individuals are randomized 2:1 to encaleret versus conventional therapy.

What we showed in our primary analysis was 76% of people receiving encaleret normalized their blood and urine calcium by week 24, which is about 6 months of therapy compared to 4% of those same individuals on conventional therapy. So it's a dramatically profound result on the primary endpoint, the co- endpoints of normalization of blood and urine calcium.

And then to your question of the durability we've seen from our Phase II cohort evaluating the same criteria that once maintenance doses of encaleret are achieved within about roughly the first month of treatment initiation, the effect seems durable and sustained. And so we've observed that cohort up to 3.5 years now. We published those data this summer, presenting durable effect and importantly, without the need for dose escalation, which we've seen with other products in this field.

So like with this Phase III, like would you have more longer-term follow-up data that will start to...

We will continue to. And what's heartening about our cohort, so more patients discontinue the standard of care arm. The control arm versus none on the encaleret arm. So it was quite well tolerated and the rollover to the long-term extension was nearly complete. So of those who completed the study, 98% of the completers rolled into the long-term extension. So we will have a rich data set to evaluate for long-term data, both on durability, safety as well as some of the long-term effects on kidney and bone health.

Yes. And then just on this Phase III, so the hypercalcemia AE, it seems like no discontinuation, but some level of titration that happened. Like does that make you believe that could that be limiting in any way in terms of the efficacy for the molecule? Or like what's sort of happening to try to identify like the right dose at the right...

I think you got it right on, which is that early in the titration, there may be excursions in blood calcium whether it's low or high, depending on the individualized dose needs for that patient. We saw one SAE that was related to conventional therapy due to hypercalcemia, one on encaleret. These are both commonplace for these patients as they try to identify the right dose.

And so I think these are familiar circumstances. Both are -- were asymptomatic and resolved with dose reduction. So they're transient and their response to the dose, they don't require discontinuation. And I think it has no -- it's a sign of treatment effect rather than lack of effect.

Got it. Got it. Yes. I mean with this one, there seems to be a fair bit of debate on just like the market size of the opportunity, right, and like effectively new ICD-10 code. So yes, what's your most like most convincing argument for that this is like a big market size? And -- like do you think that there would be more substantiation of it as you go along in terms of identifying like what -- how many patients are out there that actually need this treatment?

Absolutely. I do think one -- so to just answer your question directly, we think there's about 12,000 carriers of ADH1 in the U.S., so 1 in 25,000 roughly. And of those 12,000, we think the diagnosis rate is somewhere in the 20s, 20% today. There's a coalescence of data that we can look at to get there, which is a mix of ICD-10 coding data, a mix of individuals involved in our clinical program as well as our disease monitoring study as well as with our genetic testing program, which has yielded a meaningful amount of positive tests for ADH1.

The other element that I would point folks to just from published literature, we presented on our sponsored testing program. ADH1 is the most common isolated genetic cause of hypoparathyroidism. So if we think about the broad picture of hypoparathyroidism and the overall prevalence, which I believe is not as highly debated, and we see that ADH1 is the most common genetic cause. It's kind of hard to decouple the fact that ADH1 may actually have a prevalence similar to what we've seen in the large genetic population data sets. So I think more to come as well as increased diagnosis rates with awareness of not only our program, but also this condition and access to genetic testing.

Yes. Maybe I'll just add to what Ananth said, right? I think between the ICD-10 code, the sponsored genetic testing programs as well as the various folks enrolled in our trials and their family members, we've identified 3,500 patients in the U.S. like these are patients that we know who they are. We know the physicians. So I do think that, that's going to be the initial target population for us.

And if we just get uptake in those 3,500 patients at a genetic disease price point, right, which is -- which can be a meaningful market opportunity of over $1 billion just in the U.S. Beyond that, there's a European opportunity. Beyond that, there's an opportunity to drive diagnosis and further increase sales in ADH1. But that's kind of what gives us a lot of confidence here is just those 3,500 identified patients by the company.

Yes. And this is something that you're kind of working through like just on this patient identification path while...

