BridgeBio Pharma Inc Aktie

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?

Yes. So we're excited about depleters. I think we are going to see what data they show. The depleters are not really in competition at least with the stabilizers because, if you think about this disease, this is a mass action disease. It's just caused by the deposition of toxic monomers into your heart.

And what the depleters are doing is there as the name says, depleting it from the heart. And I think we guys are acting upstream where we are preventing their deposition. So we actually think that they are very complementary. We have an early-stage program developing an ATTR-CM depleter. So we are excited about the opportunity. We don't think it's going to cause like pricing pressure or anything like that.

But we do think it's going to allow us an opportunity to further serve this patient population and to further reduce the mortality and morbidity associated with the condition.

Great. With that, we can wrap it up. Thank you so much for this.

Thank you, Ash. Thank you to all you for joining us.

Thank you all.

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 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 Third Quarter 2025 Earnings Call. I am Chinmay Shukla, 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'll cover our strong commercial execution in Attruby's third quarter on the market. We'll provide updates on our late-stage pipeline, including the Phase III readouts of encaleret and BBP-418, which were announced this week, as well as discuss infigratinib in achondroplasia, which we expect to read out in early '26. We will end with a discussion of our robust financial position. Following our prepared remarks, we will open the call for Q&A. For the question-and-answer 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 for his remarks.

Thank you, everyone, for joining us today. As always, this is a forum in which we communicate salient aspects of our business that are of interest to investors, and we welcome your questions and feedback along the way.

On the first two of these calls we have done, I focused my early comments on Attruby, which continues to be the core of our business. As both Matt and I will elaborate on, we see continued momentum both scientifically and commercially in this franchise and are ever more confident today that we will achieve our goal of 30-plus percent market share by volume in the years to come.

But I wanted to start today by talking about our recent R&D progress. As you all know, we had the distinct privilege of announcing 2 stellar Phase III top line results over the last 3 days. It is quite the coincidence that these readouts happen to stack on top of one another after 6-plus years of working on these programs. But these few days serve as a testament to the longer-term productivity of the R&D engine we have created.

Slide 10 of our updated corporate presentation shows the industry-leading time lines that we have been able to achieve, and Slide 11 shows the remarkably high probability of technical success across our programs across the nearly 10 years that we've been operating. Probabilities of technical success north of 70% start to move us from a lottery ticket-like entity to an engineering company-like entity, one that will undoubtedly face failure, but that can reliably produce medicines that matter with reasonable cadence.

The speed and efficiency of the BridgeBio engine is only possible because we target well-described genetic diseases at their source. It's also the product of our decentralized hub-and-spoke model that is fueled by our tireless employees that are dedicated to making an impact to the patient communities that we serve.

I'd now like to highlight some of the most remarkable aspects of the data we have shared over the last few days, and I encourage those seeking to learn more to access our webcasts on each readout. On Monday, we read out our Phase III FORTIFY trial of BBP-418 in limb-girdle muscular dystrophy type 2I. The study exceeded all of our expectations, meeting all primary and secondary interim analysis end points. The primary endpoint, glycosylated alpha-dystroglycan, was successful to a high degree of statistical significance. Though even small changes in aDG have been shown to be clinically meaningful, it is remarkable to see some patients attaining normalized levels of aDG. And the 80% increase in glycosylation meaningfully move patients to healthier levels of muscle function.

Across the key clinical endpoint study, ambulatory function and pulmonary function, BBP-418 not only stopped the decline that was seen in the placebo, but showed a statistically significant incline in function. Patients are walking better and breathing better than when they started. In addition, this small molecule is distributed systemically, and we look forward to sharing additional data associated with its impact on other tissues, including, importantly, the heart muscle.

Earlier today, we shared the top line data from our Phase III CALIBRATE trial of encaleret in autosomal dominant hypocalcemia type 1. We saw profound and highly statistically significant normalization across blood and urine calcium as well as highly statistically significant normalization of PTH. Just to reiterate, a vast majority of patients fully normalized urine serum and PTH levels. As I mentioned on the webcast, when we speak of tiers in therapeutic medicine, this is the type of impact we seek.

And as I mentioned on our last earnings call, we are moving expeditiously not only to launch this drug, but also to initiate its Phase III in chronic hypoparathyroidism. Here in CALIBRATE in a cohort of 10 patients, normalized urine and serum calcium in 80% of subjects within 5 days of dosing. Importantly, this drug brings differentiated promise to the hypoparathyroidism community across at least 3 potential dimensions. First, it's oral. Second, it potentially normalizes urine calcium, the cause of downstream kidney conditions. And third, it might avoid potential downstream bone associated [ resorption ] issues that could require [ bisphosphonates ].

Finally and importantly, for both small molecules and LGMD2I and ADH1, we saw a safe profile, supporting their ability to provide lifelong improvement for patients who have no disease-modifying therapies available today. Of course, these data are only interesting to the extent that we can get the therapies into the hands of patients. This is where the ongoing success of Attruby gives me confidence that we can distribute at scale.

We have been in the marketplace for nearly a year, and I feel our message is just beginning to resonate. The numbers to support that include the fact that we have delivered 5,259 unique patient prescriptions to 1,355 unique HCPs, generating this quarter $108.1 million in net product sales. In the long term, although our goal is 30% to 35% share by volume, I believe we have the potential to be a market leader. The best point estimates to date on key endpoints at the lowest price point, backed by an aggressive research plan, support that future.

Early performance of BEYONTTRA in Europe, where physicians have been quick to recognize the strength of our data, also supports that future. Our partners at Bayer have done a wonderful job prosecuting the acoramidis hypothesis in Europe, closing in our market leadership in Germany with an NBRx of nearly 50% just 6 months into launch. In that geography, among other tailwinds, regulators have also been quick to shut down Pfizer's inaccurate claims of "near complete stabilization."

On that topic, as I was putting together in my comments, I stumbled upon an old e-mail that Dr. [ Jeff Kelly ], the inventor of tafamidis had sent to Dr. Isabella Graef, one of the inventors of acoramidis. In it, and I directly quote him, he says, "Given the variability in stoichiometry and the experiments between tafamidis and [ AG10 ] and TTR, the data always tell the same story: That [ AG10 ] is better than tafamidis, as would be expected from the determined binding constants." I have to say, I agree with him.

Moving on from competing, we are also asking ourselves what is unique about our product. As many of you know, in patients with cardiac arrhythmic involvement, we observed a 43% reduction in risk of CVH associated with cardiac arrhythmia and a 17% reduction in TEAEs related to new onset AFib. That is unique. In patients with the most common variant, V122I, we published a 59% hazard reduction, which, to our knowledge, is the largest point estimate in terms of reduction demonstrated in the field. We expect to further elaborate on these data at the upcoming AHA conference, so please stay tuned for that later this weekend.

Additionally, we've continued to interrogate what in my mind, is an incredibly unique factor, our early time to separation. In a recent [ JACC ] paper, we published that the effect of acoramidis on recurrent and cumulative cardiovascular outcomes was observed as early as 1 month. One question is why is this prompt effect occurring? One hypothesis is that the answers may reside in the cardiorenal access, similar to what has been described for [ SGLT2 ] inhibitors, and we intend to explore this further in the clinic.

In addition, we intend to bring a new clinical CMR study to the field to further interrogate Attruby's impact on disease regression as measured by cardiac function and structure. Some of you may have seen another single site CMR study recently published by [ Slivit ] et al, in which they suggest the "potentially superior effect of acoramidis" versus tafamidis on important parameters like LVEF and [ LV mass ]. These new research areas marry nicely with the continued execution of our ACT-EARLY trial, a potentially profound study that explores the effect of acoramidis in presymptomatic variant patients and in the context of this mass action disease.

Finally, we'll continue to study the efficaciousness of the drug in the context of real-world evidence studies. We've been proponent of leveraging RWE as early as the survival studies done by [ Drs. Masri, More ] and others. Given that in the modern marketplace, it is an exceptionally difficult thing to conduct double-blind head-to-head studies, RWE will serve as an important tool in identifying the right patients for the right drug. And we'll have more to publish on this front in the months to come.

These research efforts tie together with the continued strengthening of our access profile and increasing diagnosis rates of patients with ATTR cardiomyopathy. Matt will have more to say about our access program, but we continue to offer best-in-class programs and are improving with every month, the ability to "make it easy" for those patients and physicians that desire access to Attruby.

I'll end with a brief comment on future growth. The obvious growth in our portfolio today sits with the expansion program of hypochondroplasia and in chronic hyperparathyroidism, branching from our achondroplasia and ADH1 program, respectively. But shareholders should not overlook the deep ownership and close oversight we have with our sister companies. At GondolaBio, in particular, we now have 17 programs across the Mendelian landscape, including what we believe to be a potentially best-in-class asset in EPP in Phase II and buttressed by exciting programs in alpha-1 antitrypsin deficiency, hereditary pancreatitis, ADPKD and many other areas. As these programs move forward and we continue to solidify BridgeBio, we can access new growth opportunities at the right time to increase the scope of work we are doing for patients.

With that, I'll turn it over to Matt, our Chief Commercial Officer.

Thanks, Neil. I'm excited to share our Q3 progress and discuss some of the positive trends behind Attruby's continuing success, along with the excitement that the new Phase III data from both encaleret and BBP-418 have created. Starting with Attruby, as we have seen throughout the year, the ATTR-CM market continues to expand, with growth coming from all segments of the market. We have been particularly encouraged by the increase in prescribing from both returning and new physicians, with a steady rise in first-time prescribers adopting Attruby in their practice.

Importantly, once physicians begin prescribing Attruby, they continue doing so, a clear reflection of the consistent clinical performance we've seen in real-world use. This persistence stems from Attruby's differentiated profile of being the only near-complete stabilizer on the market versus a partial stabilizer and a partial knockdown. Attruby has also shown the fastest time to separation from placebo to date. While patients are getting diagnosed faster and at a younger age, many continue to go undiagnosed or progress on their current medications. When that happens, they need something that can stabilize the tetramer and do so quickly. The bottom line is that patients and physicians want a medication that works well and works fast, and Attruby continues to deliver on both efficacy and speed.

As we look towards Q4 and the 1-year anniversary of the launch of Attruby, there are several factors I would like to highlight. First, Attruby's strong launch trajectory continues to demonstrate consistent growth across all market segments. We expect this momentum to carry into the coming quarters, positioning Attruby for meaningful share expansion over time as awareness and adoption continue to increase.

Second, the ATTR-CM market itself continues to grow quarter-over-quarter, with no signs of slowing. This ongoing expansion effectively enlarges the total opportunity that Attruby is competing for and supports the sustained growth runway for the brand. Third, as the U.S. health care environment becomes increasingly cost conscious, Attruby remains the least expensive option in the ATTR-CM market. Combined with being commercialized by a U.S.-based company, this positions Attruby well for long-term competitiveness as pricing and access pressure continue to evolve.

Finally, we continue to see encouraging underlying trends for Attruby with continued growth in the total number of patients on therapy and a steady increase in ongoing treatment utilization. Together, these trends underscore growing prescriber confidence and sustained demand for Attruby. Building on the momentum from Attruby, we are now turning to the next wave of potential launches in our pipeline.

Let me begin by reinforcing how excited we are by the recent readouts for BBP-418 and encaleret, which represent one of the most remarkable dual clinical successes in rare disease drug development. Both encaleret and BBP-418 exceeded expectations across their primary and secondary endpoints, positioning each as a potential first and best-in-class therapy with a compelling value proposition. Together, these programs will redefine care for patients with anticipated strong support from the clinician and payer communities based on the strength of each respective data set, if approved by the FDA.

We expect an additional readout for infigratinib in the first half of 2026 and look forward to discussing the commercial opportunity at that time. The launch of Attruby has provided invaluable experience in scaling rare disease commercialization from building disease awareness and engaging HCP networks to executing patient identification and access strategies. These learnings are directly informing our next wave of launches, including encaleret, BBP-418 and infigratinib. Many of the same leadership, operations and market access teams who drove the success of Attruby are already in place to support these programs.

In preparation for these upcoming launches, we have continued to expand disease state education initiatives and have begun hiring key commercial leadership positions. The response to our initial positions has been remarkable, underscoring both the strength of the BridgeBio platform and the excitement around our pipeline of transformative therapies that will meaningfully improve outcomes for the communities we serve. The hiring momentum will continue to ramp over the next several quarters, leading into the respective potential approvals for each indication.

Importantly, encaleret and BBP-418 will represent first-in-class options in their indications, while infigratinib would be the first daily oral medication in achondroplasia, allowing children a needle-free option for their daily care regimen. Beyond the U.S., we're actively building the infrastructure to support global commercialization, enabling coordinated launches and sustained access. Through our expanding global footprint, we are well positioned to deliver meaningful innovation to rare disease communities worldwide, ensuring global access, continuity and impact.

With that, I will turn it over to Tom, who will discuss BridgeBio's financials.

Thank you, Matt, and good morning, everyone. I'll now discuss our financial results for the third quarter of 2025. Please note that our commentary on today's call will focus on GAAP financials unless otherwise indicated.

Total revenues were $120.7 million in 3Q 2025, consisting of $108.1 million of Attruby net product revenue, $4.3 million of royalty revenue and $8.3 million of license and services revenue compared to $2.7 million at the same period last year. The $118 million increase in total revenues was primarily due to a $108.1 million increase in net product revenue from Attruby driven by strong growth across all market segments. We also recorded $4.3 million in royalty revenue from ex-U.S. net sales of BEYONTTRA in Europe and Japan.

Total operating expenses for the third quarter of 2025 were $259.3 million compared to $193.9 million in the same period in the prior year. The $65.4 million increase in operating expenses was primarily driven by a $68.8 million increase in SG&A expenses, partially offset by a slight decline in R&D expenses. This reflects our continued investment in the Attruby brand awareness and ongoing investments in our late-stage clinical programs.

Turning to our balance sheet. We ended the third quarter with a strong cash position of $645.9 million in cash, cash equivalents and marketable securities, which provides significant cash runway to continue supporting our transition into a diversified late-stage multiproduct business.

In closing, our commercial launch of Attruby continues to accelerate, and our pipeline has never been stronger. Following the positive results from LGMD2I/R9 and ADH1, we now look forward to top line results from achondroplasia in early 2026.

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. We kindly request that you limit yourself to 1 question. Thank you.

[Operator Instructions] Our first question will come from the line of Salim Syed with Mizuho.

Great. Congrats on all the week's successes. Neil, Matt, maybe just one for you. Possible to comment on the percentage of new patient share? I know last time you provided the number, I think it was 18% to 20% on the 2Q call. Just wondering if that's increased since then? And if that remains the primary focus for growth? Or are you also seeing an increase in the switch category?

Yes. Salim, good question. I'll take a crack, and Matt, you can elaborate if I miss something. I mean I'd say our naive share, it's hard to tell, honestly, because we don't have all the numbers yet from Alnylam and Pfizer for the quarter. But our best guess is that naive share is well in the 20s. Now we've seen double-digit growth, obviously, in overall script quarter-on-quarter number. And that script growth has been even more profound in the NBRx setting. That means that we've seen a little bit of a downturn in the switch setting, and that's mostly because we're seeing a lot of combo use. There's some work that we could do in terms of reminding people that why not use the best stabilizer on top of a knockdown if you're going to go that route, but our NBRx share continues to grow nicely.

Why do we focus on that? I mean, you know this as well as I do. But ultimately, your peak steady-state share is pretty simple, right? It's a fraction of new patients that you're capturing, multiplied by the fraction of the total market that is new each year, divided by the annual dropout rate. And if you look at this marketplace, the annual dropout rate is pretty high, something like 40% is what we modeled when you certainly look at Pfizer. And the fraction of the new markets, since you're adding patients to the market, it's not just replacement over time, is going to be greater than that. So any time those two things are -- effectively, that fraction is greater than 1. What you ultimately want to do is maximize the fraction of new patients that you capture. So whatever, if it's at 30%, then we're going to be a multiplier of that on peak year share.

