Great. Welcome back, everyone. This is the afternoon session of our second day of the 2026 Leerink Partners Global Healthcare Conference. This is Mani Foroohar, Senior Analyst, Generic Medicines. Welcome everyone to Miami, and I am very pleased to be hosting Chinmay Shukla, SVP of Strategic Finance from BridgeBio. Chinmay, how are you doing?
I'm doing great. Mani, thank you for inviting us to the conference, for hosting us, and, thank you to the broader Leerink team, as well as all the investors for the interest. We are deeply grateful and, happy to answer any questions you guys might have.
Great. Let's dive in. Some of this will be a little bit repetitive, previous meetings we've had before, of course, but, let's try and get into a little more depth. I'll start with where we are on TTR. Obviously, launch has been accelerating in absolute terms with new patient adds. An experience a little bit different than some of your competitors, although this market is complicated, so apples and oranges comparisons are always dangerous. Talk to us a little bit about where we are in terms of the evolution of price and volume growth, respectively, in terms of bringing in earlier patients, and do they have a different severity mix? Do they have a different payer mix, et cetera? Like, how do we think about how that market evolves as we go into a quite mature multi-player market?
Yeah, happy to talk about that. I think the way I would think about this is our patient growth has accelerated. Just to remind everyone, we went from about 60 patients a week from when we launched at our update last year, about a year ago exactly, to now having more than 150 patients a week as of our last update. There has been substantial acceleration and actually what we saw is two waves of acceleration, right? For a start, launch accelerated from, call it 60-100, and then it's accelerated again to this higher number. That's pretty rare in genetic disease launches and we've been studying as to why we've been able to accomplish this. It comes down to a few factors, right?
I think the first thing is the clinical data. It starts with the fact that we are the first and only near complete stabilizer on the market for this disease. It's a devastating disease. Physicians and patients have really wanted a potent molecule like Attruby and have reacted well to it. Beyond the clinical data we generated in our you know on our label, we've done more work to identify the power of Attruby. I will talk to you about the AFib data, which we've talked about before, as well as the variant data. All of that has resonated very strongly with the physician community. The second thing which has caused this acceleration is just more patients are being found. That is a function of awareness of this disease going up.
It's also helped a little bit by some of the initiatives we have undertaken, like using AI for diagnosis. The third thing which has happened is that the prescriber base has broadened. We've always talked about academic centers. We've talked about community physicians. I think that there is an important nuance which gets missed here, and that is the high volume heart failure clinics. I know we've talked about this a little bit before with you, Mani, and I will say you've been early on this bandwagon.
Really now what we are seeing is these high volume heart failure clinics, you know, especially with the AFib data, which is, you know, half of these patients have some component of AFib. They're getting much more confident at keeping the patient in their practice as opposed to sending them to an AMC, and that's been very powerful for Attruby. All of this has meant that our patient volume has gone up quite a lot, as you guys have noticed. Primarily, the strength is driven in treatment-naive patients. As we've discussed before, that is the segment of the market which we are focused on, where we continue to win very strongly. We have north of 25% treatment-naive share just a year into our launch, and at launch, we had said that our goal is to be north of 30%.
We feel very good about where we are there. Finally, on the net price dynamic, net pricing for Attruby has been very, very stable. You know, we have not seen really any changes in our discontinuation rates, compliance, you know, paid drug, all of that. Our gross to net has been, you know, in that 30%-40% range, which we have guided to as our long-term gross to net. You know, it can move around a little bit in there. I think in the first quarter, maybe it's gonna tick up a little bit, but I still think it's not going to be very noticeable and it's going to be well within the range that we have given out to people.
Let's talk a little bit about the European experience. You guys don't sell Beyonttra yourselves. That's through your partner Bayer. Talk to us about where they are in terms of sequence of launches. It being a little more of a complex country by country, kind of hand-to-hand combat launch. Talk to us a little bit about where they are in terms of new patient share in the countries they launched and timing that we should think about for incremental new launches.
Yeah. That's a great question, and we're very excited about the potential for acoramidis, not just in the U.S., but globally, because we do think that this safe oral small molecule stabilizer can be the backbone of therapy for all patients worldwide. We've been very grateful for our partnership with Bayer. I think that we've been very pleased with how that's gone so far. It is, you know, we expected it would go very well, and it has. Specifically, you know, since it's their information, I'm gonna be a little more careful about it just to be a good partner to Bayer. I think what they've said before and what we have said before is, you know, it starts in Germany. That's the first country that you launch in Europe.
