Hi, everyone. Good afternoon. I'm Elie 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 four late-stage programs. Maybe just because it's topical now, let's talk about what we learned yesterday from the Tafamidis PT case.
Sure. Yes. Get right into it. Just as a reminder, this is a IP situation that is related to a competitor's drug product, so I'll stay relatively high level in and around it. Effectively, there are two 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. 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.
You know, 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. The interesting thing that they've done very cleverly, or very astutely, I should say, scientifically, is to use three orthogonal methods to effectively define what that low free energy form is. Obviously, Solid-state NMR, XRD, those two technologies tend to do the heavy lifting, typically on free energy form polymorphs. The third one is Raman spectroscopy.
What we learned yesterday was one of the key experts associated with spectroscopy, and who I think just broadly will be allowed to testify, which I think is an important piece of what we're gonna see. I also think it's reasonably apparent, at least to us, that Pfizer must have found this low free energy form in most of the material that they have surveilled. Otherwise, they would not be applying the claim against these generic manufacturers. Obviously, Dexcel has already said that they are infringing. 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.
Obviously, their experts across both validity and infringement, I think are a strong cast. They do have Ari as well and Bernie Trout testifying in and around validity. It should be a strong cast that we think will be congruent with their strong case.
You know, an 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 Vyndaqel generic. Vyndaqel as a brand has been discontinued, as you know, from the marketplace. 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 you know, not what they're running current experiments with to continue to elaborate on the health benefits of this franchise. You know, sort of like, our payer is really controlling this category that astutely. I mean, in Europe, like, Beyonttra is the leading brand. We're effectively generic as compared to Alnylam. You don't see a whole lot of payer control.
I think when you think about the economics and the channel, given the fact that patient copays are all gonna be the same 'cause this is mostly a Medicare population, that the ISPs generally are gonna want branded products and that brands are gonna continue to do the research in this space. 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, you know, VA often will use 20 mg taf. 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 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 wanna focus on your portfolio outside of achondroplasia and ATTR since I think that gets so much airtime, I mean, as it deserves. 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?
Yeah. 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%+ 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. That type of thing is super exciting for the patient population. Then the question is, how do we find and activate that patient population? The second thing that excites me is it's a broadly prevalent disease from the statistical genetic standpoint. 10-12,000 people. It's not a pediatric condition that necessarily limits lifespan.
You can imagine that the population is large. I would say a majority is unfound, not unlike ATTR, and certainly not unlike ATTR prior to the move from cardiac biopsy to Technetium scan. How do we find it in this case? The good news is there's a subpopulation, non-surgical hypoparathyroidism, where we can look. Pretty reliably, we're finding something like 20%-25% of patients have hyperactive mutations of the calcium-sensing receptor, which is what defines you effectively as an ADH1 patient. I think there's a reasonably large unmet need. I think this drug is really a beautiful product for those patients. I think there's probably 3,000-4,000 already identified patients that we could launch into now.
It's a safe oral that has outstanding efficacy. 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. Yeah, generally there's gonna be a bolus, I think associated with the pent-up demand in this space. Yeah. I mean, that's kinda what was cool about. I mean, just generally, if you like model these launches, we have this revenue inflection thing, and it's like in rare disease you typically see this acceleration, you know, there's basically a steep incline, and then there's a flattening in terms of the actual growth. 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, you know, available. I think it's for TTR, it's by the way, just new prescribers and high-volume heart centers in their practices.
I imagine it'll 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. Then as we find new patients and find new prescribers outside of the, you know, the severe endocrine population and then we'll see more growth there.
Mm-hmm. What proportion of these patients are currently on Yorvipath?
Like 1%. I don't know if you-
Really?
Yeah. It's not labeled for it. I mean, there was that New England Journal piece, but we don't see a lot of patients on it. See many more patients actually on standard of care, which is ineffective and obviously exacerbates the.
Mm-hmm.
the urine calcium. But I don't see a lot of patients on Yorvipath right now.
Mm-hmm. Okay. Let's talk about limb-girdle 2I, maybe the population there, and how you see the opportunity.
Yeah. Super exciting. I actually just flew up this morning from Orlando where MDA is ongoing, and I think that data is gonna be. We have a late breaker that we'll get a press release coming out in an hour on some of the new data associated with it. Very privileged to have Dr. Kathy Matthews presenting our data in one of the keynotes there. 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.
You know, not only are we having 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. Most importantly, those functional improvements.
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 three months. I think all of those things put together, it's like, what this is a really devastating condition. Again, no available pharmaceutical therapies. Probably something like, you know, 1,200-1,500 patients in the United States. This one's a little better identified at the get-go. Actually, there's you know, if you look at Iowa, you look at VCU, you look at some of these larger institutions, they have quite a few patients.
