BridgeBio Pharma, Inc. (BBIO) Earnings Call Transcript & Summary

Okay, everyone. We'll continue with the next session. I'm Paul Choi, the SMid-cap biotechnology analyst here at Goldman Sachs. And it's my pleasure to have BridgeBio Pharma present here. Joining us from BridgeBio is Neil Kumar, CEO. What we'll do as in prior sessions, is I'll turn it over to Neil, maybe for some opening remarks or comments on the shape of what BridgeBio is doing here in 2021 and 2022, and then we'll go into Q&A. If investors along the way have any questions, as in prior sessions, please feel free to submit them through the webcast portal. Alternatively, you can e-mail them to me and, time permitting, I'll ask them of Neil. And with that, I'll turn it over to Neil.

Great. Well, thanks, Paul, so much for the opportunity to participate in the conference. I really appreciate the time and the chat today. I'll make my opening comments brief because it'd be great to get into the Q&A. I suspect that there'll be a great deal of focus on our 4 key catalysts. But maybe I'll step back prior to that and talk really about what Bridge is as a company. Bridge is a company, as you know, focused on the broad area of genetic medicine, both precision oncology as well as Mendelian disease. And what we've tried to accomplish over the course of the last 6 years is to create a decentralized entity that can discover, develop and ultimately commercialize a broad array of important genetic medicines with the underlying objective function being the number of new and meaningful medicines that we're able to create over time that wouldn't have otherwise been created. And I think that last sentence is really key -- or the last piece of the sentence is really key, meaning that most of the programs we take on are typically either early-stage innovation that's been trapped on the shelves of the academe or later-stage innovation that we think can be repurposed for use in a devastating genetic context that wouldn't have otherwise been pursued. And what we're looking to do with all of our programs is to ensure that they're both NPV positive as well as having a reasonably high probability of [ technical ] success. And those things come together to make the company both sustainable and more of an engineering-light company that's able to take advantage of all of the innovation that's occurring in the genetic space based on cheaper exome and genome sequencing and better longitudinal data and really hopefully translate all of that into medicines that matter. The next 12 months, as you sort of alluded to it in your intro will be, I think, the most important of our corporate trajectory with 4 large readouts that hopefully will be the proven ground for the fact that our algorithm of taking well-described genetic diseases and targeting at their source has a robust probability of technical success and can lead to great products for patients. Behind that, we've just filed our second -- and just had our second FDA approval. So we've got 2 approved medicines, some 18 programs in the development pipeline and another about 15 in discovery. So the platform continues to produce both from the standpoint of novel INDs as well as also from the standpoint of Phase II and Phase III outcomes. So let me stop there and we can get into whenever you want to take -- spend time on today, Paul.

Thanks, Neil. Maybe before we get into some of the individual programs, we can maybe just start with your description of the model. And it's a little topical in the sense that the "BridgeBio model" is potentially being copied by some other biotechs here. And so I was just curious, can you maybe comment on your thoughts on the model here and notion of versus, let's say, a single asset or a single-focused company doing a diversified portfolio approach and just how you think about managing risk across the portfolio? And do you see this as maybe sort of a new wave of biotech company models here?

