Good afternoon and welcome, everyone. My name is Jamie Adolph, and I'm an investment banker here at Morgan Stanley. Today, I'm joined by Neil Kumar, CEO and founder of BridgeBio Pharma. Thank you for joining us here today.
Thanks, Jamie. Thanks for having me, and thanks to Jessica and the whole Morgan Stanley team for having me here again.
Yeah, of course. It's great to have you back. Now, before we kick off, I do have a few words to say on disclosures. For important disclosures, please see the Morgan Stanley Research Disclosure website at morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. That will kick things off. To start things off, can you give us a high-level overview of where BridgeBio Pharma stands today and how you see the company evolving from one approved product into a multi-stage, multi-asset, late-stage biotech?
Sure. Yeah, thanks for the question. As I think many in the room know, this year has really been focused on the ATRUVI launch and proving that we can marry what I've seen as a high degree of R&D productivity with some commercial productivity. Obviously, lots more to do on that launch, but we're happy with how that's been evolving. Where that really brings us right now is on the cusp of becoming, as you just mentioned, a multi-product company with three phase III readouts here in the next six months in ACH1, in LGMD2i, and in achondroplasia. The density of those readouts portends, I think, the making of the next really large, hopefully generational biotechnology company in the area of Mendelian disease.
The only thing I'd say about that is it really has been the nature of the decentralized design to provide what we call returns to scale or increased productivity per unit of time or per unit of cost as the company grows. If you look across the ecosystem of BridgeBio Pharma, and I really do think of it that way, so there's BridgeBio Pharma, there's GondolaBio, and there's BridgeBio Oncology Therapeutics. The density of readouts in terms of phase II readouts and phase III readouts over the course of the coming several years is incredibly intense. I think that allows us to dream of a company that could continue to grow with that type of R&D productivity, hopefully married with continued commercial productivity.
That's great. I may just start off. I know you've had a fantastic launch with ATRUVI. Can you tell us more about how the launch is progressing, what you're seeing with treatment-naive and switch patients, as well as how clinical data and payer dynamics are shaping the continued commercialization here?
Yeah, sure. I'll try to unpack that in a relatively short period of time. I'm following the CEO of Bayer, who said this was one of the best launches he's ever been a part of in Europe. I can say that's the case for myself as well, but it is the only launch I've been a part of so far.
So far.
So far, we've been pleased with the brand growth, particularly pleased with MBRX share growth. That's really where we've targeted much of our efforts. I think the journey with acoramidis starts with clinical differentiation. It really starts at the base of what we call 342.50, the earliest known separation against the seminal endpoints of cardiovascular hospitalization and mortality, the greatest relative risk reduction at 30 months and 42% that we've seen in the field as a point estimate, with 50% reduction in hospitalization, hospitalization being the majority of events that we see in this space in the modern trial regime. What we've tried to then do is to build off of that and say a couple of things. One is, in the broad population, how do we continue to kind of connect the dots between ever better stabilization?
Just as a reminder, and as Stefan suggested, we're a 90+% stabilizer as compared to Pfizer's about 61% stabilization. How do you marry that with actual outcomes? We had some important research that suggested that ever higher levels of serum TTR as an in vivo measure of stabilization lead to ever lower levels of mortality and hospitalization. We were able to demonstrate at this latest ESC conference remarkable hazard reduction of 44% in the context of 42 months in the context of cardiovascular mortality, highly statistically significant. Again, a better point estimate than what I saw from the knockdowns, who also presented some of their long-term follow-up. Importantly, we're starting to see and publish on improvements within the patient population, things like 45% of patients improving on anti-ProBNP by month 30. Those are going to be important as we look overall at the population.
The second step really is to think about subpopulations. I think you saw the variant literature that we published at an earlier conference this year suggesting that we had, again, the highest relative risk reduction in that space with STAT-CIG, which I don't think anyone else has been able to achieve. We also published quite broadly on our impact within the AFib population, which affected almost half of our patients. Again, what we saw as best-in-class point estimates there. We'll continue to look at that. There is an interesting paper in the Journal of Lipidology recently suggesting that folks with tafamidis are not well controlled given their DDI with Rasuva and Atorva. All these little populations where you could suggest that ATRUVI might be the best friend in this space, I think, is going to be important. It's that clinical differentiation.