So as we look forward over the course of the next 3 to 4 years, obviously, our goal is 30-plus percent market share. We're well in range to do that even with the numbers that we have today, and I expect them to continue to grow.

Our next question comes from the line of Tyler Van Buren with TD Cowen.

Congrats on another solid quarter of Attruby commercialization. So can you elaborate on the ATTR cardiomyopathy diagnosis rates and if you're continuing to see momentum build since the launch? And forgive me, but I have to ask the second one. So there are some [ centers ] that might prefer AMVUTTRA as they collect money on a much higher ASP despite the cost that it adds to the system. So curious to get your thoughts on that market dynamic. Do you expect this to impact a minority of the centers and patients? And is it something that you have to adjust your strategy to -- in those centers?

Yes, two great questions, Tyler. Thanks for them. I would say just in terms of market growth, again, until we get the full revenue numbers from Alnylam and Pfizer, I won't know precisely or be able to back into precisely, the number of scripts on the quarter. But I can say pretty reliably if you go back 1 year, so quarter and what that looked like this quarter last year, there's been a pretty robust and continued growth in diagnosis. Certainly, what we're seeing in the field is a lot of growth in diagnosis, new practices, as you can see from our ACP data, as well as doctors finding more of these patients.

I think the PYP reimbursement concerns were overstated. We don't see that being a drag in terms of people finding new patients. And there's a lot of excitement and education going on in and around this category if you go to any of the conferences, and I'm sure the same is going to be at AHA. These sessions are packed. People are keen to learn more about ATTR-cardiomyopathy. And with all the publications ongoing, there are a lot of people who want to throw their hat in to be part of the next wave of learning in this space. So I expect that diagnosis rates will continue to increase and get us closer to that 250,000 that ultimately, we should get to in the U.S.

Second question on the buy and bill dynamic. I mean, it's not -- I don't think we have to adjust our strategy because we always knew that, that was going to be the case. Certainly, there are certain centers of excellence that -- if you have a reasonable CFO at a hospital system, you're going to be 340B pricing. And so there's a lot of profit that one can take from that. But I would say [ writ ] large, unlike rheumatology. When you get out into the high-volume heart failure practices, this is not a meaningful part of the profit center associated with those practices. And so you now see a lot of cardiologists just looking at buy and bill as the way to make more money. So we haven't seen that.

And overall, I would say amidst the specialty community, you see just a lot of focus on doing the right thing in terms of data efficacy, in terms of safety and ultimately in terms of cost. Right now, you're seeing a lot of combo use. You're seeing some centers do a lot of super high-priced drug use, but I even hear physicians within those centers saying, I'm not sure I should be putting someone on $1 million worth of therapy if indeed, there's no data to back up the fact that that's more efficacious than a low-cost small molecule like ours.

So I think, again, in the long term, as you saw in the TNFs and other buy-and-bill type things, the combination of good data and what payers will ultimately do as they control this category more, I think will drive certainly that NBRx share up for the small molecule stabilizer just compared to the high cost with worse point estimates, knockdowns that are buy and bill.

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

Yes. I got to say it's a first to have 3 positive investor calls by a single company in 1 week. So congrats on that. My question, you talked about market access is a top priority for the company. Thoughts on Pfizer matching the 28-day free trial within the [ MAX ], any impact from this program that you foresee?

Yes. Great question, Biren, and thanks for the compliment there. We see it as a positive. Anytime you actually roll out a program that's generous to patients, I assume our competition is going to match it. And ultimately, it gets us thinking about what else we can do. I mean, I think if you look across the totality of our programs, they continue to be the most generous in this space.

But overall, we welcome that type of competition. It shouldn't really be accessed. Ultimately, that's driving the differential share that we gain. Ultimately, all we want is an even playing field, and that's what we've been talking about large across the payer and provider landscape and then ultimately, to let our efficacy data speak. You add anything?

No, I think that's exactly right. It's not a bad thing when someone copies a good program. And so in terms of it impacting, I don't think we've seen an impact from it. It's -- when you're the first one to do it, I think people remember that one maybe a little bit more, but we were happy to see them offer that. Any competitor ought to be thinking about doing the same thing, whether it's the free drug for life that we did for our patients in the clinical trial or with the 28-day free trial. So I think...

Maybe one final thing, Biren. Obviously, our LDN is completely differently designed than theirs, and the entirety of the patient and physician experience is pretty different, not just because of some of the programs that we've rolled out. So I'd encourage you to go and hear from patients and physicians, just how quickly are they receiving therapy in the context of our drug and how easy is it for them to continue on the drug product and regardless of the programs that are put in place, just the way we've designed this with the high-touch white-glove rare disease approach. It has some meaningful advantages.

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

You have Ryan on for Mani. Congrats on the quarter. Just -- can you talk about how you see the size of the OUS opportunity relative to that of the U.S. and ATTR, particularly as those launches start to ramp up?

Yes, I can take that, and Matt, you can elaborate on it. I think the OUS opportunity has been quite interesting, obviously, as I mentioned in my outset comments. Bayer has done a very, very nice job in the countries that they've commercialized in to date. What makes it interesting, obviously, is ultimately, in some ways, they're able to fast forward to what I think the ultimate answer is in the United States, which is accurate advertising, obviously, issuing some of the incomplete statements around near complete stabilization that our competitors have.

And I think secondly, a lot of the experts are able to look at the totality of the data and understand from a health economic, real world evidence standpoint, which therapy should be used frontline and which therapies should not. So I think we're relatively advantaged in that marketplace in terms of share. Where we're not advantaged, obviously, from an overall market standing standpoint is the price point. The price point is going to come down as we move from some of the countries we're already commercializing into countries like the U.K. And so ultimately, I expect to see the ratio of sales between Europe and the U.S. to be pretty similar to what we see in TAF. But again, I think Bayer has done a really nice job of accelerating some of those market dynamics in Europe in ways that we simply can't do given the current status of the playing field in the United States.

Our next question will come from the line of Josh Schimmer with Cantor.

Quite the week for you guys. Have you had any discussions with payers regarding what might happen to formulary positioning of Attruby when TAF generics do enter? And separately, have you discussed with payers, the use of combination therapy as it stands now? I'm a little surprised they're on board with it given the cost and the lack of data.

So no to the first question, we've been focused on Attruby solely and really getting it as on equal playing field with TAF and today. I think on the second, we also haven't had conversations around combo therapy. I think we've had conversations with physicians around it, and I expect that payers will do more to control this category as we move forward. But right now, the mechanisms of B versus D and things of that nature make it, I think, a slow-moving train in that respect. It will ultimately happen, but I don't think it happens in the next 6 to 12 months.

Yes. And I think we just really remain -- as Neil said earlier, we just remain focused on making sure Attruby is available to any patient who wants it. And as long as that is out there, we feel really good about our data, and we can fight it out in the doctor's office versus trying to fight it out in the payer space.

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

So your prepared comments noted the impressive growth, both in unique prescribers as well as prescriptions per prescriber. Can you talk about what's primarily driving that momentum, whether it's the greater penetration within existing accounts, expansion into new centers or improved conversion rate?

Yes, I won't break it down quantitatively, but it's actually kind of equivalently both. And I would say one interesting piece is a lot of these new prescribing HCPs are effectively capitated parts of center of excellence or the referrers into centers of excellence. One thing we were finding early on were some centers of excellence where our share might not have been as high, when we went and spoke to the physicians, they would say, yes, we believe that Attruby is a stellar drug, and we would like 30%, 40% of our patients to be on it. But if a patient comes in already on TAF, we're not going to change them. And so it behooved us to get out to those practices that we weren't covering. We have a smaller sales force than does Pfizer or Alnylam. But we've started to do that, and we've employed some IT techniques as well so that we get sort of alerts anytime someone is prescribing. And we're just getting to know some of those what people call ancillary or satellite practices better. So both things have been driving the scripts.

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

Just two quick ones for me. Just, I'm wondering what the marketing message is around to docs around patients with mixed phenotype for Attruby? And then actually, a higher level strategic question. After the first couple of days of this week, like the path to top line diversification here is pretty clear, and I know we're waiting on infigratinib.

But Neil, maybe following on some of your prepared comments, how should we be thinking about investments into kind of the early stage and mid-stage pipeline? And when do we learn more about those programs and catalyst time lines and things like that?

Yes. Thanks for those questions, Anup. On mixed pheno, honestly, we don't see -- I mean, this is more of a question that we get from investors than we do from physicians or in the field. For the most part, the patients that we serve have to do with cardiomyopathy, and that's the salient set of characteristics that drive their mortality and morbidity. In and around mixed phenotype, the best thing we can do is continue to hammer our variant message. Obviously, variants are where you get mixed phenotype, you don't get mixed phenotype within the context of the wild-type population.

And as we suggested in our prepared comments, we continue to, I think, publish the most impressive data within the context of the variant population. That 59% hazard reduction, I think, is the largest point estimate and the only statistically significant point estimate in that space. Again, stay tuned for some of the things that we're going to be publishing at AHA, but I think it builds on that within the variant population. And all of that connects back to the fact that biochemically, we have a differentiated binding profile for those variants. And I think if you look at the [ JACC ] paper associated with the AMVUTTRA trial, you can see that they didn't quite do in variance what people suspected they might in terms of a differentiated efficacy. So we continue to believe we have the most efficacious profile within that space and the V122Is are going to be the most common of the variant population that we see.

I would say, finally, just on that variant population, it's just another good example of how we're trying to really view Attruby is a unique property and look to see whether or not we can increase symptomatic patients, get intervene early so that they can stave off future heart failure altogether, and that's that ACT-EARLY trial. So I think we're doing quite a bit to address that marketplace.

Secondly, just in and around top line diversification. I'd say, first and foremost, we're laser focused on nailing the launch of two, hopefully, the third product to come here in early next year. Three launches for any company, I think, is a big thing to do, and it's going to be big for BridgeBio here for us to stick it. Obviously, it's going to be a couple of first-in-class launches and another competitive launch. So a couple of different characteristics as we build out our commercial muscle.

That being said, this is maybe stave off -- stave 8, 9 years ago, the most interesting time to do research and early development in rare and orphan disease, almost no competition, to be honest. And the scientific tailwinds are -- I mean, nothing short of mesmerizing. You're reading the journals, Anup, I know, just as I am. But the [ pangenome ], long-read sequencing, what we're learning about non-coding regulatory regimes, all of that is really suggesting a wide variety of new targets we can go after to help patients have profound ways. And that's why the buildup of some 17 assets in the context of Gondola. And I would say, again, as Bridge shareholders, there's zero information asymmetry between those two entities and a high degree of ownership that Bridge has into Gondola.

So at the right time, again, when shareholders and the Board and management are aligned that we have capacity, I think we have growth that we can access from there. And by the way, we're looking across the industry right now. There are several other entities out there that may be deprioritizing rare and orphan disease because investors don't view it as high a priority as [ I&I ] or certain areas of oncology. And where we do view it as attractive, we can be a reasonable partner all the way through the life cycle of early research, all the way to commercial.

So the aperture is pretty broad right now. I'd say the competitive intensity is pretty low. So at the right time, I think we'll be able to return to growth in terms of programmatic growth in the right way. But we got to stick the landing on these launches first.

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

Congrats on the strong execution. My question is around -- back to Attruby. You're accumulating a lot of real-world evidence suggesting better efficacy over tafamidis. That's great, but I'm curious what your guys' thoughts are in doing a head-to-head study to fully prove that out? I'd also imagine that could help mitigate against any risk of the future tafamidis generics, so kill 2 birds with 1 stone.

Yes. I mean, I think -- great question. Thanks for the question. A couple of comments there. Number one is, I think we've been doing a lot of this sort of head-to-head competitive, we are a better stabilizer across the fore. In vitro assays across every single serum TTR measurement that we've seen across NT-proBNP, across whatever point estimates we can look at, where you can line things up. It appears that we are a better stabilizer and that better stabilization leads to better outcomes.

I'm not so sure that, that is going to continue to resonate with the clinical community versus kind of the area that we're set off now in, which is describing what's unique about our property given the fact that it is an ever more potent stabilizer. So some of the things you're seeing in terms of publications in the variant population in terms of AFib and the cardiac arrhythmic population, some of the things that we'll be looking at in terms of the cardiorenal access, those are all completely unique. And I think aspects of the compound that are -- they won't easily be matched by the other therapies in this space. So I would say that's one thing.

The second thing is the double-blind head-to-head is something that I still think about a lot, but the double-blind head-to-head that's doable for us at this size is a double-blind head-to-head against serum TTR, which we obviously win, and I'm not so sure it drives any market share. Or a double-blind head-to-head against NT-proBNP, which I also think we will pretty obviously win. But also, I'm not sure it would drive a ton of market share.

And the reason I say that is I think people are really -- they think about different patient populations, what patients want. When we talk to our customers, they're not looking for a double-blind head-to-head to say this drug product is definitively the one I'm going to use in every case. And a good sort of eye opener on that was the [ JACC ] paper that AMVUTTRA published. But if you really cared about double-blind head-to-heads, you'd look at the [ FOO ] arm and you look at the TAF arm, both monotherapy, and you see that they deliver the exact same results.

And by the way, acoramidis beat TAF everywhere we looked in our trial. And that was actually -- baselines were very, very close in the HELIOS-B trial. So if people really, really care about these like head-to-head type studies, they would look at that data, scratch their heads and be like, what's going on. Obviously, what's going on is that the PK of knockdown starts in the 60s and ultimately gets to the 80s only after 22 months for AMVUTTRA, and that's probably why it doesn't outperform TAF in that HELIOS-B characterization.

So I'm not so sure that spending $300 million or whatever, $400 million and, et cetera, et cetera, to run a double-blind head-to-head would do much here. And then finally, you and Josh both referred to TAF generic, and I'm not going to make any comments on timing there, although I have a view that I think most of you know. But even if it does go generic and Pfizer determines that they don't want to defend this property in any way, shape or form, I mean, look, we're basically a generic in terms of pricing as compared to AMVUTTRA. I don't see payers stepping in and saying you can't use this drug or you have to step through this drug certainly in the United States anytime soon, and especially given the differentiated data that we have already presented.

And the final point on that is I really do think real-world evidence is -- I mean, you talked to the FDA, you talked to a lot of clinicians these days. They're very keen on understanding how these drugs perform in the real world. And so I think a lot of differential work that we do will be associated with real-world evidence. And I think a lot of that will actually be pretty impactful for the prescribing universe we look at, maybe even more impactful than a very specific clinical trial. So those would be my comments on that.

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

Thanks for the question. And since we're going [ to ] perspective, positive Phase III, maybe I'll [ pick it ] and ask a question on infigratinib. Neil, what are the most important differentiating elements for infigratinib in achondroplasia [indiscernible]? Is it more about efficacy or route of administration? And can you talk about safety and how important that is, what level of [ hyperphosphatemia ] is acceptable in your view?

Yes. Great question. One thing I've learned from Matt and others now having a commercial franchise is that the customer is always right, and you can never really tell why a customer may prefer one drug product versus the next. That's what makes market share relatively hard to project in the absence of double-blind head-to-head trials.

The good news here is that we're more efficacious, we're safer and we're more convenient with an oral ROA. So whatever your preference in terms of why you're determining which drug to use, infigratinib is going to win. As a scientist, obviously, down deep, I would prefer the most efficacious product win. And I think we've already demonstrated and we'll continue to demonstrate superior efficacy. Why? Because as you know, this targets this well-described condition at its source, addressing both of the salient effector signaling pathways. It's superior in every preclinical model. It's superior in animal models, it's superior in Phase II data. It's the only product that's provided proportionality impact. And I think over the longer term, we'll provide a broader diaspora of impact for this community that we serve as compared to the CMP products.