Yes. Great question. I think that the corporate model is obviously one way to solve for a variety of different -- well, a variety of different objectives. For us, what we were trying to solve for, which I think is very important is retention of focus at the level of each asset because we think that very serious focus at the level of -- this is inherent to cardiovascular disease or this is inherent to [ dermatologic ] disease is key for the productivity of R&D. But the marriage of that to a centralized infrastructure that can promote efficiency, both temporal efficiency and cost efficiency, coupled with the fact of diversification so that you can shut down things that aren't working and double down in areas that are, that was -- those were a key set of parameters that we wanted to solve for all together, which is what led to the corporate model. In some cases, people who are pursuing a similar corporate model are trying to solve for that. In other cases, they're trying to solve for other things, be it tax advantage spinoffs or they're company creators. We are effectively a decentralized company, where our -- we do not seek to create other companies out of our company. We seek to create programs that matter and ultimately, to commercialize them. I do think, though, if you look more broadly at what we've come through as an industry, this could be an important corporate model going forward. And I'll tell you why. I think primarily in the early 2000s, what was dragging the industry down was the fact that although at the point of commercialization and beyond, there were interesting medicines that were very profitable in terms of business. I think the ROI on R&D was below cost of capital. And what we turned to were diseconomies of scale and focus at the level of biotech. So you had all these small little biotechs operating. They raise the probability of technical success, reversed [indiscernible] law. And we're able to create a number of medicines, but those medicines now, what we're finding are happening in smaller and smaller markets, not all of these are blockbusters like ATTR cardiomyopathy. And so I think the next wave of corporate models that will arise -- and I think that's why people are going after BridgeBio tech models, is something that can take advantage of the diseconomies of scale but under one centralized infrastructure such that you can take more advantage of economies of scale as you move into commercial. And a company like that should be able to continue to innovate better and better, faster and faster in an area, and then our chosen area is genetic medicine. So that's a long-winded answer, but I actually think if you look at decentralized models more broadly in other industries, that is where they tend to evolve, once that centralized command and control like infrastructure comes under the weight of its own fixed cost and lack of efficiency, EG economies of scale tend to get all wrung out and now you're going to look to returns to scale, which is more possible in a decentralized model.

Okay. Great. Thanks for that, Neil. Maybe we'll start, I guess, with what probably tends to be your #1 question that you get from investors is with regard to your Eidos business. And you recently consolidated your full ownership stake there and acquired the rest of the public foot that was out there. But we're approaching part 1 of the data here for acoramidis. So can you maybe frame for us how you think about the clinical bar here for what you're trying to do with Part 1 and the 6-minute walk test. And then we can talk a little bit more about the competitive landscape as well.

Yes, sure. So just as a reminder, this is our small molecule stabilizer program for ATTR cardiomyopathy. And the goal here is to create a superior agent as opposed to anything else that's targeting the disease upstream, meaning that the disease is uniformly caused by destabilization of the tetramer that leaves the monomers that ultimately deposit in the heart or the peripheral nervous system and lead to cardiomyopathy or polyneuropathy. And within the context of our trial, we're running a nested trial as it were with Part A reading out a 6-minute walk test and Part B then all of the patients continuing on from Part A for another 18 months for a 30-month Part B readout looking at mortality and CV hospitalization. So within the confines of Part A, as you suggested, what we'd be looking for are signs of superiority because we have a superior small molecule stabilizer as compared to tafamidis. And so what we tried to do with the setup of the trial was to make sure that the patient population was relatively similar. And the nice thing is the baseline characteristic of 6-minute walk is both -- for both trials is around 355 meters. So folks are ambulating around 355 meters in 6 minutes at the start and on drug with tafamidis, folks declined a little over 25 meters over the span of 12 months. This is a devastating disease, as you well know. And so you do see that type of declination. As a healthy 70, 72 year-old will probably decline around 6 to 7 meters over that period of time. So you can see that stark difference. The goal here would be obviously to get closer to halting of the disease, so to move that 25-meter declination that was observed on tafamidis to something that's 20% relatively better or more. So you're talking about a declination of 20 meters over that 12 months or better. And I think in concert with that, you'd be looking at a couple of other things you'd be looking at the most important univariate predictor of mortality, which is serum TTR levels. Are we able to achieve higher serum TTR levels than was tafamidis, number one. And number two, we'd be looking at small molecule stabilization where, again, tafamidis showed at 80 mg, which was superior to 20 mg, a little under 50% stabilization, and we're looking to get something greater than 90% stabilization for patients on drug. So if you put all those things together with things like BNP and others, and we're able to show a superior profile to tafamidis that would, I think, be something that would be consistent with our understanding of the biochemistry. Well, both the mechanism of the disease and the biochemistry of our drug.