We couple that then with many of our commercial efforts. Obviously, you heard in Europe that they're going to be market leaders sometime soon. I think we aspire to do that. We certainly reset our expectations to be even better than when we started at 35% peak share, but it's going to take some time in the U.S. Primarily, we are the smallest sales force out there. Our share of voice, we need to bolster that over time. I just came back from Orlando, and Pfizer's got a huge 12-foot sign that says Vindamax, only approved product in ATTR cardiomyopathy. These are the types of things that we're going to have to battle against: misinformation, disinformation. I think we'll do a good job of it. Over time, the data is going to set us free.
At the end of the day, if you have the best clinical data in terms of point estimates, no double-blind head-to-head run, if the biochemistry and path and mechanism suggest that you are doing the best in terms of lowering the amount of toxic monomer that's depositing in the heart, and all of that is available at the lowest price point in the category, I'm not sure why over time we wouldn't ultimately be the brand of preference. We have work to do between now and then to get there.
Yeah, that makes a lot of sense. One thing you referenced a few times is your partnership with Bayer in the commercialization in Europe. Can you tell us a little bit more about how that's progressing and what early takeaways you have from that launch, and also how that impacts your broader international strategy?
Yeah, I won't say much more because I think many in the room were here for Stefan's comments. Maybe I'll say one, that the rapidity of the launch has been striking. Number two, that the payer physician entities in that space, I think, mirror how this category will evolve over time, having a strong look at health economic data, having a strong look at what's known about efficacy, critical experiments like switch experiments where you take one drug product, patients on one drug product, and you put them on another drug product. These are the types of things we're doing, real-world evidence studies that are comparative, and we're going to publish a lot more in that space as well.
I think as those bodies look at things, obviously, Stefan referenced the strong launch in Germany, MBRX share above 40% right out of the gates, which is quite striking, but also countries like Denmark where we've won the national bid. I think that is resetting, as I said, our expectations for what's possible with this drug. You heard him say it's an easy sell. I'm not sure that's the case. It's a thought that's complicated. I do believe a more potent and better stabilizer over time will be the preferred brand, certainly front line for patients with ATTR cardiomyopathy. Maybe before we move off of ATTR cardiomyopathy, as you and I have discussed in the past, the most important aspect here is the fact that when we entered this space, there were maybe 50,000 patients diagnosed. We've seen 40 and 50. There's probably 250,000 to 300,000 patients in the U.S.
alone. This is true of all the sponsors. I think that the collaborative work that's being done to identify patients and educate physicians in high-volume heart failure practices has been tremendous. We're just finding more patients, and we're finding them earlier, which is, I think, the most important piece of caring for these patients in a differentiated way.
That's fantastic. Now, I know you have a lot beyond ATRUVI out there, so I want to turn my attention to some of the other programs you have in development. Maybe starting with ACH1, can you tell us a little bit more about what success looks like for phase III, specifically in terms of trial design, patient finding, and market development?
Yes. ADH1, I think, is a disease condition that many folks haven't done as much work on. It's an important one, and we would be, if we're successful in this phase III, first-in-class, so a little bit of a different flavor than our efforts in ATTR cardiomyopathy and achondroplasia. The ADH1 is fundamentally a condition of low serum calcium and high urine calcium uniformly arising from gain of function mutations in the calcium-sensing receptor. What our drug does is it's a negative allosteric modulator of the calcium-sensing receptor that sets out to target this well-described condition at its source and normalize both serum and urine calcium. The reason that that's important is the diaspora of symptomatology that arises for these patients uniformly tracks low serum or high urine calcium levels.
Low serum calcium leads to things like brain fog, tetany, seizures in some cases, and high urine calcium leads to downstream nephrocalcinosis, CKD, and the like. What we showed in our phase II data was a 70% normalization, or 70% of patients were able to be normalized on serum and urine calcium as compared to 0% in standard of care. The question that you asked is, what are our expectations around phase III? Obviously, our phase II, or maybe not obviously, but the phase II was a single-site trial at the NIH, and it was also just a handful of the about 100 mutations that affect patients with ADH1. The phase III is obviously 20-plus sites, both in the U.S.
and Europe, and a multiplicity of those mutations, which is going to be critically important because a paper we recently published suggested the 10,000 to 12,000 patient prevalence within the United States alone for ADH1 importantly spans a wide variety of mutations. Biochemically, we believe our drug should be active there, but we have to prove it in the clinic. Base case, we'd like to hit on the primary endpoint, obviously, which is a difference against standard of care against normalization at the end of the trial. What I'd be looking for as an upside case is 50% plus responders. Basically, if 50% plus of these patients, analogous to our phase II, are responding to the drug, it truly is a new day in the context of ADH1.