In Germany right now, they have north of 50% treatment-naive share. Remember I said here in the U.S., we are at north of 25%. Part of that is because in Germany, there is a single-payer system, so you don't have some of the access challenges that you seem to have in the U.S. You also have, you know, systems which can actually cross-trial compare between all these different datasets. When you do that, it's very clear that Attruby offers the most benefit, and it's also priced in the most competitive way. That's where they are at in Germany. I think beyond that, the next launch will be, I think, in Denmark, and then from there they're gonna go on to broader countries, like Spain, Italy, France, so on and so forth.
I think that it's been disclosed that they've won the bid in Denmark. It's going very well. We're very excited about the momentum there. We get our royalties on Beyonttra sales start at 30% and go up to mid- to high 30s%. That's going to be a pretty significant sort of stream of income for us. Watching them launch in Europe has also taught us on how we should think about our launches for the next three drugs which we are going to have in-house. It's been a great partnership and we're really grateful for it.
Let's talk a little bit about combination therapy. I'm gonna move out of TTR momentarily, I promise. How do you think about this market evolving whenever tafamidis becomes generic, and how that will impact combination therapy and your positioning versus competitors?
It's a great question, Mani. Maybe I'll just use this opportunity to touch very briefly on our thoughts about tafamidis IP. It is a little odd to comment about someone else's IP, and I want to be upfront about it. It's not something that we really want to do, but I know that that's been a topic of conversation amongst investors. I know that there are, you know, we've mapped three potential outcomes, one being Pfizer is able to prevail, second being Pfizer settles, the third being there is a generic entry in 2029. We think that there is a very high likelihood that Pfizer, in some way, prevails here, whether it's by winning outright or by a settlement which pushes it out into the 2030s. Regardless of whenever there is a generic, right?
I think the question becomes, you know, if you look at any other category where a first to market went generic, which we think here will be in the 2030s, potentially 2035, and there was a second to market more potent drug available, the sales of that second drug have continued to grow across all sort of analogs that we have studied. Specifically, to answer your question on combination therapy, I think that there are a few things to consider here. One is that there has been no benefit shown for combination therapy, and that's just what the data says. Actually, that's also what the guidelines in the U.S. say. The U.S. guidelines tend to be conservative, but even they say that there's no benefit shown with combination therapy. You see that also in the clinical sort of commercial experience that we are having right now.
There's not a lot of combination use going on out there. There are a small group of physicians who really want to try and use it, but it's not really a big portion of this market today. I think finally, as in terms of evolution of this marketplace, I would say that ultimately our goal here is to establish Attruby as the most potent stabilizer. Regardless of whether people wanna try a combination with a knockdown, which I don't think makes a ton of sense, or a depleter, which I do think makes a ton of sense, we think that having the best background therapy, which is the best stabilizer as the starting therapy, and then you can add things on if you need it, is the way to go, and that is where I think the field is going, and that is where Attruby is positioned.
Let's talk about the depleter. You have brought in a depleter of your own as part of strategic expansion, life cycle extension, however you wanna think about it. When you look to the Neurimmune, Alexion, AstraZeneca, sort of nested Russian dolls ownership of that asset, when you look to that data set, how is that gonna inform your own strategic plan for your depleter?
That's a great question. We are looking to see the data that reads out. I think it might influence how we design our trial. Before we get into all of that, maybe let me take a step back and explain to you as to why we are so excited about our depleter program and why did we decide to start one in-house as opposed to buy one of the existing ones, which I know a couple of them were being shopped around. It really comes down to the fact that this is a mass action disease where the tetramer is dissociating into monomers. The monomers can then clump in your heart, and that can cause cardiomyopathy. The therapy which we have in Attruby is a very, very powerful drug, but all it does is it stabilizes the tetramer.
It doesn't really directly affect the monomers already deposited. There are some natural clearing mechanisms through which the heart can remodel itself, but, you know, Attruby's not doing anything to significantly accelerate that. A depleter could theoretically go in and start to remove some of these monomers, and that could be an interesting way to almost reverse the disease in a way. That is why we think it is very synergistic with a stabilizer, and that is why we've been very excited about it. The other reason why we went out and looked at depleters, and we felt like all of them had some issues which we felt we could do better at. That is where Dr. Richard Scheller comes in. He's our Chairman of R&D.