So I don't think there's any aspect. We obviously don't see the hypotensive results, and I don't think we're going to have as a robust Section 4 as the CMP products have in terms of safety. I think this will be a safer product. Grade 1 hyperfos, I think it could be -- 15%, 20% could be -- like, people do not care about that as much as the Street cares about that. Again, what they do care about are things that ultimately would be things associated with hypergrowth, spinal situations, things of that nature, and we see no evidence of of any safety issues in and around that.

So I think the drug will be more efficacious, safer and ultimately, more convenient. And I think that will open up the market, which obviously is starting to stagnate a bit. Given the current profile of the drugs, I think we can continue to address unmet need. And I think, however you want to slice and dice it, we'll have a great offering for the community here.

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

Congrats on all the progress. Maybe to connect some of the dots from your previous comments here. I mean, in thinking about infigratinib as a growth driver, I mean, you've guided to opportunities of $2 billion each achondroplasia and hypochondroplasia. Can you walk us through some of your key assumptions here given the competitive landscape? Is this more that you're capturing share from a competitor? Are you growing the market appreciably? I mean, what gives you confidence in both of these numbers?

Yes. I mean, I think, first, we do tend to estimate these numbers starting with a treatable population and making assumptions in and around there. Certainly, in the context of an already launched product, we're going to be looking to both take share as well as to grow the market. I think it's important to realize that there are substantial parts of the unmet need here that aren't addressed by once-daily injectables. We've heard that when we go out into the community, we've heard that in talking to physicians.

I think it's a bit unfair to look at the market sometimes with a suboptimal therapy and conclude that, that is the market size. I play an EPP as well. And I wouldn't look at [ Clinovell's ] product and determine that EPP is an extraordinarily small market. So I think the unmet need is relatively well described in terms of numbers of patients. And it's not in the context of this condition that we don't know how to find the patients and that they are not already well identified. So I think it just comes down to offering them something that they want, and I think this could be that from our research.

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

Congrats on the string of good news this week. I also want to understand the topic of achondroplasia, Neil. And as you know, the current approved product is -- 3/4 of the sales are coming from ex U.S., with only 1/4 of the sales from the U.S. market. And so could you maybe comment on what could be market expanding for the U.S. market in particular here? How large -- you talked a little bit about the TAM, but just sort of what are the key factors from market expansion happening here? And then in terms of the product, just sort of how much you think incremental the hypochondroplasia opportunity could be to your infigratinib sales?

Yes. Thanks, Paul. I'm a bit remiss to comment on the commercial tactics or performance of one of our competitors. There's nothing in and around the unmet need, the physician community or the community affected with achondroplasia that's starkly different between Europe and the United States. And so I think, again, a solid therapy could work well in both markets. And I'd expect actually, the normal ratio that you see with drug products to be true in the context of this category as well.

So why the launch hasn't gone that well for our competitor in this case? I mean, number one, I go back to injectables. We do hear a lot of needle phobia, particularly in the U.S. markets, which we know better since we're a U.S.-based company. So we talk a lot to folks here, and I think there is a reasonable amount of needle phobia. I can't comment on the way that they've targeted and their commercial sales force. But recall that in Europe, generally, you have centers of excellence that have taken on a higher percentage of the population in any given geography. So it's easier to identify precisely who to call on and when to call on them. So I think the dynamic could -- that could lead to a slower ramp for them here in the United States.

But again, I'd just go back to the treatable population, both for hypochon and achon. And I think that even under conservative assumptions, this is a large unmet need that then translates it to a reasonably large TAM.

Our next question will come from the line of Martin Auster with Raymond James.

This is Thomas on for Marty. I want to add our congrats on all the news this week. I actually want to circle back on the CALIBRATE data this morning. Could you provide any more detail on the serious treatment-related adverse events observed within encaleret in periods 2 and 3? And anything to say about those on standard of care in period 1 as well would be helpful.

Yes. So this is really a -- I mean, it sounds serious, serious related TEAE is a serious thing. But in the context of these drugs, it's all hypercalcemia, so basically driving calcium levels in the [ scera ] higher than what you had intended. And in the case of the standard of care is actually was quite high, again, like standard of care is taking calcium. So this does happen. You titrate it. In this case, the patient had to go into the hospital and receive IV fluid until that blood calcium was decreased.

Actually, in the case of encaleret, it was much milder. It was a very mild digression into hypercalcemia, but that patient had some altered mental status and UTI. Obviously, nothing to do the drug at all. So that's what they do in the hospital, and they were dosed down, no discontinuation.

So again, I think the most important part here is that the drug is probably -- we saw less discontinuations on drug than we did on standard of care. So the drug is safer than standard of care and obviously driving 76% normalization versus less than 5%, that's profound. And I think in large part because you've got an allosteric mechanism that very precisely targets the calcium-sensing receptor.

So very much like Attruby or acoramidis. When you've got something like that, you've got a small molecule with a very specific target, not likely to have a significant side effect profile.

Our final question will come from the line of Trevor Allred with Oppenheimer.

Congrats on the quarter. Wanted to follow up again on encaleret as well. Can you give us -- can you talk a little bit more about what gives you confidence in encaleret as a $1 billion-plus product? And can you talk a little bit about your expectations for the potential upside opportunity in chronic hypopara?

Yes, sure. I guess I don't necessarily like to talk about things in terms of the dollar amount, but I'm curious, what's your price assumption. We haven't determined the price, but what will be your pricing assumption on encaleret ADH1?

I think I'm in the range of $200,000.

So less than [ Yorvipath ]?

Yes.

Why?

I mean, it could be more than that.

That's like 8x or 10x the population. Anyway, that's an extremely low number. I've not heard that, but it let's just put it in the normal rare disease context of whatever, $300,000, $400,000, $500,000. In that range, you're talking about a couple of thousand to 3,000 patients on drug to achieve the touch of numbers that you put forth.

And we always start with prevalence here. Obviously, the prevalence is much higher than the identified population. But the thing -- and I think in large part due to like what happened over the last 5 or 6 years, where everyone claimed every large -- every genetic disease was a super large disease. Recall, this is not [ Skid X One ] or [ GACE ] or one of these conditions that severely limits lifespan. For those conditions, I think over -- you take the number and then people apply the [ Genzyme ] factor and say it's going to be 4x larger. Not usually, because those children aren't necessarily having children. Most of those mutations are germline. Those are very, very constrained populations.

Same would be true, for instance, for Canavan disease, which is another disease we work on. It's not going to be a large population. They're just -- it makes an epidemiologic sense that it would be. In this case, totally different. A large population, mostly germline that even when untreated allows people to go on and have children. Obviously, 2, 3, 4 different studies that we and others have conducted suggesting a prevalence of up to 12,000 in the U.S. That's not going to be off by an order of magnitude. 1,000 people on the ICD-10 code, 3,000 -- 3,500 patients already identified. And an easy way to identify them in terms of going and looking at the nonsurgical hypopara community and doing genetic testing is another tailwind that I believe allows us to believe that we could get a few thousand people on this drug.

I think importantly, the guidelines are already in place to suggest that for nonsurgical hyperpara patients, they get genetic testing. And so it's up to us to really drive that into the community. I'm not going to suggest that it's going to be a quick launch because we have to educate. We have to ultimately get physicians to work into their work protocol, the fact that they're genetic testing and even in the cases, as you know, of [ BRCA ] or targeted cancer therapy, sometimes you can see as little as 40% testing in the community. So it's up to us to ensure that we work with the right providers and make sure that people are looking for ADH1, where they ought to be looking.

But I would say the final thing that gives me hope that we can start to identify these patients and get them on product is just how good the drug is. When you're talking about less than 5% response on standard of care, you're talking about a lifelong set of symptoms like fatigue, brain fog, seizures. I mean, this is -- I know a lot of people in the rare disease world -- think people aren't passing away from the disease. It's not severe. This is like way more severe than having acne every day or losing your hair, both of which you have. But I mean, this is really life destroying.

And so 76% response rate, full normalization, getting close to a therapeutic cure for a majority of patients. That's the type of thing that I think will drive physician excitement and patient excitement and will allow us to find a reasonable fraction of these patients. So...

And that will conclude our question-and-answer session. I'll hand the call back to Chinmay for closing comments.

Thank you, everyone, for joining us for our Q3 2025 earnings call. We appreciate the interest and look forward to updating you on the progress of our company in 3 months. Thank you.

This will conclude today's call. Thank you all for joining. You may now disconnect.

Ladies and gentlemen, thank you for standing by. My name is Christa, and I will be your conference operator today. At this time, I would like to welcome everyone to the BridgeBio Pharma Autosomal Dominant Hypocalcemia Type 1 ADH1 CALIBRATE Phase III Top Line Results Webinar. [Operator Instructions]

I would now like to turn the conference over to Dr. Neil Kumar, Chief Executive Officer, Dr. Kumar. Please go ahead.

Thank you to everyone who joined this call, particularly those of you joining us for the second time this week. Together with our amazing team, I'm grateful to be able to share with you, on behalf of the extraordinary physicians, patients, families and caregivers involved, the positive Phase III data of our CALIBRATE clinical trial for patients with autosomal dominant hypocalcemia type 1.

As you've likely read already in our PR, today marks a new day for ADH1 patients, present and future. Those who have previously endured lifelong symptoms that include fatigue, brain fog, seizures and downstream kidney disease, today embrace a new and more hopeful reality, that there is a therapy that targets as well-described condition at its source, and in doing so, normalizes pathology in a majority of patients.

Before I set the corporate context for this readout, I want to begin with the most important slide in this document, Slide 4. It is once again my privilege to offer a heartfelt thank you to the amazing and inspiring patients and families, advocates, physicians, clinical research staff and collaborating research partners that made this study possible. A special thank you, and I'll have more to say about this in a moment, to Dr. Michael Collins, whose ideas and passion for serving patients with ADH1 gave rise to this program. As we have hopefully demonstrated in the past, we recognize our responsibility to the community that made our work possible, and therefore, plan to move expeditiously to provide this medicine to patients as broadly as possible.

Turning to Slide 5. I'll take a brief moment to provide some corporate context for today's data. After nearly 10 years, Bridge has generated 3 approvals, 2 positive Phase III readouts, LGMD2I earlier this week, and today, ADH1, along with the wealth of other clinical and regulatory milestones. Our achondroplasia Phase III is the next significant top line readout expected in the coming months. That sets alongside significant ongoing research and clinical work in areas like hypochondroplasia and chronic hypoparathyroidism, which should provide, on a risk-adjusted basis, a reasonable tapestry of impact for the patients we serve and for investors alike.

Bridge has been and continues to be an experiment in maximizing the speed of creating as many new and meaningful drugs that have profound impact on patients as possible. It's incredibly rewarding to see our work translating to potential impact at scale.

Turning back to the program of the moment on Slide 6. I thought I'd make a few final observations that are distinct from those that I shared earlier this week on the LGMD2I program. What is remarkable about both data sets, by the way, is that treated patients aren't simply saving off decline, but are improving or, in this case, fully normalizing their calcium and PTH status. When we speak of cures and therapeutic medicine, this is the type of impact we seek.

On this slide, we show how we aim to provide such impact. We often start hand-in-hand with an academic that deeply understands mechanism of biology and the need of the patient population we seek to serve. In this case, we were privileged to work with the aforementioned Dr. Collins, who we have first met in the context of an early collaboration on infigratinib. Building on his knowledge and therapeutic hypotheses, we rapidly translated scientific insights into a medicine and then proved its worth in a series of clinical trials.

As we interrogated encaleret in ADH1 and as the medicine demonstrated a safe and efficacious profile, we also asked, "What else can be done for patients with this drug?" Many of the times, the answer to that question arises from genetics, moving from, say, a homozygous recessive population to a heterozygous loss of function population or moving from one mutation to the next in the same gene as we've done in achondroplasia going to hypochondroplasia.

In this case, however, the answer came from the physiologic impact of the drug, noting that calcium sensing receptor antagonism could be an orthogonal but potentially safer and more efficacious way to address chronic hypoparathyroidism with an oral ROA, we have been pursuing this opportunity and look forward to initiating a Phase III next year.

We intend to leave no stone unturned in helping patients with the medicines we make, but that's what's to come, and it's all predicated on today, a new day for patients with ADH1.

I'll turn it to Ananth and team to tell you more about that now.

Thank you, Neil. I'd like to start by sharing a summary of the top line results of the CALIBRATE Phase III study of encaleret and autosomal dominant hypocalcemia type 1 or ADH1. We are thrilled to share that the study met and exceeded all criteria set forth as an upside target based on our learnings from the Phase II study. We observed a statistically significant response on the primary endpoint, with encaleret demonstrating superiority over conventional therapy.

76% of study participants were able to achieve target serum and urine calcium within 24 weeks of starting dosing with encaleret. Importantly, among these responders, none required conventional treatment when administered encaleret. Additionally, over 90% of the study participants demonstrated a parathyroid response to encaleret, demonstrating activity of the molecule in a broad swath of the patients administered to treatment. Encaleret was well tolerated, with no discontinuations from the active arm of this study.

To put these results in context, ADH1 is a serious genetic condition, for which there are no therapies currently indicated. We estimate that the prevalence of individuals carrying variance associated with ADH1 to be approximately 1 in 25,000. This estimates to about 12,000 individuals in the U.S. alone, who may exhibit symptoms and signs of ADH1. This prevalence estimate comes from a triangulation of several general population genetics databases, including Geisinger, All of Us, the U.K. Biobank and the Mass General Biobank, which support an estimate of 1 in 25,000. Of those carrying variants associated with ADH1, we currently believe about 3,000 to 5,000 are diagnosed today in the United States, with an anticipated increase with improved recognition of this condition.

ADH1 is uniformly driven by activating or gain-of-function variance of the calcium sensing receptor, abbreviated CaSR. These variants of the receptor increased its sensitivity to extracellular calcium, leading to dysregulation of calcium homeostasis, causing the pair of thyroid glands and the kidneys to behave as if the blood calcium concentration is higher than it actually is. As a result, individuals living with ADH1 experienced chronic hypoparathyroidism characterized by low parathyroid hormone, low serum calcium and elevated urinary calcium excretion.

The clinical manifestations of ADH1 are primarily associated with hypocalcemia in the acute setting and hypercalciuria or elevated urinary calcium in the chronic setting. ADH1 patients may experience hypocalciumic seizure, [indiscernible] and neuromuscular irritability, and exhibit calcification of the kidney due to activating variance of CaSR.

Encaleret is an investigational oral medication from the class of drugs called calcilytics, which act as negative allosteric modulators of the calcium-sensing receptor. Through this mechanism of action, encaleret decreases the sensitivity of the CaSR to extracellular calcium. By correcting the sensitivity of the CaSR, encaleret is theorized to restore PTH secretion, decrease urinary calcium loss and maintain serum calcium and urine calcium within their respective reference ranges.

We designed in encaleret on the following 3 principles: the first of which being, that is the only investigational treatment directly targeting ADH1 at its source. We hypothesize that by targeting the CaSR, mineral homeostasis can be restored in patients with ADH1. Secondly, encaleret addresses the common clinical hallmarks of this disease, namely low parathyroid hormone, low serum calcium and the associated symptoms of hypocalcemia and high urinary calcium excretion associated with long-term renal complications. Finally, encaleret is presented in a convenient oral tablet that can be taken by mouth.

I will now hand the call to Scott to share the exciting detailed findings of the study.

Thank you, Ananth. Before I present the study design and share the top line results from CALIBRATE, I want to take a moment to acknowledge the incredible dedication of the study participants, their families, and the investigators and study staff who made this research possible. Your contributions to clinical research are invaluable.

The CALIBRATE study is a randomized global open-label active comparator study of encaleret for the treatment of autosomal dominant hypocalcemia type 1. The study was run in 25 clinical centers in 10 countries in North America, Europe, Australia and Japan. The study enrolled patients with genetically confirmed ADH1, biochemical findings of hypoparathyroidism, including hypocalcemia and inappropriately low parathyroid hormone.