What I think that does is it brings a whole lot of excitement out, both from patients who have been identified, about 4,000, a little over 4,000 patients in the U.S. today, but also for physicians who are seeing nonsurgical hyperpara patients, where we find about 25% of patients actually have calcium-sensing receptor mutations to go and look and see whether or not there are really ACH1 patients hiding within that broader community because you have a truly remarkable drug that's waiting for them. I'm excited for this readout. I'm hopeful that it provides really a new day and the first new day for ACH1 patients after a long time.
Yeah, that's great. We're certainly hopeful for that as well. As you think about entering a new market like this one, how important are tools like ICD-10 coding and other ways to raise patient awareness for your path forwards here?
Critically important. I think the establishment of that code just earlier this year, actually last year, has been critical in the identification of an additional 1,000 patients. 1,000 patients obviously helps with the tracking. I think in this case, we need to marry it with a couple of things. One is patient finding associated with the diaspora of clinical symptomatology. I don't even think you need complicated AI algorithms on this one. There's a relatively straightforward set of parameters that one can look for. For instance, the UK Biobank that makes the pool highly that yields a lot of ACH1 patients. Let me put it that way. The second is sequencing or some sort of genotyping within the context of the nonsurgical hyperpara patient population. I think all of that is doable.
I also think the excitement from physicians around this molecule, given the data that we just published at Endo in chronic hyperpara, is pretty remarkable. You know, if you think about HP, chronic HP, which I think a lot of people do know that marketplace from Ascendus and other sponsors, number one, the opportunities to have a more efficacious drug, the 80% normalization, especially on urine calcium, I think is fairly unique in this space. The second is to have an oral drug. The third is to have a drug that has an orthogonal mechanism to PTH replacement so that you might get around the downstream bone issues that arise with PTH administration. All of those things, I think, could be quite profound for the chronic HP population. In general, will drive excitement in and around this drug within the marketplace.
That's great. I know it's a little dependent on upcoming data, but once approved, how do you think, how quickly do you think the market might develop here?
Great question. As a first-in-class launch, I think what we'll see initially is a bolus, certainly amongst patients that have already been identified. The real question is, we look at launches like in XLH, for instance, the sort of best-in-class launches, how do we begin to develop the market beforehand? One of the things that we didn't have going into the ATRUVI launch was any sort of capital so that we could get medical affairs on the ground early, get a lot of the disease awareness on the ground early. Here, we'll have a better chance, I think, to develop the market prior to launch. I expect that within the ADH1 community, at least that first few thousand patients that are identified would rapidly adopt the drug. After that, we'll have to see how we push into that new space. Hard for me to tell.
Yeah, that does certainly make sense. Next, I want to touch on your LGMD2i program. I know you have phase III going on. Can you tell us a little bit more about how you view success in that program? How are you thinking about, you know, specifically endpoints, patient recruitment, and fitting in the broader treatment landscape?
Yeah, good question. For those of you that don't know, LGMD2i is not LGMD2b or 2d. I get a lot of questions on that from the SIREPTA activity. This is actually a much more common limb-girdle muscular dystrophy that shares nothing in common in terms of the pathomechanistic signaling, but rather arises, again, uniformly through loss of function in an enzyme called FKRP. The way the disease works is you have a lack of glycosylation against the alpha dystroglycan complex within the muscle. What the drug is seeking to do is to provide substrate back to the enzyme, which is loss of function, but not full loss of function, so that you might increase glycosylation against the ADG complex and therefore rectify the symptomatology in this condition. Once again, we're working on a first-in-class product. Importantly, it's a first-in-class product that's a simple small molecule that's incredibly safe.
There have been other approaches to this using gene therapy. There are problems. You don't want to go too high on FKRP with it, and it doesn't seem to affect as many patients as you would like. The small molecule approach yielded very interesting results in our phase II. If you look at glycosylation in both the homozygous population, which is more common, and the more deleterious heterozygous, compound heterozygous population, we saw an almost 100% increase in glycosylation of the ADG complex, which is remarkable. We saw by Pearson correlation 0.9 decreases in CK, which is a nice measure of muscle damage. Against the history of natural history of the disease, improvements in things like ambulation and others were observed. I would caution that it was an open-label trial, so one never knows.