We've worked with him for a very long time. He is an antibody expert, as is widely known. When we sat down with him and we thought about what would a good molecule here look like, we realized we could design one on our own, and that's why we started our in-house depleter program. It's going to be in the clinic, probably at the end of next year or early in 2028. I think as these other trials read out, we'll think about the patient selection as well as where exactly do we take this and how do we trial it, based on that data. It's a little too early to give more specifics than that, but that's how we are thinking about it and that's why we're very excited about this opportunity.
Let's slide from TTR down the pipeline chart to achondroplasia. A fairly mature market, but one that's still growing. You've got a couple of agents in there, although both with different mechanisms of action than you. Talk to us about your strategy for U.S. launch, switch versus new, versus new patients, and then we'll move on to OUS after that.
Yeah, happy to talk about that and thanks for the question on infigratinib. You know, before we talk about the commercial launch, it is important to be grounded in the data and the clinical profile because that guides a lot of what happens commercially. Just to very quickly recap what we have seen, infigratinib targets the disease at its source, and like you mentioned, you know, it's a differentiated and I would argue, a much better and direct way of addressing achondroplasia as well as hypochondroplasia and other targets. These are all FGFR3 gain-of-function mutation-caused conditions. Targeting FGFR3 directly is very helpful in that context, and that's what we do, so we target both the JAK/STAT as well as the MAPK pathway, whereas some of our competitors only target one of the two pathways.
That mechanistic superiority has then translated into significant clinical differentiation, right? Whether we talk about height, where we have the best point estimate at 2.1 cm per year, but beyond that, height is not the most important thing here for the community. It is proportionality, which is what matters. We are the only agent that in a placebo-controlled clinical trial at 12 months was able to show a static effect on proportionality. I think people are really underestimating the impact of that data set and what that means for the community. Beyond that, the drug was remarkably safe, right? We had less than 4% hyperphosphatemia, and we didn't really have any other major AEs that anyone was worried about.
When I take that whole clinical data and I put it together with the fact that this is an oral agent, that really means a ton of good things for the commercial opportunity. That brings me to directly answering your question, right? A profile like this should help us get a lot of switches because there are people you know taking 3,000 injections is just not the right thing for children and the families who are going through this. It is much better for them to have an oral option available, so we're proud to have that hopefully be available next year to them, and I think that that's going to drive a lot of switching. In the naive section, I would say there are two further segments of the market, right?
One is whatever is the incident population, which you know, we'll have a fair shot at. The other segment of the market, which people are not really paying a ton of attention to, I would argue, is the expansion of the market by bringing online children and families who currently don't take any sort of an intervention because they don't want to take an injection, which can be very painful, and I know that now there's some talk in the community of actually having to monitor for hypotension on the competitors, which is a pretty major issue with children, as well as excessive headaches. The other issue is proportionality, right? Like, you want to see effects beyond height. It's not a cosmetic thing.
It is a situation where we can actually affect the well-being of the child. That is where this proportionality data will help us expand the market. I'll leave you with this tidbit. You know, we've analyzed about 500 or 600 launches, and then we'll publish a paper on it, which I know sounds very nerdy. One of the things that we are now able to do is look at cases where you had, you know, not just cherry-pick, but look at all cases where you had injections in the market and then an oral came on. When we analyze a bunch of those analogs, what we see is five years after the entry of an oral option, the market expands by about threefold.
That is the real opportunity here on bringing online new patients, new children who were not before being, you know, having this option as well as getting switches.
From there, let's go out to look at the global opportunity.
Sure.
Obviously, for achondroplasia, OUS is a larger part of the market versus U.S., than in many other indications. This is common in a lot of rare diseases. Talk to us about how your approach to launching is in different geographies and other places where you would be more likely to distro, partner, et cetera. Like, how do you make those decisions?
Yeah. We're currently going through that at our company. We have an excellent head of international that we've hired, who used to work formerly at Alexion. He's a very experienced individual that we're very proud to have on our team now. He and his group are now working through how to map the global launches for the next three products that we have. We have retained worldwide rights to all of them. That's kind of important in this climate, I would say. I think what I would also point out is, I think the opportunity for something like achondroplasia is probably ultimately gonna be similar in the U.S. and Europe for infigratinib for an oral option, right?