Patients aged 16 and above were enrolled. After signing informed consent, they entered a 16-week standard of care optimization period, during which time they had calcium active vitamin D doses adjusted to prespecified target serum and urine calcium values. Once optimized, they entered a 4-week standard of care maintenance period, period 1, during which time, doses of standard of care were kept stable.

Following this period, they underwent randomization in a 2:1 ratio to either encaleret or to remain on standard of care. At the time encaleret was initiated, both calcium and active vitamin D were discontinued. Patients randomized to encaleret were initiated on 54 milligrams twice daily, and the encaleret dose was titrated based on serum calcium assessments through the dose titration period, period 2. Those that remain on standard of care, the doses of standard of care were managed to avoid hypocalcimic symptoms and to minimize urine calcium excretion.

Following this 20-week period, they entered a 4-week encaleret or standard of care dose maintenance period, period 3, during which time doses were kept stable. Efficacy was evaluated at the end of period 3 at week 24 by assessing clinically meaningful biochemical parameters, including the albumin corrected serum calcium, the 24-hour calcium excretion and intact PTH. Additional measures of 125 hydroxy vitamin D, magnesium and phosphate, bone turnover markers, bone mineral density, kidney function and quality of life measures were also assessed as secondary end points.

The primary endpoint was the responder status of individual participants. To be deemed a responder, the albumin corrected serum calcium and the 24-hour urine calcium excretion had to be in the respective target ranges for each of these objective parameters. This composite endpoint is the first time that a drug is being evaluated to demonstrate both normalization of serum and urine calcium in a clinical trial in this patient population. Key secondary endpoints also included the responder status for individual biochemical parameters.

This slide depicts the disposition of the study participants. 70 participants entered period 1. 67 of these were randomized with 45 to encaleret and 22 to the standard of care. One participant on standard of care withdrew to the inability to comply with the study protocol. 66 participants completed period 3. One participant in the standard of care arm opted not to enter the long-term extension. Ultimately, 65 patients continue to be followed in the long-term extension.

This next slide describes the baseline demographics, and there is a similar distribution in age, sex and race across the 2 treatment groups. Among the 67 participants randomized, 46 unique calcium sensing receptor variants were represented. The baseline biochemical characteristics were similar between the 2 treatment groups and consistent with the known clinical presentation of ADH1 with hypocalcemia, hypercalciuria, low serum PTH, high normal phosphate and low normal magnesium concentrations. Approximately 80% had evidence of calcification of the kidneys by renal ultrasound.

The primary efficacy analysis was performed on the group randomized to encaleret, comparing the responder status of both serum and urine calcium at week 4 when they were on stable doses of standard of care, to the responder status at week 24 when they were on stable doses of encaleret. 76% of participants randomized to encaleret met the primary endpoint, achieving both albumin corrected serum calcium and 24-hour urine calcium excretion in the target ranges, and the difference of 71% was statistically significant from the responder status at week 4.

A key secondary analysis was performed comparing the responder status of 2 treatment groups at week 24. Those randomized to encaleret and those randomized to standard of care, and confirmed a statistically significant difference between the 2 groups. Among encaleret responders at week 24, nonrequired conventional therapy during period 3.

In another key secondary analysis evaluating the ability of encaleret to increase endogenous PTH, 91% of those randomized to encaleret had intact PTH concentrations above the lower limit of the reference range at week 24 compared to 7% while they were receiving standard of care at week 4. Similarly, the responder status when comparing the 2 treatment groups at week 24 confirm a statistically significant result. This is a clinically important point. Encaleret drives the secretion of endogenous PTH by the parathyroid glands and the reabsorption of calcium by the kidneys, both of which are responsible for the physiologic regulation of the serum calcium concentration.

We next looked at the impact of encaleret on the individual components of the primary endpoint, namely the albumin-corrected serum calcium and the 24-hour urine calcium over time. First, the serum calcium. Those participants randomized to encaleret had a rapid and sustained increase in the albumin corrected serum calcium into the target range, as shown in the blue curve. The serum calcium remained below the reference range for those randomized to remain on standard of care as depicted in the gray line. The difference in the change from baseline at week 24 versus week 4 was statistically significant. The difference in the change from baseline was also statistically significant when the between group analysis was performed for week 24.

When we turn to the 24-hour urine excretion, for those participants randomized to encaleret, there was a reduction in the mean 24-hour urine calcium excretion, as observed by the blue curve, while the mean urine calcium excretion was unchanged for those who remained on standard of care in the gray line. We observed a statistically significant difference in the change from baseline at week 24 versus week 4 for those on encaleret. The difference in the change from baseline was also statistically significant when the between group analysis was performed for week 24. The serum and urine calcium data confirm the restoration of calcium homeostasis achieved when standard of care is discontinued and intolerant is administered over a 6-month treatment period.

Encaleret was well tolerated with no discontinuations in the encaleret arm. The frequency of treatment-emergent serious adverse events was low and similar between the 2 treatment arms. There were a few related serious adverse events. The majority of adverse events were mild or moderate in severity, and the encaleret related adverse events were generally due to signs and symptoms related to ADH1 or to the mechanism of action of intolerant.

These data that I have shared with you demonstrate that encaleret restores physiologic mineral homeostasis in patients with ADH1. We randomized and evaluated 67 participants with genetically confirmed ADH1 and demonstrated statistically significant differences in responder status in patients randomized to encaleret compared to when they were on conventional therapy.

Among the responders on encaleret nonrequired conventional therapy during the encaleret dose maintenance period. Encaleret was able to meaningfully restore endogenous physiologic PTH secretion when compared to treatment with conventional therapy. Clinically meaningful changes in serum and urine calcium and those administered encaleret were served at week 24.

In general, encaleret is well tolerated, and the adverse events were expected and consistent with the known mechanism of action. Encaleret has the potential to be a novel and important treatment for patients with ADH1.

I will now turn it over to Mary Scott to discuss the next steps for the program.

The team is looking forward to an eventful year ahead. We plan to continue to engage with the FDA in the coming months as we prepare for an NDA submission in the first half of 2026. And we're targeting submission of a marketing application in Europe in the second half of next year.

Because of these exciting and promising data, the team is looking to extend the potential patient populations that may benefit from encaleret. We aim to initiate a Phase II/III study in pediatric patients with ADH1 early next year as well as a Phase III study in chronic hypoparathyroidism.

Finally, we look forward to sharing results from the CALIBRATE study with the medical and scientific community at relevant conferences in the upcoming year. Alongside these efforts, our commercial leadership team will be preparing for a planned launch of encaleret.

And I will pass it to Matt to provide more details.

With today's positive data announcement, BridgeBio's commercial engine is poised once again to deliver a blockbuster launch, this time in ADH1. Built on the foundation of the successful launch of Attruby, we will leverage our proven commercial infrastructure to successfully bring encaleret to patients. Our commercial functions, including market access, strategy, analytics, operations and marketing are already activated and have been preparing in parallel with Attruby's launch to ensure we are fully prepared for this next opportunity.

Our proven launch playbook enables fast and efficient mobilization, allowing us to capitalize on the best-in-class data you heard today and offer patients a therapy that addresses the underlying cause of ADH1, defining the standard of care. We will continue to shape the market by educating on disease state awareness as we prepare for launch. This will all be done in the backdrop of broad global access as we plan to launch in encaleret across the world to as many patients as possible.

Our approach is data-driven and highly targeted, leveraging AI and analytics to identify the right patients. Similar to the ATTR-CM market in 2019, ADH1 remains significantly underrecognized, representing a meaningful opportunity to expand diagnosis and treatment. The ADH1 market is also fairly concentrated, with most patients being managed by endocrinologists. This allows us to launch in a focused, cost-effective and sustainable way. Together, these capabilities allow us to reach patients faster and deliver encaleret with precision and impact.

We are also well positioned from a market access standpoint, with systems and payer relationships already in place to support coverage, titration and long-term adherence. This proven infrastructure refined through our Attruby launch, ensures we can move quickly to secure access for patients while maintaining a high-touch support model for providers and caregivers.

As we move closer to approval, we look forward to discussing more of our commercial strategy, but the message for today is clear. BridgeBio is ready. Our engine is built. Our playbook is proven, and we are well prepared to deliver another successful blockbuster launch.

At this time, I'll turn it over for the Q&A portion of the call.

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

Congratulations on another stellar Phase III data set within 48 hours. The first question is the 76% response rate in calcium curves, they're particularly impressive considering the point estimate is higher in its multicenter Phase III compared to the single center Phase II and then a more diverse set of variance. But can you elaborate on the responses in the calcium curves? And if they were consistent across the variants? And biologically, why that might be the case?

And the second question is just related to the larger chronic hypoparathyroidism indication, if you believe these results are derisking for encaleret?

Thanks, Tyler. I'll let Scott address the question regarding the response rate as well as the translatability to the chronic hypoparathyroidism program.

So regarding the first comment about the variance. What we've seen is that the variants that are responsive all seem to behave similarly. So we get good-quality PTH responses. Now the dose might be different in individual variants, but we do see robust PTH responses, and then subsequently see increases in the blood calcium and decreases in the urine calcium. So what we've seen to date has been very consistent across all the variants that we've observed.

Regarding the chronic hypoparas question, the Phase III study and the Phase II study have established that encaleret is a safe medication for patients with hypoparathyroidism. And again, the calcium sensing receptor is responsible for activity in the parathyroid glands as well as in the kidney.

What we do know from the proof-of-concept study from a month ago, when that was presented at the ASBMR, is that there are PTH independent effects of the calcium sensing receptor that result in low urine calcium and a maintenance of blood calcium. So we feel very confident moving forward in the program with chronic hypoparathyroidism, and are really looking forward to studying patients with that condition.

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

Great, guys. Congrats on the data. I guess one for me on the safety side here. Could you just maybe comment on the hypophosphatemia data in any -- perhaps any bone biomarker data that you may have measured?

Salim, these are great questions. These are -- I'll just remind the audience that these represent top line results. We do not have individual line listing data at the time. But I will pass it to Scott to address our overall safety observations, with the expectation that more evidence will follow with more [ wholesome ] analysis.

Did you ask about hypophosphatemia?

Correct. Yes. I think it was in your Phase II slide, but I didn't see anything. Yes, right. But now you're Phase III.

Yes. So certainly, that's right. In Phase II, we did see some hypophosphatemia that was transient and related to the dose of encaleret that was administered, and it was reversible upon lowering the dose of encaleret. We did not see very -- well, we may have seen very few hypophosphatemia events during the Phase III study, but again, these would be easily managed by lowering the dose of encaleret. So we're very confident moving forward that hypophosphatemia is not going to be a problem in the clinical management of these patients.

And Salim, I'll just add, perhaps one element that Scott alluded to, which are encouraging the data we observed in this Phase III study seems highly consistent with the observations from our Phase II evaluation of the molecule. And then the reminder from that study, most of the adverse events that were reported were reported early in the titration of the molecule once maintenance doses were achieved. These adverse events were resolved with those adjustments.

Okay. And anything on the bone biomarker data that you guys may have measured?

We did not have those data available to us at this time.

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

Great, and really quite some streak around here. So I want to ask, first of all, on your confidence level in the ADH1 commercial opportunity, there's some noise out there about the number of patients as well as the ability to find and diagnose them. So can you speak to the effort that's going to be required here to build this into the $1 billion plus market you foresee?

And then a quick follow-up I have is, in your responder analysis, were patients allowed to continue using vitamin D?

Okay. Thank you, Cory. There are 2 questions there. I'll start with the first one on the patient opportunity. I would start by saying, there are a couple of tailwinds that we described in our webcast last month, that provide encouraging data points of where these patients are in the current diagnosis rates, those being a new ICD-10 code that has been established specifically for autosomal dominant hypocalcemia. Where in the claims data in 2024 alone show over 900 claims attributed to that ICD-10 code. As well as new guidelines that were published earlier this year, that recommend genetic testing in all nonsurgical hypopara patients.

I'll pass it to Matt to elaborate briefly on our commercial plans, and then we'll address your latter question on the [indiscernible] conventional therapy.

Yes. I mean I think the way to think about this launch is to expect a gradual but steady launch. When the other medicines like this that shows these kind of results, people talk about it. Patients talk about it. Physicians talk about it. Other PCPs talk about it. And that kind of discussion creates awareness. And the more awareness there is, the market naturally grows. So of course, we're going to continue to mine the data, but we feel very confident in the commercial viability of this product and that it will be another outstanding launch for Bridge.

Okay. And Scott, I'll pass to you on the conventional therapeutic question as it relates to our response rate.

So when patients are started on encalaret, they discontinue their calcium supplements and active vitamin D. With the administration of encaleret, it will stimulate parathyroid hormone. And as you may know, parathyroid hormone then has activity in the kidney to activate the enzymes to create active vitamin D in the patients endogenously. So with encaleret treatment, patients do not require long-term active vitamin D therapy.

Your next question comes from the line of many Mani Foroohar with Leerink Partners.

A follow-up [ one ] on the commercial strategy part on Tyler's question earlier on parathyroidism. So as you think about developing this in that second indication where the availability of options is a little bit different than ADH1, patient population that are -- everything is a little bit different. How should we think about the cost effect analysis side, pricing -- justified pricing and value? And how do you think about commercial strategy, given that you're going to be launching positively in that indication quite a few years out? And just give a little bit of compare and contrast of the strategy of launching into each of these 2 indications, given the competitive dynamics are quite different.

All right. That's a great question. I'll let Matt address these points.

Yes. I mean I think -- the way you think about -- they are 2 different launches, but they're related. I mean, you're still -- it's all about getting awareness out both of the different disease states, but also what the medication can actually do. And I think the fact that as of today, we're reporting hitting all primary and secondary end points, it doesn't get really any better than that. So yes, we have to go out and educate, but that data alone is going to pull people in.

And then as we move into more indications with that, it's just kind of this natural progression. In some ways, it's nicer to start with a smaller indication because you get your sales force established, you can get their routing established, kind of work out any kinks that you need to and then move into the larger opportunities. So if you have your choice, I think this is the way you'd like to do it. So I think that just benefits us to make sure that then both launches will go extremely well. So I think -- and in terms of competitiveness, again, the data speaks for itself. I think we have a lot of confidence based on what we've presented today, that this medication is going to do extremely well in as many indications as we can get it approved for.

And on top of that, I think there are elements of the evidence side that help Bridge that commercial opportunity if we are privileged to extend our indication in the patient population eligible for encaleret. Two points being one, this would be the only orally administered medicine, if we are successful, with the broader development in the chronic hypoparathyroidism indication as well as a consistent safety profile that we've demonstrated, Scott alluded to, in these patients ADH1 in the sort development program of encaleret.

That's helpful. Congrats again.

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

Congrats on the data. Maybe first question is how long did it take for patients in the encaleret arm to reach an optimal dose? And maybe second question is what's the read-through on achieving intact PTH above the lower reference range in ADH1 and the read-through to chronic hypo-PTH?

Thank you for that question. I'll let Scott address those 2 questions.

So with the administration of encaleret, we've known since early Phase I that patients will have a PTH response within 30 minutes of administration of the drug, and that's been true for Phase II as well as in Phase III. And then subsequent to the increase in PTH, we see increases in serum calcium within the first couple of days.

Within the Phase III study, by day 3, we saw 71% of the patients had achieved a blood calcium within the reference range, and that's very excellent data for us. The patients will then continue their titration, and most patients will wind up on their maintenance dose within 2 to 4 weeks after starting the drug.

Can you clarify the second part of the question that you had, please?

Yes, you would observe that patients in the trial achieved intact PTH above the lower reference range. I think it was 91% of patients in the encaleret arm achieved that. And so I wanted to understand what the read-through of that is the chronic hypo-PTH setting.

Right? So again, in patients with intact parathyroid glands, they will respond, and that's what we've observed. What's really important is that the calcium sensing receptor expressed in the kidney also has very strong control over calcium reabsorption. And we now know that, that is a PTH independent process.