Yes. I also think what's interesting to me is it's only been a couple of weeks since we announced our data, and we've already had families as well as physicians come inbound to us, think that they have this disease that they would really like to be on the drug. And so that's also been something which has helped us to continue expanding the number of 3,500 identified patients in the U.S.

Yes. Yes. I think our familiarity with the marketplace and even this last week, Kidney Week at the American Society of Nephrology, there were cases presented on ADH1 as well as providers who mentioned that while we know a lot of the patients today are cared for and diagnosed in endocrinology clinics, they may present in stone clinics as well under nephrologist care.

We've learned a cohort of patients at the stone clinic who have positive variances on their calcium-sensing receptor gene. So I think there's certainly room to not only grow our familiarity with where these patients are, but grow the diagnosis rate amongst those who have signs and symptoms as well.

Got it. Okay. So I think this is kind of a unique dynamic that you have that you're also pursuing for a hypopara indication with the same molecule. And I know like the pricing strategy can be a little bit custom for this type of a dimension in which like on the hypopara side, there is more like established therapy in sort of crowded market versus this being like a more targeted indication. So what does that -- yes, what's the solution to that effectively?

Yes. I think we will start -- when we launch an ADH1, we will price it like an ADH1 drug. And I think that as we generate data in chronic HP, which we are very excited about, once we have that data and once we are serving the chronic HP population, we can talk about thinking about the price a little differently. But at launch, you should expect to see an ADH1 price.

Got it. Okay. All right. I think like Neil threw out this like $300,000 to $500,000 range on the 3Q call. I don't know if that's sort of in the same ZIP code of where you thinking about this or...

Yes, I think what Neil is trying to say is if you look at sort of genetic diseases, on the low end, I would look at things like Crysvita, right? I mean Yorvipath is approved in HP, which is a much bigger indication, and that's priced at about $300,000.

But really, the more comparable disease, I would say, are X-linked, Hypophos -- XLH, which is Crysvita, which is about $400,000, Voxzogo, which is also bigger market than this, that's also around $400,000.

On the high side, you would look at drugs like Exondys or Varcat, which are -- which can be $750,000 to $1 million. So that's a pretty broad range. But like, yes, that's kind of how we get to that sort of $300,000 to $500,000 range, which $300,000 to $500,000, which Neil was talking about on the call.

Right, right. How much does like the durability of treatment also factor into that dimension, right? Like do you have a sense on like is this going to be chronic?

We do think this is going to be chronic. But Ananth, do you want to talk about some of the long-term data, which you guys already have?

Yes. I mean, so it opens a question about the -- just the therapeutic hypothesis here. And what we're trying to do with Encaleret is we're trying to restore the wild-type or the native properties of the receptor. And that is what we are showing with the normalization rate.

So we're trying to normalize calcium homeostasis, calcium metabolism in these patients. And so that's why we do expect it to be a chronic therapy. And if it's continuing to yield the benefits like we're seeing in our Phase II cohort 2, 3.5 years longer, we certainly expect that patients will continue to persist on that therapy.

Great. Awesome. So back to you, Anna. Thanks for bearing with me. So just on limb-girdle. So yes, here, you've had another positive Phase III. So maybe if you can talk about like the primary secondary outcomes and what are the key data points that you showed?

Yes, absolutely. So yes, BridgeBio had a very exciting week. So we read out 2 positive Phase IIIs. We read out 2 days before announced trial. So this just to take a step back, we're developing BBP-418 for limb-girdle muscular dystrophy type QI. And this trial was an interim analysis, which was originally planning to look at a particular biomarker that is close to the disease, looking at changes in glycosylated alpha-dystroglycan. But we actually saw a really profound effects on clinical outcomes.

So this is like the first time, I think, really in the muscular dystrophy space that in a randomized controlled trial, we're seeing not only significant stats sig differences from placebo, but we're also seeing improvements relative to baseline.

And so just to go to that in a bit more detail, what we saw was this significant increase in glycosylated alpha-dystroglycan at both 3 months and at 12 months. It was way in excess of what we were expecting to target. So we were hoping to see around a 5% increase in this particular protein to see clinical benefit. We saw 17% increase at 3 months, and then it continued to increase at 12 months. So it ended up being around 24% increase in that protein.