Just because I think there are more people who are needle phobic in the U.S. than Europe. In Europe, the injections, you know, don't have some of the issues that they have in the U.S. I think it's going to be a very standard launch. I think that the regulatory filings are probably gonna be 3-4 months behind the U.S. The launch is gonna be 3-4 months behind the U.S. We're going to start with Germany, and from there, we're gonna cascade out to other countries. Our plans are still being finalized on that point right now, so more to come as we further solidify it, but hopefully, this gives you the picture for the next 12-18 months.
I want to talk a little bit about how to think about the achondroplasia market in terms of timing of your launch versus timing of your hypochondroplasia data and how your medical science liaison strategy plays out to get those same physicians who treat those same patients to get leverage on that data set.
That's a great question. I think that let's start with, maybe I'll first map out the achondroplasia timelines and then I'll overlay the hypochondroplasia timelines and then, you know, we'll try to weave the two in together, right? On achondroplasia, we expect to file our NDA in the second half of this year. It has breakthrough designation, so we think that there's a good chance that it gets priority review. Ultimately, of course, we have to have the dialogue with the agency. But I think that sets us up well for a launch in the first half of next year for infigratinib in achondroplasia. Then from there, you know, we'll continue to go forward.
On the hypochondroplasia side, you know, we kicked off the trial last year for our phase II, phase III, our trial for hypochondroplasia and using infigratinib. Actually, the enrollment of the trial was extremely quick. It was much faster than what we had modeled internally, and we expect to get some phase II data out, second half of this year. It is also important to note that our top line infigratinib data was so strong for achondroplasia that we have now accelerated the hypochondroplasia trial, and so it's now like going full speed ahead with its phase III trial portion.
The way all this plays out is we'll be able to go talk about the further expansion into hypochondroplasia, you know, in a compliant way with our MSLs, with the KOLs, and there's going to be a steady cadence of data first, you know, this year, more at conferences next year. Remember, we are also gonna keep publishing on our achondroplasia data like we have done with Attruby. Ultimately, I think that trial probably reads out in 2028 or so, and that's kinda how that's going to go out.
Okay. Talk to me about how to think about the margin profile of the company. Obviously, the balance sheet issue has become markedly less acute, and there's a lot more comfort as you've addressed cost of capital, refinancing, et cetera. Obviously, revenue growth has helped. Not the most innovative thing I've ever said, growing revenue is good. Let's talk a little about what happens to the margin profile as you roll each of these assets on. As you roll on achondroplasia, as you enter ADH1, et cetera, limb-girdle. Like, how should we think about modeling gross margin and how much of that drops to operating margin from an operating leverage perspective?
Yeah. I'm going to maybe not get into super specific guidance right now.
Yeah.
Just because as much as I like creating news, I don't like creating news that much. But I think, let me try to paint a picture of how the company is going to shape up because it's very interesting, and it's something that, you know, even experienced people have a hard time truly grasping because, one, I don't know of any other company who's launched four products in such quick succession, all in huge markets, with three in one year, potentially. It's a very unusual position to be in. It's a privileged position to be in, and we hope we can capitalize on that to serve patients. I think the way I think about it is these are all small molecules. They're all very easy to manufacture. You know, our COGS expense is not that much.
It's you know, very low. I know that while I'll not give guidance, I know that sell-side models are at 95% or so, and that kind of intuitively makes some sense to me. Again, I wanna emphasize that's not our guidance. That's how it seems to me Wall Street is modeling it. Beyond that, I think most of these assets don't really have a heavy royalty burden. We have sold a small royalty on Attruby of 5% to Blue Owl and CPP, although that hits below the line. And then we have a royalty out to Novartis and Inserm on infigratinib. Otherwise, they're all de minimis royalties on ADH1 and limb-girdle. As I then think about going from gross profit to operating income, you really have to think about R&D expense and SG&A expense, right?
What I would say is that our R&D expense is, you know, flattish from 2025 going into 2026. It's probably gonna drop a little bit for the existing portfolio starting 2027, 2028. The reason for that is, you know, we've been very disciplined on our burn and our finance team has done a remarkable job of working with the business and identifying opportunities to optimize costs. I think that we have multiple trials ongoing right now with pediatric ADH1, hypoparathyroidism, hypochondroplasia, and we're also wrapping up, you know, on OLEs for all the phase III trials, which we've just read out over the last three, four months. There is R&D expense, but we are working very hard to maintain a flat spend there. Our SG&A expense is going to go up.