There's 150, I think, MDA centers of excellence across America. I think they all have reasonable numbers of LGMD2I patients or at least LGMD patients. Then the question is, you know, you just have to genotype them. Prior to probably not a huge deal to, you know, not genotype them because there weren't a lot of available pharmaceutical therapies. Now I think people will be doing that more.
Mm-hmm. Makes sense. How should we think about the pathway to approval and the use of this sort of surrogate or biomarker?
Yeah. I think given the fact that we had these statistically significant impacts on outcomes and inclusive of a modified North Star, you know, our dialogue with the agency. Oh, and I should also say, you know, 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. Here it's been remarkably consistent, not only in terms of patient to patient, but also the subpopulations. If you look at the compound hets versus the L276I homozygous patient population.
If you look old versus young, if you look at, you know, severely affected in terms of FVC, non-severely affected, it's a very constant, sort of a gorgeous forest plot of, you know, we've shown some of that publicly, and I think the rest of it will be shown this afternoon. I think given all of that, you know, the agency's dialogue with us has been oriented toward full approval, and that's how we would expect to proceed.
Mm-hmm. That's exciting. What about your conversations with ex-U.S. regulators?
In Europe, we haven't had as detailed of discussions yet. What we anticipate having those in about two months, where I think I'll have a better understanding of how they're thinking about the data set. I don't imagine it would be highly discrepant to what has happened thus far. The data's the same data.
Mm-hmm.
Yep.
Well, it's exciting. I mean, this time next year, you could be launching two or three more drugs.
Yeah. Super exciting.
How are you thinking about the commercial build-out, particularly ex U.S., and what that might entail?
Yeah, great question. I mean, I would say by and large, the commercial build starts with the decentralized model that, I mean, you know, that we employ here in the U.S. Every affiliate is really gonna be almost like if you think about big pharma, the global product lead or whatever, like, yeah, every affiliate really owns the science, they own the medical affairs, etc. They get to hook up to this centralized commercial infrastructure that we have, at least in the United States, which does patient services and market access and distribution and design and sales force incentives and training and all of that stuff. I think it's, they're gonna be highly efficient launches from that standpoint.
We're never gonna have to build the type of field force that we had to build for TTR for any of these, even including in achondroplasia. 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 a partner with Bayer in Europe. We've got Hassan Jurdi, who's done a lot of this work at Alexion. 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. 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. That's one advantage. The second advantage is for every single one of these trials that we run, they have been global trials. You know, just like with TTR actually, and I think you can see this from Attruby's leadership in Europe. In part, it's been great job from Bayer. In part, that's been, you know, obviously the more marked focus on just looking at point estimates of 30 months and price points. I think it's also been true that the goodwill you build up when you run these international trials and we've run, you know, almost 30%-35% of our population comes from Europe in all of these clinical trials.
You know, people have experience with these products and what they can do for their patients, so.
Makes sense. Turning to Attruby, we saw an acceleration in new patient starts.
Yeah.
In Q4. What was the driver of this, and what should we expect throughout 2026?
Yeah, I think by and large, a big driver has been 'cause you saw the uptick not only in scripts, but you also saw it in terms of number of prescribing physicians. This is not just us. This, 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 quote-unquote AI algorithms and things of that nature could do to help just physicians think about, "Hey, this might be an ATTR cardiomyopathy patient." I think that's what 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, you know, 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. Like, you know, the cardiac arrhythmia data was really, really interesting, I think, to physicians, especially in that quote-unquote, community or JV setting. Because not only did it show impact on AF and obviously hospitalization in the context of the cardiac arrhythmia population, which is like the majority of the patients. 50%-60% of these patients have some sort of AFib involvement. Most importantly, what it showed is the drug's active in non-AFib and AFib patients, similarly. You don't really have to worry about, 'cause AFib can be a complicated thing to manage.
The simpler you can make the therapeutic choice and actually the way you manage patients, the better off physicians and patients are. 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. That's the second big driver of what we're seeing, is just a 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?
Yeah, to be honest, I mean, we've hardly been able to gain across the board. I would say, like, we started at a slight disadvantage in the academic medical centers, you know, because they had experience with some of these other things through polyneuropathy. Obviously, the knock-down economics are a little bit different in academic medical centers where they might focus more. Again, I think, you know, for our prescriber base, it really comes down to the efficacy. I think, you know, there's two 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 us a solid in publishing their two papers on that as well, lead to ever better decreases in risk of mortality at 30 months. I think that's you know that's been one thing. Then the second thing I think is the early separation. Maybe hasn't caught as much on in the community setting, but I think in the community setting, I mean the non-AMC setting, or non-COE setting. 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 one month.