Maybe just a quick one on the biology, and then a follow-up on the regulatory, which is you talked to the differences in stabilization versus tafamidis, how linearly or not does that correlate with what you were saying earlier on the mortality outcomes? And then secondly, what is the sort of FDA commentary or guidance been on with regard to -- respect for accelerated approval here given that what sounds like you've planned to lay out here is filing on your Part 1 data?

Yes. Great question. So just in terms of the first, the response equation, if you were between the amount of monomer that's left or the amount of stabilization one can get and clinical response, first was establishing the context of polyneuropathy, where you saw that every time you did better in terms of stabilization, [ inching ] away from tafamidis 20 mg to diflunisal, you did better in terms of the results. And when you went from diflunisal to inotersen, you did about the same, and inotersen to patisiran, you did a little better. So every time you got a little bit more a declination of the monomer you did better for patients. In terms of on cardiomyopathy, what that response curve looks like, you've got 2 pieces of evidence. One is the serum TTR Univariate prediction model that has been published on. And the second is the actual ATTR-ACT data showing it almost 20% relative risk reduction between the 20 and 80 mg dose based on about 13 percentage point increase in stabilization. So you can see going from I think it was something like mid-30 stabilization that they thought was 20 mgs to something a little under 50% with 80 mgs resulted in almost a 20% relative risk reduction, and we're going up 45 percentage points or about double that. So any which way you cut it, you should be able to see quite a bit of superiority in mortality if the disease continues to have -- I wouldn't say a linear because I don't know if it is linear. Obviously, there's only 2 dots in CM so far. But like if you continue to see that type of response.

Okay. Great. Maybe looking a little bit downstream, Neil, as you think about commercial opportunity, you will likely be here second to market in the category. So how do you think about your approach here? Obviously, part of this is dependent on data and label and so forth. But what have you learned so far, I guess, from the Pfizer [indiscernible] launch that informs your strategy here?

Yes. Great question. I just realized, I didn't answer the second part of your first question, which was we have had discussions. In fact, the agency was quite helpful to us in terms of trying to define what could be run as a placebo-controlled trial, which I think is quite unique, by the way. I think all of the rest of the trials, including what's coming on vutrisiran's trial will be on top of -- at least 30% of patients will be on top of tafamidis. So I don't know how you tease those effects out. We were able to run a clean trial with drop-ins only after Part A. So yes, our expectation is that we'll be able to file on 6-minute walk data, which is obviously an endpoint that the cardiorenal division is familiar with. The question you asked around commercial strategy, look, I think, number one, in a devastating condition like this, in an orphan condition like this, one is always focused on efficacy as the main differentiator. The market is large. As you've seen, tafamidis is well above $1.5 billion in run rate just after 18 months. And I think only being available in 6 or 7 countries. And the diagnosis started at around 5,000 patients is above 20,000 now, and you continue to see that sort of exponential growth of people looking both within the HFpEF population and elsewhere. And so from a commercial market standpoint, we think the market is very large. We think ultimately, the differentiation will come from being a more effective agent. Past that, I think it will be about trying to position these small molecule stabilizers, since this is a mass action disease, in places where we can do the most benefit for patients, which will be earlier and earlier in the disease trajectory. So finding the disease earlier, we've been talking about and planning to run a prevention study. How can we basically take our understanding of the fact that you do better as you get into an earlier context for patients and maximize the opportunity there for both patients and for the commercial brand.

Great. Maybe just on that last comment that you made, Neil, with regard to thinking about it in earlier patients and the diagnosis piece of it, we're talking about typically so far in these studies, 70-something year-old type patients here. But how does the curve potentially bends towards younger patients here before they become sort of systematic or classic HFpEF patients? Is that something you thought through? And what is the opportunity there versus where Pfizer is currently marketing?