The one thing we do know from the natural history of this condition is that it's very difficult to tell in a year whether or not you're improving against things like, you know, 100-meter walk time or modified North Star, things of that nature. It's very noisy. In fact, patients and KOLs in this space have termed this almost like Chinese water torture for the muscle. You know, you get loss in functionality that's devastating and debilitating, but it happens slowly over time. Our discussions with the agency have focused on the potential to run a nested trial, one where we fully bear the responsibility of showing that this drug has meaningful impact for patients in a two-and-a-half-year-long or three-year-long trial, but that we have this early readout, which we expect sometime in Q4 here, where we look at three-month impact on ADG glycosylation.
We'll look at CK, and then we'll look directionally at some of the functional endpoints to see what the drug product is doing versus placebo. That's the upcoming readout. It's fully enrolled. Last patient last visit is behind us. I would say the enrollment pace was quite a bit quicker than we expected. Generally, in my experience, that suggests that the unmet need is quite high. Probably 3,000 patients in the U.S. is what the literature suggests, and our STAT-Gen team suggests 4,000 in Europe. I think the opportunity size is roughly double what Exon 51 DMD looks like, so something in that range.
That's great. That's encouraging to hear. Next, I want to touch on infigratinib. Can you tell us a little bit about your program there in achondroplasia and how you're thinking about the phase III study?
Yeah, sure. Just as a reminder, as many of you know, achondroplasia is the most common form of dwarfism that uniformly arises from gain of function mutations in FGFR3. We have a drug that, again, targets the condition at its source by inhibiting FGFR3, but rather uniquely as compared to, and this is a competitive space where the goal is to be best in class to some of the downstream mechanisms that only focus on one of the two signaling pathways, the MAPK pathway with the CMPs. Our goal was to obviously provide differential efficacy, and I think we've done that.
The phase II published in the New England Journal suggested that not only did we have meaningful improvements on change from baseline and average height velocity, but even more importantly for this community, we were able to point to statistically significant improvements in things like proportionality and others that I think this mechanism uniquely is able to deliver that others cannot. That gave us the confidence to go into our phase III and actually turn down the age of enrollment to three. Oftentimes, you don't want to do that. You want to leave it at five or above to boost your point estimate on change from baseline AHV. I think it's fairly well established that this molecule is going to be a superior, certainly in terms of mechanism, and I think believe in clinical efficacy products.
The question is, how do we bring it to as many patients as possible as early as possible? That's the phase III design. Again, that's reading out first quarter of next year. I think important to mention with this one, similar to ACH1, and actually a bit similar to LGMD2i, although the follow-on indication there in Fukuyama is quite small. Here, you've got what I think people colloquially call a pipeline in a pill. There are many other skeletal dysplasias that are driven by FGFR3, FGFR2 dysfunction. The hypochondroplasia unmet need and opportunity is high on our radar. We are enrolling that phase II. As we're speaking then, it's been enrolling ahead of schedule. I think, again, a clear message around the unmet need. At Endo, we published, I think, encouragingly on Crouzon, Pfeiffer syndrome, some of the other more deleterious skeletal dysplasias.
If anything, I hope ultimately what BridgeBio stands for is we'll go after the big markets, but we'll go after the small markets as well when we have a really nice tool for it. It's true in Canavan syndrome. It's also true in some of these smaller FGFR-driven conditions. The final thing I might add is here, I think you should expect to see some competition from China. We've profiled, I think, all three of the major FGFR selectives that I think mostly are like Tyrra, and that means mostly they're pretty dirty if you do a kinome scan. I would expect to see announcements in and around someone buying them. I don't think there'll be credible competition unless the safety profile is dramatically improved, which we don't see because many of these are hitting FLT4, VEGFR2, and a variety of other kinases that you'd rather stay away from. I like our profile for the foreseeable future here.
That's great. One thing too, I know you mentioned some Chinese competition. There are a few other, I think, U.S. and EU programs in development. Can you talk about how your FGFR differentiates from theirs as well? Is it along similar lines?
Yeah, so there's really two dimensions to that. The first are the programs that are ahead of us, which are effectively CMP, either one, and I should mention, either once-daily injections or once-weekly injections. I always like to focus on efficacy first. I don't think I would do a program just for a convenience sake, although I think a single daily oral versus a single daily injection from the context of when you're born to whenever your growth plate closes is a pretty meaningful advantage, and we see that in our market research.