And so there's historic data from patients with another genetic disease called familial hypercalcemic hypo calciuria, those patients had hypercalcemia and hypocalciuria, and they actually were treated with parathyroidectomy in the past. And it's interesting because now they have no PTH, but they were able to maintain a normal blood calcium and a very low urine calcium. And the expectation, again, based on the proof-of-concept data that we shared last month at the ASBMR, is a similar phenomenon. So patients don't have PTH. We will give them encaleret, which will suppress their urine calcium excretion and be able to maintain a blood calcium, and that's the expectation. So we are very confident moving forward in the chronic hypopara space because of the PTH independent effects of encaleret on the kidney.

Your next question comes from the line of Joshua Schimmer from Cantor.

Congrats on the results. Can you talk to the pace at which you continue to identify new ADH1 patients with your efforts? As you identified patients, are you finding that any are already on Yorvipath? If so, what percent? And how do you think about the dynamics of perhaps converting them from Yorvipath to encaleret and what challenges they might be in doing so?

Thank you, Josh. So I'll let Matt address your questions around the pace at which we are identifying new patients and the proportion of those patients that may be treated with PTH analog.

Josh, thanks for the question. You heard probably earlier on, we think that the prevalence is around 12,000, and we've identified already about 3,000 to 5,000 patients. We're not really seeing those patients on Yorvipath. So I don't think there's a big conversion strategy necessary. I mean I don't want to say it's not effective, but it doesn't seem like doctors are reaching for that. And now with specific data in ADH1 patients, I don't think that the convincing will be in terms -- this is going to be more of a finding the patients. And then once you find the patients, the data is so good that those patients will then take it. So it's like -- it's an identification game more than a switching game.

So I don't think that's going to be our -- what we need to do from a commercial front. And I just think slowly over time, especially now with the data out, we will identify more and more of those 12,000 patients. And 12,000 patients arguably should also grow over time because, again, there's now a very good option for patients. When there's not a good option out there, people don't look for patients, and they're not really thinking about treating. Now with a great option, people start looking, they get more curious, and that leads to more diagnosis. So I think you're going to see just that steady increase over time, both leading to the 12,000 and then expanding the 12,000 to a bigger number.

And just qualitatively, Josh, I would characterize that our observation is the rate of diagnosis continues to increase with time and with building awareness around the community. So we are observing increased utilization of that ICD-10 code as well as increased utilization of genetic testing to identify patients.

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

Congrats on a solid data set. First, can you give us a teaser on how the harder endpoints looked in the study? Did you look at urgent care visits, hospitalizations, renal endpoints and anything else?

And then secondly, it looks like you do have at least 3,000 patients diagnosed addressable today. So by the time you launch in the first half 2027, how many patients do you think will be ready to go? And why wouldn't you have direct line of sight to thousands of patients?

Thank you, Andy. I'll defer to Scott on the first question regarding our clinical outcome measures in the study, and I'll let Matt address the second question regarding the current patient population.

So regarding the hard endpoints, this is evidence that would require a longer-term follow-up, and we are continuing to follow patients in the long-term extension for the renal outcomes as well as for bone health, like bone mineral density, because those are endpoints you wouldn't see any changes over the first 6 months. But with the effects that we're seeing with encaleret, again, being able to manage the blood calcium and the urine calcium over long periods of time, we are expecting that we'll see benefits in these harder endpoints over time.

And for the second part of your question, I mean -- so we already have thousands of patients identified. So I think we're well on our way to being able to serve as many patients as possible. But again, I'll just repeat from before, you really need an option, not only for patients to be out seeking treatment, but for physicians to be considering, looking for that particular diagnosis.

And remember now with the new ICD-10 code, we've also made that diagnosis. It's not only easier in terms of sort of finding those patients and making sure everybody understands what it is they're dealing with, but that helps payers from a specific reimbursement perspective, and it also helps with the awareness so that physicians start thinking, you know what, I should be looking for this because if I find it, I can treat it and I can treat effectively. So I think you're right. I do think the number is going to grow. We're going to grow it from where it is today and again, expand the market beyond the 12,000.

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

Congrats on going 2 for 2 this week. My first question is, based on the data you've seen so far, can you maybe comment on were there any subpopulations you're seeing that might inform your enrollment criteria for your planned hypoparathyroidism study, any enrichment or patient population strategies that you can maybe comment on?

And second, Yorvipath got a priority review in its FDA application. Are you assuming the same here for encaleret?

Thank you, Paul. On the latter question, while encaleret is eligible for prior review based on its fast track designation and the lack of indicated options for ADH1 today, that may be considered. We have not received confirmation or had the appropriate dialogue with the FDA to confirm that.

The first question regarding subpopulations, I'll pass to Scott to address that point.

So with the chronic hypopara -- well, first of all, with the ADH1 program, it's not a large enough patient population that we study that we have subpopulations that identify anything. But what I will say with the chronic hypopara study moving forward is that we will be focusing on patients that have hypercalciuria. So again, because of the effects that we're seeing with encaleret, the physiologic effect on the kidney, that's the focus will be on patients with hypercalciuria.

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

Congrats on the update. Just 2 quick clarification questions, if I may. So the first is on safety. Can you talk about if there were any dose reductions due to hyperkalemia for encaleret or anything we should be considering there?

And the second question is, can you just remind us why you compared on the primary endpoint of serum calcium relative to standard of care at week 4 versus encaleret at week 24 for the primary endpoint? I know in that slide, you also say that week 24 responder hits stats for that comparison. But are the -- should we be thinking about proportions there that are similar to the primary analysis?

Anupam, on your first question, do you mean hypercalcemia or did you mean to say hyperkalemia?

Calcemia, sorry.

Thank you. I'll let Scott address that first point around safety and dose reduction due to hypercalcemia.

So encaleret is started at a dose of 54 milligrams twice daily. And what we've observed to date is that approximately 75% of the patients wind up on 54 milligrams or lower. So there is certainly titration early on because of hypercalcemia. Importantly, no patient has had to discontinue encaleret for hypercalcemia. So we've been able to manage all patients. They may go down to a dose of 4.5 milligrams, but they're certainly manageable on encaleret.

And then to your second point on the question of the primary endpoint comparing week 24 to week 4, this was our prespecified primary endpoint. As it enables a within patient control, given potential heterogeneity in the calcium sensing receptor variant in the individual response curves to either conventional therapy or encaleret, but within patient control, allows individuals to serve as the control arm for the primary analysis, which enables a more robust and complete comparison to conventional therapy. But as you mentioned, the secondary analysis of [indiscernible] secondary analysis was also met with a highly statistically significant response comparing the response at week 24 of encaleret to conventional therapy.

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

Let me also extend my congrats on the back-to-back wins here. I have 2 questions, one regulatory and maybe I'll start with the AEs as a follow-up to Anupam's question. Can you characterize the hypercalcemia AEs that you observed with encaleret a bit more, particularly in period 3? Like when did these events typically occur? And is a 22% rate acceptable?

And then on the regulatory front, you enrolled patients down to 16 years of age? Is it possible you could get a label that is inclusive of the pediatric population? Or could you potentially seek an accelerated approval for [ peds ] with the upcoming planned trial serving as your confirmatory?

Thanks, Danielle. On your first question, we do not have the complete data on the time points of the reported AEs. But if we look at our Phase II data, which mapped quite well, these were experienced early in dose initiation and resolved with those adjustments. And as Scott mentioned, we observed that the majority of patients maintenance doses were achieved within the first month of initiation.

And then I'll pass it to Mary Scott for the question on the pediatric program label. Go ahead.

Yes. Thanks, Danielle. And given these promising data, I completely understand why you asked the question and why we would love to be able to extend to a broader patient population. But what we anticipate is that the indication would reflect the population that we studied in the CALIBRATE studies, so down to 16 years of age, and then extending to younger pediatric patients down to birth is what we are intending to do by starting the Phase II/III study in pediatrics that will enroll our first patient early next year.

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

Congrats on the data for the second time this week. Just 3 quick clarifying questions for me, if I may. Regarding safety and tolerability, I know you touched upon hypophosphatemia, but did other AEs of note arise. Two, just to confirm, in the responder analysis, did patients discontinue using vitamin D? And then three, any concerns over the potential for ADH1 to be added to PTH's label? Would it challenge use at all? We asked because the developer there has commented that wow, the number of ADH patients has been few. They've responded rather well.

Okay. On the third point, I'm not quite sure if we've seen any evidence of response to PTH on a -- in a population level, I don't think that's been prospectively studied or reported. We see some case reports, but certainly not a robust comparison to the cohort.

On your second question regarding Vitamin D in the responder analysis, I'll just remind folks that none of the responders of [indiscernible] the 76% that we reported at week 24 required conventional therapy with either calcium supplements greater than 600 milligrams a day or active vitamin D.

And on the questions on hypophosphatemia or additional AE characterization, I'll turn it to Scott.

So again, during the titration period, we do see some hypocalcemia and hypercalcemia. And I think those are the important events that are observed during the titration period, but they're all manageable through, again, titration of encaleret.

We have time for one more question, and that question comes from the line of Trevor Allred with Oppenheimer.

Congrats as well on the great data. I just want to ask, commercially, is there anything you can disclose regarding sales rep deployment? Are these patients seen in endocrinologist centers of excellence? Would you expect to initially target these routes? Or do you look to immediately expanding the community to maximally identify the available patients?

Yes. Thanks, Trevor, for the question. This is Matt. I'll take that one. I mean we're definitely going after all the patients wherever they may be. So -- but having said that, this is -- these patients are all seen by endocrinologists. So it's not -- this isn't like a needle in a haystack type of patient finding. We know where to go, we know where to look. With the new ICD-10 code, these patients are going to start to become easily identified.

So I wouldn't expect that we're going to need a large sales force and you've been able to -- in order to tackle this, but we're looking at all that right now. The nice thing is we have a little bit of time to put that together. But I think this is going to be fairly straightforward. I'm not anticipating an overly complicated launch or any need to overly complicate our sales team.

And just keep in mind too, with the Attruby launch already almost a year underway, we have a lot of the teams already in place and in the field. Our market access team franchise is fully booked -- are fully built and out. We already have relationships with payers. So in terms of getting access for patients, that's already in place. So we're really just talking about adding the sales reps, which -- that's kind of a nice position to be in. And we're not -- we don't have to do the full build from scratch because we already have a lot of those positions in place.

And that concludes our question-and-answer session. I will now turn the conference back over to Ananth for closing comments.

Thank you, operator. I would like to close just by reiterating our gratitude to the collaborators that have made these incredibly robust and encouraging results possible. We are encouraged by the opportunity to serve the patient population with ADH1, and we hope you all have a great rest of your day.

This concludes today's conference call. Thank you for your participation, and you may now disconnect.

Ladies and gentlemen, thank you for standing by. My name is Krista, and I will be your conference operator today. At this time, I would like to welcome everyone to the BridgeBio Pharma Limb-Girdle Muscular Dystrophy Type 2i/R9 FORTIFY Phase III Interim Analysis Results Webinar. [Operator Instructions] Thank you.

I would now like to turn the conference over to Dr. Neil Kumar, Chief Executive Officer. Dr. Kumar, please go ahead.

Thanks, everyone, for joining this call. Together with our amazing team, I'm grateful to be able to share with you on behalf of the extraordinary physicians, patients, families and caregivers involved, the positive Phase III results of our FORTIFY clinical trial for patients with limb-girdle muscular dystrophy type 2i. The strongly positive and consistent data the community work tirelessly to generate come together at this moment to portend a new and better day for current and future patients struggling with this condition.

Before I set the corporate context for this readout, I want to begin with the most important slide in this document, Slide 4, a thank you to the amazing and inspiring patients 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 desperate and disparate as MoCD Type A and ATTR cardiomyopathy, we recognize now our responsibility to the community that made this work possible. And therefore, plan to move expeditiously to provide this medicine to patients broadly.

Turning to Slide 5. I'll take a brief moment to provide some corporate context for today's data. As many of you know, Bridge was founded almost 10 years ago to target well-described genetic diseases at their source. Our efficient R&D engine has helped generate almost 20 INDs and 3 approvals to date and we hope to add BBP-418 to that list in short order.

Today's data represent the first of 3 major current and upcoming Phase III readouts for us with results from our ADH1 and achondroplasia efforts expected in the near term as well. Together, these an ongoing earlier-stage program should provide on a risk-adjusted basis, a reasonable tapestry of impact for the patients we serve and investors alike.

Turning back to the program of the moment on Slide 6. I thought I'd make 2 final observations that pertain more broadly to our efforts. First, although we deploy many different modalities in an effort to target causal drivers of mendelian disease where we can, we often use small molecules. In many of the disease areas in which we play, there's sometimes a misconception that small molecules while perhaps being more efficient to develop or safer, can't provide the type of efficacy other modalities can.

Here, with perhaps the most impressive data set generated to date in the muscular dystrophy space, we once again show that the quantitative impact on the causal genetic driver is what counts and that small molecules can provide optimal impact safely and obviously, in the most cost-efficient form for society in the long run.

Secondly, we were profoundly enthused to observe improvement for the patients in this trial. It's not a new concept, but a good reminder that intervening to take away the biochemical insult can result not only in the halting of ongoing pathology, but indeed an improvement. Reliably improving patient lives is the ultimate aim for any therapeutic we develop, and BBP-418 has met that high bar.

With that, I'll turn it over to Christine and team to tell you more about the specifics of this remarkable trial results and the next steps for this program.

Thanks, Neil. First, I'd like to thank our ML Bio team, who have worked at a high pace with high standards to achieve this milestone. I'd also like to thank the community of collaborators, patients, caregivers, investigators, without them, this would not be possible.

When I speak with patients, I'm first inspired by their courage and struck by their hope for our therapy. Because LGMD2I is a progressive disease, what they can believe in is something that could stop or slow the progressive loss of daily function. These data show BBP-418 could be transformative and not only slowing the loss, but improving clinical function too.

On Slide 9, the data are striking and how consistent and how robust it is across all key endpoints measured. The results were highly statistically significant for glycosylated alpha-dystroglycan at 3 months, at 12 months, CK at 12 months and our functional measures, a 100-meter time test, and FVC at 12 months.

On the next slide, we compare these results to our expectations. Relative to our base case, this was really a home run scenario. We expected robust biomarker changes in glycosylated alpha-dystroglycan and CK, which were demonstrated and exceeded our expectations. We do not expect statistically significance, however, on the functional endpoints. The study wasn't powered for Cisco significance on functional endpoints. So the fact that we saw such high statistical significance on 100-meter time tests and FVC at 12 months is really quite remarkable.

Not only did we see separation from placebo, we saw improvement in the treatment arm. This is remarkable. And the first time that I'm really aware of, of any therapy demonstrating functional improvement in a randomized controlled study in limb-girdle. This underscores the potential for BBP-418 first to market for a disease-modifying therapy for LGMD2i/R9.

I will now turn it over to our Chief Medical Officer, Dr. Doug Sproule, to walk through the data.

Thank you, Christine, for that kind introduction. It is a distinct pleasure of mine to have the opportunity to present the top line Phase III FORTIFY interim analysis data. It is a special privilege as a member of this community to be able to present such impressive data.

Before I present the data, I would be remiss without expressing the immense appreciation that we have for the patients and their families who have contributed and sacrificed so much to advanced care and research in LGMD2i/R9, particularly call out the tireless work of our patient advocate community partners and the many physicians, clinical trialists, caregivers, clinical research staff and other collaborating research partners who have all contributed in such a major way to this data and the ongoing advances that we see in the field.

Moving to Slide 13. FORTIFY is our ongoing randomized placebo-controlled Phase III study of BBP-418 versus placebo. This is a well-controlled and balanced study, comparing patients treated with BBP-418 versus placebo in a double-blind, randomized controlled manner. All patients are randomized 2:1 to receive BBP-418 versus placebo.

We are reporting the top line results of our interim analysis that involved the first 72 patients to complete at least 1 year of clinical study. I'll be discussing our interim endpoints that we have assessed in a formal statistically rigorous manner. That is including our biomarker glycosylate alpha-dystroglycan. The change from baseline at 3 months as well as at 12 months.