Yes. Well, so obviously, we have designed our trial very similar to where Pfizer designed their trial so that people could line up the trials. But I think the future for our brand and tafamidis and everyone else, I suppose, probably most importantly for small molecules, wouldn't be to move earlier since this is a mass action accumulation disease. So how do you do that? I will separate that into 2 buckets really. One is the hereditary context and the other is the wild-type context. The wild-type context, what you're looking for are clues to get people to look earlier because typically, when we're picking up this disease, you might already have a heart that by weight is like 10% amyloidotic plaque. It can be quite advanced by the time we're picking it up. So there are certain signs, carpal tunnel, other types of things. If we're looking earlier at wall thickness through Echo, we might be able to find these things earlier and get the drug on board. So we are trying to design, as I mentioned, a primary convention study that incorporates those "risk factors" and so that you could run a study, that study will be long, but you have to run that study out for some time to show that you could dramatically reduce risk of disease occurrence or ultimately HF progression there. Within the hereditary context, it's not clear what the penetrants of, say, V122I is, it's been reported to be less than 10%, but it's likely not. It's likely to be higher than that would be my guess. So let's say, it's 30%, 40%. One could genotype, certain populations have followed them along and see whether or not as they start to develop maybe another -- a second or third hit in terms of risk that you get drug on board and then see whether or not you can ward off disease. And then there are a few pathogenic variants where the presentation comes earlier, and there -- that might be another context where you can run a trial and explore that experimentally.

Great. Super interesting. I think as people look at the ATTR landscape, they are focused on while your data is coming up towards year-end, potentially early next year, they are looking at alternative approaches versus stabilization, including CRISPR, which is now in the clinic. And so we are, potentially within this month, seeing some of the early data from that. And just was curious, how do you think about these other approaches to TTR. It's not necessarily focused on the cardio side, but just how do you think about these in vivo technologies at this point?

Yes, that's a good question. I mean I just want to think about it in where is the -- where folks targeting the disease? Like there's one way to target the disease where you're just trying to -- again, aside from responding, a part of these monomers are depositing, right, so you just want to decrease the amount of monomer. If we fundamentally are able to stabilize people at the 95th percentile, there's no monomer being created up and above the [indiscernible] clearance rate effectively. So I'm not really sure why you want to be knocking down TTR, which is an important protein. No one is half as sufficient or null for it, no animal is half as sufficient or null for it. The best univariate predictor of decreased mortality is increasing serum TTR level. So I don't really understand why knocking it down for the same efficacy would be advantaged in as opposed to stabilizing it. And I've heard now from some of the knockdown companies that -- well, they worry about the CRISPR safety of eliminating TTR in a lifelong way, but that's basically what you're doing with SI too. One might worry about off-target effects and things of that nature. But by and large, I think if you're talking about targeting the upstream monomer production, which you are with CRISPR and you are with SI and you are with small molecules, I suspect the very potent small molecule would be the game in town, not unless someone didn't respond for whatever reason. So that's one. I think the thing that's interesting, and certainly, obviously, on everyone's mind these days is whether or not antibody associated clearance of the plaque could also be an additional and useful proposition. And there, I think we have to see. I mean there's going to be data from Prothena. There's going to be data from [indiscernible] over the course of the next year or 2 where we might be able to see a synergistic effect not only of the prevention of ongoing plaque deposition, but also potentially immune mediated clearance of the plaque. So that's exciting. And I think that would be great for patients if both approaches worked.

Great. Is that something you see as potentially synergistic in terms of the antibody approach with what you guys are doing at dose? And is there any evidence either early, preclinical or what have you that supports a combination approach here?

Well, yes, there is nothing. I mean, we've obviously looked at that approach pretty hard, but we -- but there is no evidence to suggest any efficacy associated with it, but I'm hopeful that there could be, yes, I do think it would be synergistic, especially given the fact that for these later-stage patients, as I mentioned, there's so much plaque that's already deposited. And I sort of -- I mean I could be proven wrong. We have internal debates on this. But even if you halt the amount of deposition, I think if you pick it up early enough, people could potentially get better. If you pick it up quite late, that could be problematic and maybe you would need some sort of a clearance mechanism to really have a great impact on the disease.