From the efficacy side, the reason to believe in the differentiation for our product is not only the clinical data that we've published, but also the fact that in targeting the condition at its source, what we're able to do is shut down signaling through both the JAK-STAT and MAPK signaling pathways that collectively are responsible for chondrocyte differentiation and proliferation. If you look at cellular models, if you look at the mouse model, if you look again in the clinic, there's literally no assay in which targeting that condition at its source doesn't lead to outsized advantages in terms of efficacy. That's against any of the CMPs because the CMPs are effectively just touching the MAPK signaling pathway. The second concept has been more selective FGFR3 inhibition to stave off what people had discussed as a potential downside to broad FGFR2, 1, and 3 inhibition, which is hyperphoss.
Again, we saw no hyperphoss in our phase II. On a blinded basis, we're seeing very little hyperphoss in the phase III, so I don't think that's going to be an issue for these programs going forward.
Great. That's good to hear. Looking beyond those, you have a number of other programs and two pretty meaningful baskets that are BridgeBio Oncology Therapeutics and GondolaBio. Can you tell us a little bit about those and what you're most excited for in those programs?
Yeah, sure. Last year, we sort of took the step to de-conglomerate, if you will. The company so investors could be more aware of some of the value that we were trying to provide patients and investors as well and make us more capitally efficient. Capital efficiency is a big deal to us. It obviously waxes and wanes as to how much investors believe we're capitally efficient based on how much of the pipeline they value. I'll give you a good example. ACH1, should it be successful, will have gone all the way from our early studies through its phase III readout in less than $200 million.
Wow.
All of our phase IIIs, inclusive of ATRUVI, will have gone through all of their campaigns in less than $300 million. I think that's pretty good capital efficiency for the types of opportunities that we're looking at. I think there are opportunities to drive further efficiency into the pipeline. Nevertheless, it was important for us to kind of break things up. On the BridgeBio Oncology Therapeutics side, I'll let Eli talk about it. I know he's talking this week, but a super exciting array of products. The first two of which I think is kind of a first-in-class, if you will, direct inhibitor of G12C on and off, where they should be announcing data next year. The second is a first-in-class.
There's one other company, actually Bayer, that has a PI2K alpha breaker, which is an exciting mechanism, both in terms of pairing with some of the other mechanisms around KRAS inhibition or actually HER2 and in the context of potentially monotherapy. That's on BBOT. In terms of Gondola, this is a super exciting effort right now, focused again on early-stage Mendelian disease discovery, where we've seen most investors sort of walk away from the space. I was telling someone earlier today, Howard Hughes, medical investigator, will come over to your house these days and talk about, well, this is my new idea about trinucleotide repeats. You can really form a lot of great, I think, high-value but early programmatic things today that you couldn't have maybe four years ago when competition was higher. Really exciting pipeline there.
I think helmed by a very exciting EPP phase II readout that we expect again in the fourth quarter here. EPP, as a reminder, is a disease of excess PP9 in the sera. It's both phototoxic as well as driving liver toxicity. The goal is to tamp down PP9 levels. There is an existing approach which limits the amount of glycine that goes into the erythrocyte or red blood cell that's been pioneered by a company called Disk Medicines. We think that there are several hurdles on that medicine, inclusive of it takes a long time for it to take effect, weeks. PP9 reduction is 50% or less. Ultimately, there are toxicities associated with that compound that stem a bit from the glit associated mechanism. You've seen that in the schizophrenia trials that were conducted before, as well as the dizziness associated with their phase II. What's our goal?
Our goal is more profound PP9 lowering in a matter of hours, not weeks, and ultimately to have a safer side effect profile. If we're able to deliver those things, I think that's a huge and meaningful step forward for patients. I think it's just another fingerprint of the R&D productivity that's ongoing in the BridgeBio ecosystem that hopefully we can continue to bring to bear if we can continue to show promising commercialization efforts with ATRUVI and hopefully some of these other launches to come.
That's fantastic. Clearly, a lot to look forward to over at BridgeBio Pharma.
Indeed.
That wraps up all the questions I have for today. I appreciate your time. Maybe I know you touched on a lot. Can you just wrap it up with a brief summary of the upcoming milestones you have for everyone here?
Sure. Yeah. Upcoming milestones are inclusive of ADH1 phase III readout, inclusive of the LGMD2i phase III readout. Both of those will be in Q4 of this year, inclusive of our achondroplasia readout Q1 of next year. I would anticipate announcements around phase III's launching in both hypochondroplasia as well as chronic HP, with the encalor compound for the latter and the infigratinib compound for the former, sometime in the first half of next year. Lots of activity just within the mothership of BridgeBio here.
That's fantastic. All right. Great. Thank you so much for joining us here today.
All right.
I'll talk to you next week.