We are also assessing creating kinase such as a widely used and well-established marker of muscle injury and breakdown. And we are assessing 2 important and clinically meaningful clinical measures in -- widely used in neuromuscular research. The first is the 100-meter time test, which is an assessment of ambulatory function as well as fatigue. And the second is a broadly used measure of pulmonary function forced vital capacity.

As I've mentioned, this is a double-blind randomized controlled trial. The placebo and BBP-418 arms were stratified by age, by ambulatory status as well as by genotype to allow a well-balanced and well-controlled study that I am eager and proud to present today.

Before I get into the clinical markers, I wanted to give my colleague, Uma Sinha, the opportunity to discuss the dramatic results from our alpha-dystroglycan glycosylation bioassay. And so with that, I'll pass the baton to her to speak.

Thank you, Doug. It's an incredible pleasure and a source of pride to be able to present the biomarker data that the whole team have worked long and hard on, most importantly, the patient samples, which allowed us to develop the biomarker assay, I'm incredibly grateful for those.

First, let me remind everybody about the mechanisms of this disease. LGMD2i/R9 is caused by mutations in FKRP, that lead to decreased enzymatic activity of FKRP. This, in turn, reduces the extent of glycosylation of alpha-DG. Hypoglycosylation of alpha-DG is the core defect in the disease. And this is consistent with the genotype phenotype association of L276i mutant and other heterozygous FKRP genotypes that are in the literature, and we have also tested in our natural history study.

The hypothesis that we are testing here is that by BBP-418 dosing, we're targeting the disease at its source, restored glycosylation of alpha-dystroglycan and thereby enabling the muscle to continue binding laminin at the expected level. We have developed a proprietary validated Western Blot assay to accurately and reliably measure glocosylated alpha-DG directly in skeletal muscle tissue. This is important on multiple levels. It's a proprietary assay. FDA has reviewed our approach and agreed that it is reasonable.

So what's novel about this assay? The assay uses 2 antibodies for immune detection of alpha-DG. One directly measures glycosylated alpha-DG and the other measures the core protein. It's important to remember that the first antibody is detecting the functionality moiety. The moiety responsible for laminin binding.

In this slide, we are showing you representative data from Phase II. Both glycosylated and non-glycosylated protein is being shown here. And as you can see in the untreated patients, there's barely a signal for the glycosylated alpha-DG protein component. In this data, we have confirmed that upon BBP-418 dosing, already at 3 months, we are detecting an increase in the glycosylated alpha-DG level, which is sustained at the 6-month level. This was the dose-finding Phase II data, so it allowed us to build on our hypothesis.

Another thing that we have done is use this validated assay to measure baseline levels of glycosylated alpha-DG across our natural history, Phase II and Phase III studies. I'm happy to report that the results have been consistent and given us more faith in what the assay is measuring. As Doug has already mentioned that change from baseline in glycosylated alpha-DG was the primary endpoint of the Phase III trial. We have observed a robust and rapid increase in glycosylated alpha-DG at 3 months.

I'd like to focus on the 3 salient points that this data set is telling us. One is that the change from baseline in alpha-DG is robust and seen rapidly at the 3-month time point, very statistically significant. Then this increase is sustained through the 12-month period. The third point I'd like to remind everybody about is that our knowledge in the natural history study as to how the baseline levels of glycosylated alpha-DG behaves, that has been confirmed at the study. There was essentially no change in the placebo arm.

Our preclinical data in mouse models as well as in the natural history study told us that targeting a 5% change in glycosylated alpha-DG would be expected to be clinically meaningful benefit in the patient population. As you can see from this data, we saw an increase of 17% of control at the 3-month time point, and the effect was sustained at the 12-month time point with a 23% change from baseline. Target was 5%. So we have definitely exceeded expectations here.

I'd like to now turn this over to Doug to delve deeper into the clinical data.

Thank you, Uma, for that fantastic overview of the glycosylated alpha-dystroglycan bioassay. I'd like to build upon those amazing and dramatic results that we're seeing from our bioassay, which shows an approximate doubling in glycosylated alpha-dystroglycan levels amongst patients treated with BBP-418. We're seeing a similarly dramatic large statistically significant reduction in serum creatine kinase amongst patients treated with BBP-418, a difference of 82%, a decrease of 82% from baseline at 12 months.

This is an amazing observation, but just to put in a little bit of context, a large proportion of patients treated with BBP-418 achieve levels that are within 1 or 2x the upper limit of normal. And this suggests a marked reduction in muscle breakdown, that's indicated by this reduction in serum creatine kinase.

And thus, we've demonstrated with the bioassay that we have an impact on cellular physiology that we're improving and increasing glycosylated alpha-dystroglycan levels. And that's translating to a large and important reduction in muscle breakdown that's measured using and demonstrated using serum creatine kinase.

And this is the results that we expected to see to be perfectly frank. We have confidence in this compound, but what is most exciting is what I'm going to talk about in the next few slides that this physiologic effect, this biologic effect that we're able to demonstrate now and excitingly translate as well to signs and signals of meaningful and important clinical impact.

We are excited to present data that is demonstrating that third link in the chain that we're demonstrating the impact on the physiology that's translating to reduce muscle breakdown. And now we're then able to report excitingly an impact on clinical function as well. We are observing a 0.27 meters per second improvement amongst patients treated with BBP-418 versus placebo in the 100-meter time test. I put a little bit of clinical context, the 100-meter time test, is a broadly used clinical and clinical research tool to assess ambulatory function and fatigue in patients with neuromuscular diseases.

As we have seen in the natural history of the disease and demonstrated in our placebo arm, we see a consistent and inexorable decline in performance on the scale. And we see a 0.12 meters per second decline in patients treated with placebo. In contrast, we're seeing an improvement in patients treated with BBP-418 in their velocity performance on the 100-meter time test. And this translates to an approximately 14-second faster performance amongst patients treated with BBP-418 when compared with patients treated with placebo as far as the time to complete this test. This is a statistically significant results, and it's a clinically meaningful result that we're seeing in patients treated with BBP-418 on their ambulatory function.

And moving to the next slide. We're seeing a similarly dramatic and remarkable and improving performance in pulmonary function in patients treated with BBP-418 versus placebo as well. So amongst patients treated with BBP-418, we see a 3% increase in percent predicted volume from baseline, which represents an approximately 5% increase in percent predicted volume versus placebo. Again, taking a step back, pulmonary function is a critical system and impacted in patients with LGMD2i, has a marked impact on morbidity and mortality.

Forced vital capacity is measured in meters, but then adjusted for the gender, height, weight, age of a patient to give a percentage of what they -- how they should perform on this test. And what we know from the natural history is that we see an inexorable 2% decline in loss year upon year upon year upon year. And that's actually seen in our placebo arm as well.

And in contrast, patients treated with BBP418 have experienced an improvement in pulmonary function, improvement in forced vital capacity that represents a 5% difference between the -- in percentage predicted volume in 1 year between patients treated with placebo versus patients treated with BBP-418. This is a broadly clinically meaningful as well as statistically significant result that we're observing in patients treated with BBP-418 in this study.

And again, this summarizes and not to beat a dead horse, but frankly, to beat the dead horse, we're seeing not just stability. We're seeing not just a slowing of the reduction in loss compared with placebo, but we're seeing an absolute and statistically significant and clinically meaningful improvement in patients treated with BBP-418 that not just with placebo, but also with their baseline status. And that's a remarkable and really unprecedented result.

It's a -- particularly in the context of a double-blind randomized clinical trial. This is the most impressive placebo-controlled data, in my opinion, in the LGMD space by a wide margin, perhaps in the entire muscle disease community to this date. And I'm extraordinarily proud and excited to have had the opportunity to present this data to you today.

I'm equally proud and happy to report that we have a continued highly favorable safety profile of BBP-418. We have no new or unexpected safety findings that have been observed in our Phase III study. These are results that are consistent with our Phase II study, consistent with everything that we previously reported.

We have a low discontinuation rate overall. It's higher on the placebo group. And we have no treatment-related serious TEAEs that have been observed in our Phase III study. So the interim analysis continues to support that favorable risk profile as well as what I would consider a much increased benefit profile of the product.

We're excited to present this top line results today. what we've executed on to date sets the stage for an ambitious year and years ahead for our program, and we're extremely excited to move this program forward aggressively into the commercial phase of development. We plan to engage the FDA to discuss our pathway for NDA submission later this year or early 2026.

We intend to present the broader Phase III data from our FORTIFY interim analysis results at the Muscular Dystrophy Association Clinical and Scientific Conference in March of 2026. We furthermore intend to file an NDA with the FDA in the first half of 2026 and anticipate a U.S. approval and commercial launch of BBP-418 to treat patients with LGMD2i/R9 potentially in late 2026 or early 2027.

And with that, I would like to introduce my colleague, Matt Outten, our Chief Commercial Officer, who will present our overall commercial strategy.

We are very excited about the data discussed today, which set the stage for BridgeBio's next commercial launch. Over the past 18 months, we've been preparing for this moment, building on the successful launch of Attruby to establish a robust commercial foundation across all functions, including market access, operations, analytics and marketing. We will now leverage this infrastructure to launch BBP-418, supported by a dedicated field sales team that we have been proactively planning in anticipation of today's results.

Our proven launch playbook will enable rapid mobilization for a launch that positions BBP-418 as the standard of care in LGMD2i/R9. We will continue to drive education and awareness as we move toward approval. It's important to remember that today represents the first and only positive data in LGMD2i/R9, a major milestone on our path to approval and for the community that we serve. We look forward to sharing more about our commercial strategy as we get closer to approval.

But for today, there are 2 key takeaways. First, the data are as strong as we could hope for heading into launch. Second, our commercial organization is ready to execute, drawing on the same experienced teams that successfully brought Attruby to the market, and we are poised to do it again with BBP-418.

With that, we will now open the discussion and start the Q&A portion of the call.

[Operator Instructions] Your first question comes from Tyler Van Buren with TD Cowen.

Congratulations on the tremendous results. It looks like the results exceeded your home run scenario for the interim. So curious just to better understand what you think explains the outperformance. And the 5% FVC benefit seems striking. So maybe you could elaborate on the clinical significance of that 5% as well as the 14-second improvement on the functional outcomes? And why would the FDA allow patients to continue on placebo for another 2 years, given these data?

Great. Thanks, Tyler. I don't think that was one question, but we'd love to answer all of them. I'm going to turn it over to our Chief Medical Officer.

This is Doug Sproule. So I'll address the first question, which was regarding why we saw the results that we did and whether we were surprised by the results.

I have personal belief in this compound and personally, this is my hope and expect, hope that we would see this. I believe that this product would have demonstrated this at any point. My biggest concern, frankly, with the endpoints and the ability to demonstrate a material effect over a relatively brief period of time.

There's 2 aspects, I think, that drive how we were approaching the study and explain the outside results. The first is that our study was structured around the concept of stability. It's been reiterated over and over and over again from the community that just stabilizing the disease, stopping it from getting worse was an important advance that they would consider a strong win. And so our program was based around that as being kind of the minimal efficacy that would be clinically and frankly important for patients and really a meaningful advance for the field.

We also expected and always concern ourselves with the concept of a placebo effect. So any time you do a study in a placebo-controlled manner, patients perform differently than they might in an otherwise -- in an open natural history perspective. And so those 2 aspects were brought into account as we designed and structured this study.

And so while this is an upside scenario, it's something that we hope to be able to demonstrate. It wasn't what we considered necessary. This is gravy on top of the turkey, so to speak. And so I think that explains why we're seeing it. There's such a much greater difference in placebo versus the clinical improvement that we're seeing on these measures, and that was drives the statistic.

I think the second question was regarding the meaningfulness of these measures, particularly FVC. And FVC forced vital capacity is a broad clinically -- a broad tool used in clinical practice across multiple specialties. And FVC has been used as an endpoint in a number of different trials, both intrinsic pulmonary disease as well as in the neuromuscular community.

Depending on the different studies, there are different approaches for what would define clinical meaningfulness in a specific disease. But the difference we're seeing at 5% is broadly within and above the ranges that people generally consider as intrinsically meaningful in clinical trials and in clinical practice for this disease and in our -- in clinical practice in general use and specific for this disease.

The third question, I can't...

The third question was about the ability to continue treating people in the study in the placebo arm. And I think on that question, Tyler, I think it's a good question. Obviously, with the strength of this data and the clean safety profile, it's something that we're going to have to align with the FDA on before we can make any -- on the optimal path forward before we make any changes.

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

Congrats guys. If you don't mind, I'll also ask 3 questions.

So I guess the first one here is just on the different subgroups you guys had in this trial, the 276i homozygous patients versus the other FKRP genotypes. Can you maybe just articulate if there was any difference between the 2 groups? If you saw more or less benefit in one versus the other?

And then just a clarification just on the end that was in the different clinical endpoints here. I think you had like 49 on 1, 46. This is all for the drug arm, 40 for like 100-meter time test, 35 on FVC. Can you maybe just clarify why the different end on the different clinical measures at 12 months?

And then just lastly, if you think this mechanism could be used in other LGMD subtypes?

Thanks, Salim. Uma, do you want to take the first part of that question?

Sure. So as you could see when Doug showed the study design, we had a very broad enrollment criteria for the Phase III trial. It included both the homozygous 276i patients, that's about 75% of the study population representing what we see in real-world evidence. The other 25% with the heterozygous and the other FKRP genotypes. We have seen very robust and highly statistically significant results in both of these genotype segments. And this is quite consistent with BBP-418 to be a disease-modifying therapy, an oral disease-modifying therapy with a potentially very broad inclusive label.

As you can tell, the data is very new to us. So we are analyzing all subgroups and getting clarity on what the data means. Again, very, very promising, highly statistic with -- highly statistically significant data. Additional details as they emerge, we're going to be presenting it in future medical meetings.

I'll turn it over to Doug to answer the question.

The second question was why do we see different ends on some of the different endpoints. And the quick answer for that is that the data incorporates the available data. So in the case of the 100-meter time test, there are some individuals who are unable to perform the test and are therefore not incorporated into the analysis.

For FVC, we applied -- our collaborators applied a rigorous standard to ensure validity of the test and the assessments, and there were certain patients who were excluded based on their inability to perform the test correctly. This is incorporated into the test statistic and is -- the test statistic that we are reporting is a conservative adjustment to reflect that.

Yes. The other part about it, Salim, is just the enrollment rate. So like, for example, the primary endpoint of glycosylated alpha-dystroglycan at 3 months, that was all the patients available at 3 months, but then, of course, not all of them made it to the 12-month time point at the same time as collateral case.

And then I think your last question was about the applicability of 418 in other LGMD. So yes, we do believe that it could be applicable for LGMD2M and 2U in the U.S. and Europe. These are a little bit smaller conditions than 2i. In Japan, it may have potential in Fukuyama. That is -- that's a muscular dystrophy that is actually kind of a found mutation in Japan. So specific to Japan, but actually the second most common form of muscular dystrophy in Japan. So those are probably the most likely mutation expansion opportunity for 418 specifically.

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

And great to see such strong data. I wanted to ask more about the commercial opportunity. I'm curious, at this point, what percentage of patients are diagnosed today, both and if you can split it between in the U.S. and globally? And then from a strategic standpoint, do you plan to commercialize 418 yourself outside of the U.S., or would you look to out-license the molecule?

I am going to turn over to Matt.

Cory, thanks for the question. So first, we plan to launch ourselves globally, and we've been preparing in anticipation of positive data. And those assumptions that we put into that include about 7,000 patients between the U.S. and Europe and about 2,000 to 2,500 of those are in the U.S.

And then just to give a little bit of color on some of the commercial parameters that we're looking at, we'll start to refine our pricing assumptions, things like that. But I would -- as you're thinking about what to expect, I would expect sort of normal rare disease pricing similar to other recent rare disease launches. And we'll be using the current infrastructure that we have to kind of put all this together and should be another blockbuster drug for Bridge.