Great. Maybe shifting gears to QED. Congratulations on your recent approval for Truseltiq. Probably, this is now your second commercial stage asset. What I want to maybe talk about is you decided not -- even though it's a small indication, you decided necessarily to go it -- alone in terms of the commercial piece. And so can you maybe talk to us about the core genesis of the deal with Helsinn and how you assess their capabilities? Because I guess, for most investors, they're probably not necessarily a brand name in the oncology space.

Yes. Great question. So I think this all emanated from a couple of concepts. Number one is our observation that actually unlike some of the non-oncology genetic diseases, a smaller franchise on the oncology side is very difficult to profitably commercialize unless you already have an established infrastructure. I think we're seeing that across the industry. And so we -- and that's certainly true in Europe. So what we wanted to do was to find a European partner, and we were out talking to a number of people who had infrastructure there, Helsinn included. We came to really admire that team. And ultimately, as we were proceeding down a European -- a Europe-only partnership, we sort of expanded the scope. And we've expanded the scope for 2 reasons. Number one is, certainly, they have quite a few capabilities in around and call on these specific physicians. But two, they were willing to structure a deal such that, not only would they help us to get out on the smaller indication, but ultimately, they were invested in the upside of the franchise, which we're primarily interested in, which is that adjuvant urothelial market, FGFR3 driven adjuvant urothelial market, which we think is a $1 billion-plus market, where we are a leader there. So they're allowing us to do a 50-50 split in the U.S. They're helping us fund a bunch of the R&D. They're bringing capabilities so that we can reach the community [indiscernible] and educate people around FGFR mutations. And I think we're going to be able to do a lot more for patients and a lot more for this program in concert with them than we could have done alone. So I think broadly, in oncology, our focus is, I think we can develop the drugs. I think unless it's like some sort of a monster franchise, it's harder to possibly go at alone in the commercial setting. There's just a lot more infrastructure that's required.

Okay. That makes sense. I think another one of the things people are focused on just with regard to Truseltiq and the FGFR space is that there is increasing competitive intensity. You are now the third commercial stage asset on the market now, and people are focused on potentially emerging ones from relay and [ kinase ] and so forth. And so as you think about the competitive development here, I guess, do you have a view as to some of these emerging clinical stage assets and how they stack up versus [ interbranded ].

Yes. I mean I think that if you look at the FGFR space, obviously, beyond the first wave of broadly nonselective FGFR inhibitors within the selective FGFR 123 inhibitor space, that comes down to the strategy of -- there's 2 of them in the second-line and first-line space right now that are on market. It's ours and insights with [ PMI ] and obviously, referring to J&J's in the urothelial. In the urothelial sector, I think that strategy was played right by us. I mean we'll have to see how the data plays out, but most people were starting with advanced metastatic from working their way up. Our thought was turned out to be right, which was that the immune therapies were going to have quite a bit of impact there. And so we started at the other end where we had already seen 50% ORRs and FGFR3 positive UTUC patients. And so that's where we've got a little bit of a jump start on the competition in that marketplace. Now FGFR3 driven cancers aren't going to be the -- where the big market is, it's not going to be where relay plays. Relay is going to have to -- and other FGFR2 selective inhibitors are going to play in the smaller claims carcinoma market. And look, my hope is based on the ORRs that both us and insider team that there could be something even better for patients. I'll be rooting for relay, if they're able to do that. Again, I think from a strategic point of view, an FGFR basket and FGFR3 driven cancers are going to be much more the larger market associated with this. So I'm rooting for the competition that's earlier, I think that best and would be great for patients. They could put some of our claims and carcinoma efforts under pressure, and that would be further out, obviously, and a smaller piece of the overall pie.

Okay. Great. Maybe turning to the other side of the QED business and your development program in achondroplasia. I guess one of the things in the space that people are most focused on is the PDUFA for vosoritide. And so depending on how that comes out, I guess what are you as a management team trying to glean or figure out from what happens with vosoritide? And how does that potentially inform your development strategy?