It's probably not the kinetics of monomeric deposition in the heart. Could be something else, and we believe it has to do with the cardiorenal axis, which we continue to explore. That would be the second thing. Like, you know, AMC I see as picking up there. Then certainly in these high-volume heart failure doctor practices, you know, I think we've done a good job of educating on the benefits of a superior stabilizer. You know, it generally has been paying off for us in that setting as well. I'd say both settings we've been picking up, net, either brand or naive share.
Mm-hmm.
Yeah.
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.
Okay. Well, that's encouraging. In terms of thinking about the price evolution long term, I think that's really where a lot of the, you know, interest in this conversation comes from. How are you thinking about this, you know, even say over the course of 2026 with the evolution of first gen, but then of course longer term, when we see potential generics, regardless of what year that may be?
Yeah, it's a good question. I mean, you know, obviously the price has been going nothing but up in the channel right now. That's only true in the U.S. and that's true because of the dynamics of the channel. You know, like I said, 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. What helps us more is the hyper-generous access programs that we have.
You know, 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 non-response. Like, how are you gonna necessarily step one thing versus another? It really comes down to it's a devastating deleterious disease, and a physician's gonna feel like one product is better than another to put their patient on, and they often will. You know, I mean, I think there are some people who are very cost sensitive and might be using diflunisal, as I mentioned earlier, at 20 mg tab. 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. You know, I can't. You know, this is never gonna be a 100% answer, there. 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 hypocon relative to achon?
Yeah. I think achondroplasia again was. I mean, I expected that trial to be materially positive, but I think that, you know, the 2.1, the third standard deviation for the Z-score and certainly the proportionality with the P value probably slightly exceeded my expectations. There again, that makes me excited about what's coming with hypochondroplasia. Hypochondroplasia's 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. I think in hypochondroplasia, first and foremost, we wanna show some, you know, statistically significant impact on change from baseline in AHV.
I think to really just get into the setting of hypochondroplasia, I think people will, you know, already given the mechanism and given the results in achondroplasia, I think people will be quite excited about that type of product.
How are you thinking about the commercial opportunity in hypochondroplasia relative to achondroplasia?
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 hypocon has been very high, which at first I thought hypocon was a little less well diagnosed, it probably is, to be honest. The enrollment rate's been terrifically fast, actually in our Phase II. I would say, you know, the statistical genetic prevalence is pretty similar between hypocon and achon. I don't think there's as many identified kiddos 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, you know, 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. You know, I'd say on the achondroplasia side, we believe probably $2 billion, and that's not including hypochondroplasia. I don't. You know, we haven't quite modeled. We have to get on our Phase II first to start including that in our peak year models. I think for both ADH1 and LGMD2I, we have them at a $1 billion peak. What 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 two indications.
I think those are two meaningful marketplaces for us that are probably getting a bit of short shrift. 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 hyperparathyroidism this year, this summer. That's a monster market and that could materially change the marketplace for encaleret. But again, we haven't hit on that yet. That would be my ordering for the stuff that is post-Phase III.
Mmm-hmm. Okay, great.
Yeah.
That's helpful. Taking a step back, I mean, you have a very unique business model on 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. I, you know, obviously right now, we're in the midst of a fairly heavy execution phase, and we wanna make sure that we get great labels and launch these drug products for the patients that we serve. Then secondly, elaborate on all the opportunity associated with the existing medicines. Hypochondroplasia, we talked about. Chronic hyperparathyroidism 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. Then we have a fifth program in Canavan disease, which I don't think will be super material commercially, but is very, very important to the patient community that we serve. Beyond that, we have obviously...
Well, maybe not obviously, but we have a, you know, this is maybe one of the most exciting and also non-competitive times in genetic medicine that I've seen. It kind of reminds me of, like, when we started BridgeBio. There's so much substrate and no one cares because everyone's doing, like, obesity and I&I. We've been able to accrue a very exciting pipeline at GondolaBio, which is kind of our off-balance sheet partner for doing R&D. 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, you know, ADPKD and alpha-1 antitrypsin deficiency and TSC, and I think with the potential for like eight development candidates in the next six months there.
I think broadly, like, you know, outside of what we might do with our sister organization, we're more focused on organic versus inorganic growth. Like, inorganic growth is very expensive, and the fact that we're getting to INDs in $15 million or less and all of these Phase III that we just talked about today were like $220 million or less all the way from front to back. I feel like we can do that work for the patients that we serve pretty efficiently, and we have a lot of ideas. Our hope is that we're able to kind of recapture 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.
Yeah, thank you. Appreciate you having me here.
Thank you.