Yes. And I think I would add just on the diagnosis rate. I think it's a little TBD right now since there's nothing available for these patients right now. There's no therapy, and this will be the first to market for disease-modifying therapy. But I will say I think there are some tailwinds already that exist in the market. There is sponsored genetic testing that's available, for example.

And I guess anecdotally, our experience with the clinical trial enrollment may suggest that there's actually kind of maybe more patients identified than we thought. I mean with the clinical trial enrollment; we enrolled it 8 months faster than expected and 20% more patients than we expected. And so the demand for treatment and to be in a study there, again, suggests that there might already be a large follow-up locations [indiscernible].

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

I'd like to add my congratulations on the data. I had a quick question about correlation between [indiscernible] alpha-DG and the various functional measures. Can you share with us to what extent we could get a little bit of sense of the correlation between one and the other are recognize you're limited to what you've already disclosed? And where what might we look to see a more sort of detailed disclosure of how the one correlates with the other?

Thanks, Mani. That is going to be part of the ongoing analysis. This is really only the top line data, and we're going to use that data to have a discussion with the FDA, and then we'll present a fuller data package most likely at the NDA in March.

Your next question comes from the line of Josh Schimmer with Cantor.

Congrats on the data. Maybe just clarifying for the U.S. patient population, you said 2,000 to 2,500 patients. Are those all identified? How did you kind of come up with that estimate, especially because you suggested it potentially could be higher?

So the question was about just how we came up with our patient estimates -- patient number estimates. I think that's the question. Yes. So yes -- so the estimates are derived from basically the prevalence in the Northern European population. So this is a disease that has a found mutation in Northern European. And so the prevalence is much higher in Northern European countries and places where Northern European immigrated to. And so if you take those prevalence rates and extrapolate them out to the broader population, that's where we come up with.

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

Congrats on the data. I guess given the strength of the results on the clinical functional endpoint and you talk about NDA filing in first half 2026, do you still plan to pursue the accelerated approval pathway, or is there a path to full approval?

And then maybe second question on path for ex U.S. approval. Will you pursue approval prior to readout of the full analysis? And then I guess third question is, when can we expect the final full analysis from the trial?

Yes. Thanks for the question. I think it's a good question. So obviously, given the strength of the data, the improvement on the functional endpoints and the same safety profile, it is the key question that we want to align with on the FDA about whether to seek an accelerated approval, which is our original strategy or if this data as we think support a full approval in the U.S.

In Europe, we are also going to align with the European regulatory agencies on a path forward there. And I think the key principle for us is given the strength of this data, how do we accelerate access for patients as quickly as possible.

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

Congrats also on the compelling data set. So aside from the FDA meeting that you have, what gating items, if there are any, are still outstanding before you can file the NDA? Do you need to run any other peripheral studies in the meantime, or even -- do you even have enough drug for commercial launch? And secondly, does it make sense to file for breakthrough designation?

Yes. So the gating item really is just alignment with the FDA on whether we're seeking accelerated approval or whether we're seeking traditional approval. And I don't even -- we don't anticipate that's going to affect our time lines. We still anticipate filing our NDA in the first half of next year. We already have priority review. We also have the rare pediatric designation on this program as well. So at this point, I don't think that filing for breakthrough is going to give us any additional benefit.

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

Congrats on the excellent data. I have a few questions. So first, I'm just curious, maybe you can walk us through how you selected the 100-meter time test and FVC as a functional endpoint measures for the 12-month analysis. Is there something specific about these that would make them more sensitive to a change after 12 months than, say, NSAD or 10-meter walk test?

And then were the changes observed in the placebo arm on 100-meter time test and CK levels also consistent with natural history? And then maybe just a clarification. In your prior conversations with the agency, were they generally supportive of a potential full approval filing with 12-month data that showed significant improvements on functional benefits?

Thanks for the question. Doug, do you want to take the clinical question...

I'll take the clinical question, and then I'll kick it back to Christine for the regulatory question.

So the first question is why those endpoints? And how is that different from the other potential endpoints that you might excel. We selected specifically the 100-meter time test and FVC because of the expectation that these were 2 endpoints that would be likely to be able to show relatively early association and improvement with -- following administration of the therapy.

The 100-meter time test is the, I would call it the modern version of the 6-minute walk test, the measure of ambulatory function and fatigue that is highly sensitive to changes in function and ability that shows a better ability to differentiate decline in higher functioning patients than the 10-meter walk test. And so we felt that this is a more sensitive scale than the other ambulatory measure.

FVC has been well established by [indiscernible] history of the disease to show pretty outsized decline. The 2% decline that we see in the placebo arm mirrors what we see in the natural -- in published natural histories. And that's a pretty stark year upon year upon year decline. And so this was specifically chosen because of the decline that we expected to see in the untreated patients.

What we're demonstrating today, though, is not just an avoidance of that decline, but a pretty marked improvement in the overall function in those 2 measures. And with regard to the regulatory question.

Yes, I'll take the regulatory question. So maybe just to back up, I mean, the way we designed the study was kind of really in alignment with the FDA, which is the primary endpoint was the North Star endpoint at 36 months. That was the endpoint the FDA strongly encouraged us to use for approval. But given that, that incident is relatively insensitive one, takes a long time to show treatment benefit. That's why we wound up with the study with the interim analysis at 12 months. So the primary endpoint was based on the glycosylated alpha-dystroglycan, right?

The strategy was to see accelerated approval based on the biomarkers based on the fact that they are the cause of this disease, and we're targeting the disease at source of directly impacting glycosylated alpha-dystroglycan. So our prior discussions with the FDA have all been about accelerated approval on -- and the -- I guess, the potential to use glycosylated alpha-dystroglycan as the surrogate. We weren't really expecting statistical significance on the functional improvement at 12 months. And so that really wasn't the tenor of our prior discussions. But given that we have seen the scope, and it has significant functional improvement as well as the clean safety profile, which we did expect, I think that's where we want to reopen discussions with the FDA.

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

Congrats on the data. So Christine, maybe I can follow-up on your just prior comment. Anything more you can share on the nature and severity of some of the treatment-emergent adverse events you saw in the treated group? And then also, can you say anything about the baseline characteristics and the severity of the patients enrolled in the study just to help us further kind of put the efficacy that we're seeing into context?

Yes. Thanks, Anupam. I think on the treatment-emergent events, we aren't sharing a lot of detail right now only because we need to be careful -- mindful of the integrity of the ongoing study before we have the discussion with the FDA. I think what we've said, of course, is that there are no new ones that we've identified, and that the safety profile is very consistent with Phase II.

I don't know, Doug, if you want to add any more color to that in terms of what...

It's personally a tricky question because the numbers are very low, and we want to avoid further impacting study integrity. Then there were no new TEAEs, certainly nothing associated with therapy. The risk -- safety and risk profile has not changed from what we've described previously.

Yes. And encouragingly, what we said as well, the continuation rate was very low and it was higher in the placebo arm. And I think in terms of the baseline characteristics for the Phase III, it's very consistent actually with our Phase II study population. I don't know if anything else.

I mean it's a mixed cohort and we'll be presenting additional -- we'll be presenting -- continue to present this in greater detail as we move forward. There's a mixed cohort of patients with homozygous L276i and patients with other genotypes that roughly matches the general population. The predominance were ambulatory patients because of the structure of the study. There were a sizable cohort of non-ambulatory patients enrolled as well that are incorporated in appropriate analysis, including FVC. So this is a broad study that we believe will provide sufficient for a relatively expansive label.

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

Congratulations on the data. My first question is, can you maybe comment on if the magnitude of benefit was the same in pediatric patients as it was in the adult patients just in the context of the natural history. I think your international enrollment was largely limited to adults. So maybe just some clarity on that would be helpful.

And my second question is, as sort of a first-in-class for this therapy, do you anticipate a potential FDA Ad Comm might be held for this just given the novelty of the category and just sort of the unknown treatment options for this particular disease? Congrats again on the data.

Yes. Thank you. So on the pediatric subgroups, all the subgroup analyses are ongoing. So we'll disclose that at a later time. On the sorry, what was the second question -- Ad Comm, right. Ad Comm. So I actually -- prior to the data, I actually thought an Ad Comm was more likely than not. And now I think it's the opposite. I think given the data, how robust it is, how consistent it is, how overwhelmingly positive and the clean safety profile, I'm not really sure that there's -- I don't know what we're going to discuss. So I think it's less likely now.

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

Congrats on the data. I wanted to ask on your expectations over the long-term outcomes. I mean, granted things are still early, but it did appear that the alpha-DG levels continue to improve somewhat over the 12-month interval. So is there the potential that longer-term exposure can drive even better responses, or alternatively, is there a limit to how much you can replace and at some level, patients will decline at -- albeit at a more modest level?

Yes. Thanks. I'll turn it over to Doug.

Yes. So obviously, we'll need to see ultimately. Our expectation based on what we seen from our natural history -- from the natural history studies, what we've seen from the longer-term data sets from the University of Iowa is that patients who are not treated will experience a continued ongoing inexorable decline along the fashion that we're seeing in our placebo arm, and that will continue in the longer term. We believe that this demonstrates a change in trajectory. The magnitude of that and the continued directionality, obviously, will remain to be seen. But we expect that, that gap and that difference between the treatment and placebo arms will continue to grow with longer and longer therapy. But again, that remains to be demonstrated to date.

And one more thing, which is the data that we showed, that's the change from baseline, the 1-year time point. We essentially already doubled the baseline level of glycosylated alpha-DG. So about 21%, 22% has already increased by 23%. So yes -- so it's a remarkable increase already at 12 months.

Yes. And to put that in context, what we believe was clinically meaningful was absolute increase of 5%, right? So the fact that we're getting a 17% increase already at 3 months is pretty meaningful.

And that concludes our question-and-answer session. And I will turn the conference back over to Christine Siu for closing comments.

All right. Thanks, everyone. I think based on the strength of the data, and we're very excited about the potential here. This could be very transformative for these patients, for this community and could offer really -- we could be first to market with an oral dis-modifying therapy, those are functional improvement. So we're excited. Thank you.

Ladies and gentlemen, that does conclude today's conference call. Thank you for your participation, and you may now disconnect.

Thank you for standing by, and welcome to the Autosomal Dominant Hypocalcemia Type 1 investor webinar. [Operator Instructions] I'd now like to turn the call over to Ananth Sridhar. You may begin.

Thank you, operator, and good morning, everyone. We're pleased to have you join us as we provide a presentation to discuss encaleret, a small molecule that we're developing for autosomal dominant hypocalcemia type 1, abbreviated as ADH1 throughout this presentation.

On our next slide, you'll see our forward-looking statements. This presentation will include forward-looking statements. Actual results may differ due to various factors.

On this call, I'm privileged to be joined by Dr. Rachel Gafni, a senior research physician at the NIDCR of the National Institutes of Health, will present an overview of ADH1 and of encaleret. I'm also joined by Dr. Scott Adler, the Chief Medical Officer of Calcilytix Therapeutics, the BridgeBio affiliate that is dedicated to the development of encaleret. Dr. Adler will provide a review of the encaleret clinical development program.

I will also provide our perspectives on the market opportunity for ADH1, and we will conclude the presentation with a question-and-answer session. Before I hand the call to Dr. Gafni, we wanted to illuminate the patient experience with ADH1. And by doing so, we thought the best way was to start with the video featuring Jessica, an individual living with ADH1 and her story.

[Presentation]

Thank you for inviting me to join this call. My name is Dr. Rachel Gafni, and I'm a senior research physician at the National Institutes of Health and a principal investigator and Co-Chair of the Calibrate Steering Committee.

Under normal circumstances, blood calcium levels are kept within a narrow physiologic range and this tight control is mediated by four organs under the regulation of parathyroid hormone. When the calcium level is low, the parathyroid glands respond by synthesizing and secreting PTH, which in turn, acts to increase calcium levels by several mechanisms.

In the bone, PTH stimulates bone resorption liberating calcium into the bloodstream. In the kidney, PTH increases renal calcium reabsorption and promotes conversion of 25-hydroxyvitamin D to the active 1,25-dihydroxyvitamin D, which in turn promotes intestinal absorption of calcium. PTH also inhibits renal phosphate reabsorption.

Now while PTH is an important circulating hormone that is doing much of the work, it is, in fact, the calcium-sensing receptor that is controlling this complicated dance. In the parathyroid when the calcium-sensing receptor sense us high levels of calcium, PTH synthesis and secretion are decreased. Likewise, in the renal tubule high levels of calcium sensed by the receptors leads to decreased calcium reabsorption to rid the body of the excess calcium.

Heterozygous activating variance in the calcium-sensing receptor cause a rare form of hypoparathyroidism called autosomal dominant hypocalcemia or ADH1. And these variants in the receptor increased tissue sensitivity to extracellular calcium, essentially tricking the parathyroid and the kidneys into thinking that the blood calcium level is higher than it actually is.

As a result, patients with ADH1 have decreased PTH secretion, decreased blood calcium and increased urinary calcium. The clinical manifestations of ADH1 are similar to other forms of hypoparathyroidism and hypocalcemia, which can include significant neuromuscular irritability. Manifesting symptoms ranging from mild paresthesia, which is the sensation of pins and needles or tingling in the hands and feet and face to severe muscle cramps, seizures and even death.

The long-term complications are often treatment related and include nephrolithiasis, nephrocalcinosis and chronic kidney disease. And it's important to note that the high urine calcium may be worse in ADH1 compared with other forms of hypoparathyroidism because these patients experience both decreased PTH as well as altered calcium-sensing leading to reduced calcium reabsorption. Treatment is often difficult in conventional therapy with calcium and activated vitamin D does not correct the underlying pathophysiology and has the potential to worsen long-term complications.

As the name indicates, ADH1 is an autosomal dominant condition. So what does that mean? Humans have 23 pairs of chromosomes, and 22 of these pairs are called autosomes, while the 23rd pair are the XY chromosomes also called sex chromosomes. The gene for the calcium-sensing receptor is found on the third chromosome, with each parent contributing one of the pairs to their child.

When a parent has ADH1, there is a 50-50 chance with each pregnancy that they will pass on the pathogenic variant to their child. And unlike autosomal recessive disorders like sickle cell disease and cystic fibrosis where the child needs an abnormal gene from both parents to have the condition. ADH1 is a dominant condition, meaning that you only need one altered copy of the calcium-sensing receptor to manifest the disorder.

It's also common for someone with ADH1 to have a de novo or spontaneous variant, which means that they are the first person in their family to have the disease. Moving forward, that individual still has a 50% chance of passing it along to their children and future generations. While for decades, we have suspected the diagnosis of ADH1 based on family history, along with clinical and biochemical findings, genetic testing is important to make a definitive diagnosis and conduct genetic counseling.

At present, the prevalence of ADH1 is estimated to be one in 25,000. In some cases, ADH1 can be difficult to diagnose based on symptoms alone and patients may experience a prolonged delay before receiving a final diagnosis. But when you do identify that first individual with ADH1, family screening is recommended to both identify and rule out ADH1 in other family members, and this can be done through biochemical and/or genetic testing.

According to a systematic literature review, the median age of a diagnosis of a hypocalcemic related disorder is 4 years, but a genetically confirmed diagnosis of ADH1 is delayed with a median age of 25 years. Currently, the standard of care for individuals with ADH1 is conventional therapy with calcium and active vitamin D supplementation given in divided doses throughout the day.

Some patients also require magnesium and potassium supplements. And the goal of this treatment is to increase the blood calcium enough to alleviate the symptoms of hypocalcemia. However, increasing the blood calcium in these patients also increases urine calcium. So we are forced to titrate the medications to the lower limit of the normal range for blood calcium or even, frankly, below normal to minimize the rise in urine calcium and its associated comorbidities. As a result, patients often continue to experience hypocalcemia related symptoms.