It is interesting to note that if I look at the total spend of the company, operating spend, cash spend of the company, we were at about $100 million before we read out acoramidis phase III. To launch acoramidis, we went up to around $200 million of total spend. I think with these next three launches, we're gonna be somewhere around $300 million, maybe a little higher, maybe a, you know, somewhere around there, by the end of 2026, going into 2027. You are getting a lot of lift here where you're doing three more launches for the price of your first launch. I do think that that bodes very well for long-term margins.
That's one of the points that we were trying to make at our earnings call, that just the ability of this engine to generate cash, which we can then reinvest in R&D at high IRRs to serve patients and to serve shareholders, I think is quite underappreciated in my personal view.
Let's talk a little bit about these launches. We talked about achondroplasia, obviously we have a TTR ongoing. Let's talk about when we're gonna see the transition to commercial for limb-girdle. How we should think about, you know, about pricing, launch velocity obviously is a little bit different than TTR. You don't have a big pharma building it out for three years ahead of you ahead of time. The market's kind of yours in this patient population. Walk me through how we should think about that.
Yeah. Let me talk to you a little bit about it. Again, just to briefly recap the data, right? We hit stat sig on not just the biomarker, but also functional endpoints like FVC, 100-meter time test as well as NSAD, which is super important. We're going to have a plenary talk at MDA, I think today or tomorrow. And so I would encourage all of you guys to check that out because I'll have some more data there. I think this kind of profile where you're actually not just stabilizing a disease but reversing a disease means that we should be able to get value in terms of pricing, as well as I think that patients are going to be excited to be on this drug.
I know we've publicly said that, you know, there are somewhere around 2,000 patients in the U.S. who have limb-girdle. You know, maybe half of them have already been identified, so that's going to be the target at launch for us. And then from there, we are finding more patients. I think that we are looking at misdiagnosis done currently hiding in Becker's as well as some of the other limb-girdle dystrophies, and that's kind of where we're finding some more patients too. It's very exciting opportunity ahead of us there, and it's a billion-dollar-plus molecule.
Sliding down the pipeline chart further. If you don't like this, you should probably just stop having so many positive pivotals.
I like this very much.
We go to ADH1. Obviously a different size market, different level of maturity, et cetera. Talk about where we are in terms of timing towards pivotal, towards filing for approval and that model build that's a little bit different.
Yeah. ADH1 is going to be a true, you know. It's significantly underdiagnosed. It in many ways reminds me of the TTR market when Vyndamax was launched. We've done a good job of identifying almost a couple thousand patients in the ADH1 market, but we know that the prevalence in the U.S. is about 12,000, so we have a long ways to go. Again, the data there has been very helpful. I know I probably sound a little nerdy talking about data on every question, but the clinical data does guide the commercial opportunity. Here we have a molecule which basically cures the disease in more than 3/4 of the patients, right? It normalizes blood and serum calcium both. That's helped us.
I think we're doing a lot of patient finding through algorithms, but also through just old school family mapping, as well as testing programs because, you know, a sixth of the hypoparathyroidism patients probably have ADH1. We are trying to drive awareness that, hey, if you have hypoparathyroidism and if it's non-surgical, you should probably screen the patient for ADH1 and test them. It's a easy-to-use kit. And that's also helping us find a ton of patients, and we disclosed, you know, more than 1,700 patients in claims databases over the last two years.
That's helpful. Can you remind us to give a sense of approximately what the margin profile of that asset is? 'Cause it doesn't have the same royalty burden as the other.
Yeah. I think that again, you know, could normally these kinds of molecules end up having 70%-80% margin, just because, you know, they're not that expensive to launch. I think that is the profile after we have done a ton of investment and work. I wanna be very clear about it. It's not on the first day we've invested throughout this period, but yeah, that's kind of the number which I would say there.
Great. That's helpful. We're kind of winding down to the end of our time here. Thank you so much. Looking forward to seeing more data and a couple more launches from you guys soon.
Yeah, no, thank you, Mani, for hosting us, and we're excited about the opportunity ahead of us to serve patients and I think that's gonna translate to significant shareholder returns. Beyond that, I know in our pipeline, I just wanted to flag, we also own an equity stake in GondolaBio, which is an extremely exciting early-stage R&D engine, which, you know, over time we can think about integrating again. But that's a discussion for another day, assuming our cost of capital improves. Thank you.
Great. Thank you.