Then we saw -- an 80% decrease in serum creatine kinas, which is demonstrating an impact to the site of the muscles, so getting less muscle breakdown. And then the thing that was super exciting is we saw improvements on -- a measure of ambulation and then also a measure of pulmonary function, so forth vital capacity. So the differences we were seeing now were on the ambulation, it was an increase in velocity of 0.14 milliseconds, a difference from placebo of 0.27 milliseconds. That kind of doesn't sound very much, but went over 100 meters that means the patients are walking 14 seconds faster on treatment than on placebo.

And then on the SEC, this is like an endpoint that's been used to approve other drugs. It's very well known. What we saw there was a 2% decline in the placebo group, which is consistent with natural histories and then we saw a 3% increase in function on drug. So this is like an incredibly strong data set. And this is considering this data set, we're now going to go to the FDA and before the end of the year to discuss whether we -- this data set could support a traditional full approval as opposed to the original strategy, which was an accelerated approval.

Yes, maybe one thing I'll just add is as a scientist it is pretty profound to see that we now have 2 molecules. Normally, when you make a drug, you're trying to slow the progression of a disease, once in a while, you get a drug like Attruby, which is amazing at just halting the progression of the disease.

But now we have 2 molecules in Encaleret and BBP-418. Which are reversing the disease, which are approaching towards the cure for the disease. And that's actually very exciting to us from just a scientific perspective.

Yes. Yes. And then just limb-girdle as well, kind of similar vein of question just like what's the most like hard concrete evidence that you have in terms of patient numbers?

Yes, great. And you'll also hear that a lot of the sort of tailwinds are similar in this space than in the ADH1 space. But so essentially, we estimate around 2,500 patients in the U.S. That's based off of prevalence estimate based on we know the carrier frequency of the disease-causing alleles. We also know that there is like an existing patient pool based on like registry data.

And then we also had the clinical trial enrolled incredibly fast. So we enrolled 20% over what we were targeting are initially in 8 months early. So there's definitely a lot of unmet need and like patient interest. These patients are typically cared for at sort of MDA clinics. So that's a known entity as well, it's about 150 MDA clinics in the U.S. And a lot of these patients are currently cared for in those clinics.

We do know that there's probably some patients that know they have some kind of muscular dystrophy that are not currently genetically diagnosed. And we anticipate that with this being the first disease modifying therapy, hopefully, to come to market there would be an increase in diagnosis similar to what we saw in the SMA space just prior to launch.

And then on top of that, what's kind of nice in this space is that there's already sponsored genetic testing. So it's pretty typical than a muscular dystrophy patient once they go to a clinic, they will be put on to sort of expansive muscular dystrophy panel, which includes these genes and so then they get a diagnosis of LGMD2i.

And then, I guess, just to speak to something that Chinmay said earlier, there are other expansion indications here. So all the data so far is in LGMD2i but there's also an opportunity in 2U and then Fukuyama Congenital muscular dystrophy.

Got it. Okay. That's great. I have a couple of quick questions from the audience here. So maybe just, I believe this is for ATTR. So just like the under diagnosis of the disease and improving diagnosis has one of -- has been one of the key growth drivers. Where do you think we are in terms of penetration of the diagnosis?

That's a great question. I think that we are very much still in the early innings. So maybe taking a big step back, I think that the prevalence of ATTR-CM in the U.S. is probably around 250,000 at least. I think that there have been probably 50,000 to 60,000 patients diagnosed with the disease so far. That means that we are what -- barely a 1/5 fit of the way there. So we are very much in the early innings. And one of the things which we track is number of PYP scans, and you can see that, that continues to increase every year.

And then you obviously see the treatment-naive patients and that you can just look at the claims data, that also seems to be increasing every year. So lots of signs which point to the market growing and accelerating. And I think we are very much in the early innings. We're probably around 20% to 25% diagnosed right now.

Got it. Great. And then one last question here. How do you think the depleters fit into the therapy if they come to the market? Does having a disease-modifying therapy put more pricing pressure on the current stabilizer and silencers?