So what about using parathyroid hormone replacement in patients with ADH1? First of all, the data are quite limited as most industry-sponsored studies of PTH analogs have deliberately excluded patients with ADH1 from their trials. Secondly, unlike other causes of hypoparathyroidism, where the parathyroid glands are either missing, damaged or underdeveloped, patients with ADH1 have normal parathyroid glands with the capacity to produce PTH in response to the appropriate stimulation.

Finally, we know from small investigator-sponsored studies that while PTH 1-34 can raise the blood calcium in patients with ADH1, it will not necessarily correct the hypercalciuria not only because intermittent short-acting PTH 1-34 does not recapitulate normal physiology, but also because patients with ADH1 still have altered calcium-sensing at the level of the kidney.

For example, in a study of twice-daily PTH 1-34 therapy that we conducted in 31 patients with hypoparathyroidism, including four participants with ADH1, we found that nephrocalcinosis was not prevented in this patient. The image on the left is the normal renal ultrasound of a 40-year-old man with ADH1. And 1 year later, he had developed nephrocalcinosis while on PTH 1-34 despite maintaining his blood calcium at the lower end of the normal range.

So in our drive to provide more precision medicine, it made sense to pursue a therapy for ADH1 that directly targets the underlying genetic cause and restores normal physiology, rather than applying a band-aid of PTH analogs that incompletely addresses the problem at hand.

This led us to encaleret which is an investigational oral medication from the class of drugs called calcilytics. Calcilytics are negative allosteric modulators of the calcium-sensing receptor which decreased the receptor sensitivity to extracellular calcium essentially shifting the response of the parathyroid and the kidneys to the right which should, in turn, lead to increased PTH secretion and increased renal calcium reabsorption.

It should be noted that these drugs were originally developed and studied in large clinical trials for the treatment of postmenopausal osteoporosis with the hope that increasing endogenous PTH secretion would increase bone density. Unfortunately, these drugs were not effective in osteoporosis and further study for this indication was abandoned.

However, results from these osteoporosis studies did demonstrate a rise in both PTH and blood calcium levels in these patients with osteoporosis leading us to hypothesize that normalizing calcium-sensing receptor sensitivity with encaleret has the potential to correct the hypocalcemia, hypercalciuria and low PTH in individuals with ADH1. Thank you.

Thank you, Dr. Gafni. I will now describe the encaleret clinical development program. As Dr. Gafni has described, activating variants in the calcium-sensing receptor increased the sensitivity to calcium causing the parathyroids and the kidneys to behave as if the blood calcium concentration is higher than it actually is. As a result, patients with ADH1 have decreased PTH secretion, decreased blood calcium and increased urinary calcium excretion.

Encaleret is an investigational oral medication from the class of drugs called calcilytics and acts as a negative allosteric modulator of the calcium-sensing receptor. Through this mechanism, encaleret decreases the sensitivity of the calcium-sensing receptor to extracellular calcium. Correcting the sensitivity of the calcium-sensing receptor is able to restore PTH secretion, increase serum calcium and decrease urinary calcium excretion into their normal ranges.

Encaleret is the first and only investigational treatment targeting ADH1 at its source. By targeting the calcium-sensing receptor, mineral homeostasis can be restored in patients with ADH1. Encaleret addresses the common clinical markers of disease, namely low PTH, low serum calcium and its associated symptoms of hypocalcemia and the high urinary calcium excretion. Encaleret is also dosed orally.

I'd like to briefly review the design and the results from our Phase IIb study of encaleret in ADH1. On this slide, the Phase IIb open-label study was divided into four periods. During period 1, six patients with ADH1 received encaleret in escalating doses over 5 days while undergoing frequent blood and urine sampling. Period 2 was an inpatient period that included those six patients, plus an additional seven patients.

During period 2, patients received individualized dose titration for 5 days. These 13 patients then entered period 3, a 24-week outpatient period with scheduled assessments occurring every 1 to 8 weeks. Participants then entered a fourth period, which was a long-term extension with assessments every 3 months. The key study objectives were safety and tolerability and calcium metabolism. Additional secondary measures are listed here.

Calcitriol or calcium supplements were discontinued upon encaleret administration and patients were instructed to consume at least 1,000 milligrams of dietary calcium per day. I will next present the results from 42 months of continuous outpatient treatment with encaleret.

On this slide, the baseline characteristics of the study participants are shown. 13 subjects with a mean age of 39 years, bearing nine different calcium-sensing receptor variants were enrolled. All with the typical biochemical features of ADH1, namely hypocalcemia, low PTH and inappropriately normal or frankly elevated urine calcium. 3/4 of the patients had nephrocalcinosis by renal ultrasound. The baseline kidney function was variable in the group with a mean estimated glomerular filtration rate of 84. All study participants were being managed with calcium and calcitriol supplements in fairly typical doses divided throughout the day.

On the next slide, I show you the safety and tolerability for the study as these were primary endpoints. Encaleret was well tolerated with few adverse events. Two serious adverse events occurred very late in the long-term extension and were unrelated to encaleret. The only treatment-related adverse events were instances of transient low blood phosphate concentrations and some instances of mild hypercalcemia with no patient exceeding an albumin corrected calcium over 10.9 milligrams per deciliter. All treatment-related adverse events resolved either spontaneously or with adjustment of the encaleret dose. No other concomitant therapies were required.

On the next slide, these figures display the mean pharmacodynamic responses to individualized twice daily dosing of encaleret. The first 24 weeks of treatment are shown on the left half of each graph followed by an additional 36 months of treatment as part of the long-term extension on the right half of each graph. The upper panels show robust responses of blood and urine calcium with increases in the albumin corrected blood calcium into the normal range on the left and decreases in the urine calcium excretion into the normal range on the right. In the lower panel, you can also see robust increase of PTH into the normal range. These responses were maintained throughout the 42 months of treatment.

In the next slide, when we evaluated the blood and urine calcium responses to encaleret, we observed that nearly 70% of the patients were able to achieve both a blood and urine calcium within the normal range when none of them were able to achieve that while on standard of care. This finding led us to select this composite endpoint for the ongoing Phase III study in patients with ADH1.

In this slide, to summarize in 13 patients with ADH1, encaleret administered twice daily for 42 months, restored mineral homeostasis as demonstrated by an increase in PTH, correction of hypocalcemia and normalization of mean 24-hour urine calcium excretion. The 13 participants continue on encaleret in a long-term extension study. I will next briefly discuss the ongoing Phase III study in patients with ADH1.

The Phase III CALIBRATE study is ongoing. The last patient last visit occurred at the end of the summer and top line results are anticipated this fall. The study design is outlined here on this slide. After a screening and standard of care optimization period, patients 16 years of age and older entered a 4-week standard of care maintenance period. They were then randomized 2:1 to encaleret or standard of care for 20 weeks. Those randomized to receive encaleret had standard of care discontinued and then encaleret or standard of care was titrated to maintain blood calcium in the target range.

Once titration was completed, the participants entered a 4-week maintenance period when doses of drug were kept stable. After completing the 24-week study, all study participants were given the option to enter a long-term extension study when all participants received encaleret. The primary endpoint of the study is the proportion of participants achieving blood and urine calcium within the target range at week 24. The secondary endpoints are as listed. We are looking forward to top line results in the fall.

This past weekend, our collaborators at the NIH presented data from a study of encaleret in patients with postsurgical hypoparathyroidism. In this proof of principal study of 10 participants, urine calcium excretion rapidly decreased following calorie administration and importantly, the albumin corrected blood calcium also increased into the mid normal range.

We believe that the mechanism of action is through a PTH independent effect on the calcium-sensing receptor expressed in the kidney. An important observation is that none of these study participants had both blood and urine calcium within the normal range while on standard of care, but 80% were able to achieve this endpoint within 5 days of encaleret administration. These findings suggest a potential path for improved calcium control in an oral medication.

Additionally, encaleret will have a benefit in controlling 24-hour urine calcium excretion and potentially avoiding long-term PTH mediated effects on bone health. We look forward to initiating additional clinical studies of encaleret in patients with chronic hypoparathyroidism. I'll now turn it back to Ananth for the market opportunity.

Thank you, Scott. And now to present some of our perspectives on the ADH1 market opportunity, we wanted to start with our estimate of the disease prevalence. We have evaluated various genetic databases and what started as an initial query of the Geisinger cohort, we evaluated about 1 in 25,000 individuals carry variance associated with ADH1. We replicated that work in a broader cohort, including the U.K. Biobank, All of Us cohort and the Mass General Biobank, which accounted for over 700,000 individuals of genetic data.

In assessing the CaSR genotypes associated with ADH1, we found a very similar prevalence of about 1 in 25,000. If we apply this rate to the U.S. population, we estimate there are about 12,000 individuals with ADH1 were prevalent in the U.S. Of those 12,000, we currently believe about 3,000 to 5,000 are currently addressable based on their symptom presentation and the current diagnosis rates.

Turning to the next page on Slide 28. We wanted to recap some of our genetic data from our sponsored testing program, which we have presented at recent medical meetings. In this program, we are testing for all known genetic causes of hypoparathyroidism included in a 26 gene panel. Within this panel, we have learned that about 40% of nonsurgical hypoparathyroidism cases are genetic in their etiology.

And of those genetic cases, the majority are associated with CaSR variants associated with ADH1. This work is illuminating that ADH1 is the most common isolated cause of nonsurgical hypoparathyroidism. And the proportion of nonsurgical hypoparathyroidism patients with genetic hypoparathyroidism or genetic etiology is quite high.

Turning to Slide 29. We believe there's a few features of this marketplace that serve as tailwinds to accelerate diagnosis. And one element, we are sponsoring a genetic testing program, which I covered evidence from in the last slide. This is a no-cost testing program for providers to identify potential genetic variance positive of hypoparathyroidism.

There's also a newly established ICD-10 code that is dedicated to ADH1 and ADH2. Finally, new management guidelines for hypoparathyroidism are recommending the need for genetic testing in all patients with idiopathic hypoparathyroidism, especially patients with a family history. These elements provide a tailwind to the broader ecosystem that we believe will accelerate diagnosis rates alongside our active development program.

Turning to the next page. When we look at the CALIBRATE study that Scott presented, we believe that there's an opportunity for encaleret to become a first-in-class medicine for ADH1 patients. In our base case, we believe that any significant benefit over standard of care will really be practice changing especially when paired with a safety profile consistent with current standard of care.

And the upside home run scenario that would really be paradigm shifting, we believe that if a majority of patients respond to therapy at the week 24 time point as assessed by target blood and urine calcium within the normal range, we would be blown away.

Additionally, we would hope to see mean parathyroid hormone within the normal range, which would be reflective of restoration of the endogenous axis of parathyroid hormone synthesis and secretion. This result would be practice changing and would drive meaningful utilization and adoption based on our understanding of the market opportunity. With that, we'll conclude our call and open it up to question and answer.

Thank you, we will now begin the question-and-answer session. Operator Instructions] Your first question today comes from the line of Salim Syed from Mizuho.

This is Bennett for Salim. Regarding the potential in chronic hypoparathyroidism broadly speaking, could you discuss how encaleret could differentiate versus like hormone replacement therapy? And then the upcoming pivotal, should we expect to see the same endpoints used in the proof-of-concept study in encaleret? And finally, if I may, how important would it be to get the benefit on urinary calcium in the level?

Thank you, Bennett. Scott, I will defer to you for that answer.

Thank you for the question. In order for differentiation, first of all, encaleret is an oral medication and I think would provide convenience for patients in avoiding daily injections. I think importantly, the focus would be for encaleret to decrease urinary calcium excretion in the patient population, which in doing so, will also increase the blood calcium. So again, focusing on the effects in the kidney and preventing long-term complications, including kidney stones and the development of chronic kidney disease.

I think it's a really important point that any decrease in urinary calcium excretion is beneficial to patients and that's been well demonstrated in the patients with recurrent calcium stone formation. So again, the differentiating points would be maintaining blood calcium, decreasing urine calcium and then having an oral medication for this patient population.

Your next question comes from the line of Tyler Van Buren from TD Cowen.

Great. Thanks so much for hosting the webcast. Very clean data, obviously, in Phase II, especially for only 13 patients. But just a follow-up. As we think about the probably success for the ongoing Phase III, can you just confirm that the way you're measuring the primary endpoint of serum and urinary calcium levels and normalization that is the exact same as what you did in Phase II?

And also what you would expect the standard of care control arm to do based upon historical data? And then finally, just you talk about the enrollment pace, how it evolved throughout the study, the number of centers involved and how that experience might enable commercial uptake upon a potential approval and launch?

Thank you, Tyler. I heard three questions there. One is, how the Phase III assessment may differ from Phase II? What the standard of care response may be in the overall study dynamics and enrollment? I'll let Scott answer the first question in the last regarding the Phase III study, and I'll defer to Dr. Gafni on her perspective of standard of care response, the primary endpoint.

So as far as the primary endpoints, they are measured in the same way. I mean, we'll receive both blood and urine calcium collected around the same time as each other. So the patients will collect 24-hour urine collection and have a blood sample measured within a day or so of that collection. And it is the same as was done in the Phase II study.

We had 25 centers globally in the Phase III study. And again, it's a rare disease. So the patients that were being seen at that center were included in the trial and then additional patients in surrounding areas were referred into those centers. And so it did take us 18 months to enroll the study. But again, we had very good participation from those active tertiary care centers that see patients with this condition. And then Dr. Gafni is going to address the standard of care response rate.

Thank you, Scott. Just to add to what Scott was saying, the primary endpoint for the Phase II study, which was a single site study done at the NIH with the 13 patients, the primary endpoint was actually safety and tolerability because this drug has not been given to patients with ADH1 and it only been used in healthy volunteers and people with osteoporosis. So yes, we were collecting everything the same, but the primary endpoint was different between the two studies.

In terms of standard of care response, I can't speak to the entire CALIBRATE protocol. But at our site where we have 17 patients plus other patients who screen failed, really nobody on standard of care treatment has normal blood calcium. If they do have mid normal blood calcium and they're being overtreated, their doses have not really been optimized because we target their blood calcium for safety reasons at the lower end of the normal range or even slightly below. So some patients might not have frankly elevated urine calcium on standard of care, but it's certainly inappropriately elevated for the level of blood calcium that's targeted. Did that answer your question?

Yes. That's perfect.

And Tyler, one addition to the enrollment dynamics just to clarify for the audience here is that we were able to exceed our enrollment target by about 20% given the demand for this study, and we enrolled 71 participants as noted in our presentation.

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

In the Phase III, what type of a treatment difference would you need to see to achieve statistical significance? And the second question on the Phase II long-term follow-up about the 42 months, are you looking for renal outcomes and measuring of renal outcomes on the long-term follow-up for both, I guess, the Phase II as well as the Phase III? And what do you hope to see there?

Thank you for your question. Scott, would you like to address these?

Just happy to do that. So the statistical power of the study we expect to see -- we're powered to see a difference of 30% between standard of care and the active treatment. And we are well powered over 90% powered to see that difference. And that's in the Phase III study.

From the Phase II perspective, yes, we are following up on all renal endpoints. We are looking at both estimated glomerular filtration rate of a measure of kidney function over time, as well as looking at renal ultrasounds over the course of the study. Dr. Gafni is the principal investigator of the Phase II study. And so I'll defer to her if she would like to comment on the renal ultrasound findings from that Phase II study.

I hope you can hear me. Somebody just started drilling very loudly directly above my office. Okay, it went away. Yes, we are following the renal ultrasound as well as the urine calcium and other urine metabolites and creatinine and glomerular filtration rate and cystatin, see as Dr. Adler referred to.

As of now, we're not really seeing any changes in the renal ultrasound. Some patients who had a history of frequent kidney stones, some of them have continued to have intermittent kidney stones while others haven't had kidney stones at all. We're not seeing progression of existing nephrocalcinosis on ultrasound, keeping in mind that this is usually a permanent finding. It doesn't regress once you have it. So our goal is really to avoid progression and worsening of renal calcifications. I hope that answered you properly.