Yes. Great question. So just as a reminder, this is an FGFR3 driven disease, again, that we're applying low doses of entry for, and hopefully, we can do something profound in terms of better in the efficacy based on the fact that we're the only agent that targets the disease at its source, both in terms of AGV as well as in terms of a broader diaspora of symptomatology that's important for these [indiscernible]. So that's the hope here. I think what we're looking for from vosoritide is obviously duration, what the agency requires around duration. Good news is we're in Phase II, so we're dose-selecting. By the time we understand what the agency would like, we'll be able to design our Phase III appropriately, it would be a year or 2 years, based on the feedback that they get. And then past that, I think we already know what the data is in terms of the [indiscernible] efficacy-wise, 1.3 centimeter per year or placebo adjusted 1.5 or so centimeter per year. So we want to do better than that. We're the first and only oral agent that I know of. So you'd be looking to go from daily injection to an oral administration with higher efficacy and hopefully better AGV scores as well as, as I mentioned, the promise of hopefully being able to impact others.

So you pointed to your data, which is coming up here, your first in-human data later this year. I guess one question would be, what will you guys be disclosing here? And then I guess, given that the trial start was not too long ago, you won't necessarily have that much follow-up. So will we be able to get sort of a clear picture as to how infi looks here with this initial Phase I data?

Yes, I think so. So the trial design is that you have a 6-month running and then you measure AGV over 6 months. So we should have a pretty clear view as to what the drug is doing on AGV and what the dose response looks like. We'll also be looking at [indiscernible], the key biomarker here. So -- and critically, we'll be looking at safety. I mean there's -- I think if you stack up the risk of this program, a light amount of inhibition of 1 of the 2 effector pathways, MAPK seems to result in increased AGV, as we've seen from both BioMarin and some of the preliminary [indiscernible] with Ascendis. So it feels like the efficacy should be there because now you're inhibiting both MAPK and the JAK/STAT signaling pathway. And I think we should see a more profound effect on the key parameters of the disease. So I think the biggest risk in my mind is the risk of -- it's the risks around safety since FGFR inhibition has never been tried in children, obviously, was tried in adults and it got 2 way higher doses than we're even contemplating here quite safely. But that's why we're moving slow and we're moving to these various cohorts to make sure that we don't do anything untoward. And I think that ultimately with 6 months of AGV data plus safety data, that will be the pretty robust data set for us to be able to choose a dose and understand whether or not we have a better agent than does BioMarin.

Okay. Great. Maybe pivoting to one of your key potential readouts here, which is in CAH, and this is your most advanced gene therapy program. People are clearly focused on the CRF1 programs from Neurocrine and Spruce here and so can you maybe provide some context as to what constitutes a good result for your early-stage program versus their Phase III programs?

Yes. So just as a reminder, this disease is uniformly driven by a loss of [ sip ] enzyme called 21 hydroxylase. And when you don't have the 2 things happen, you get a shunting of the pathway toward androgen production and you have no cortisol -- endogenous cortisol production. So these children are treated with exogenous steroid and typically super physiologic doses of that steroid. And that drives them almost into a Cushingoid like symptomatology. So you get a broader flux through the top androgen production pathway and then you sometimes will back off but you don't want to back off too much because that results obviously in [indiscernible] crisis. And even at great centers, you can lose a couple of children, unfortunately, a year to that. So this would be the only program. So CRF1 could play a role, but it only plays a role in the top end of that flux pathway. So it only plays a role in terms of the androgen flux. And at very best, it would allow for a little bit of steroid reduction. But this would be the only thing that would replenish endogenous cortisol production. So it should correct the top end of the pathway and the bottom end of the pathway and replace the function of steroid production back under the HPA access. You get the proper and associated diurnal regulation. And so what we will be testing for is something pretty different than what Neurocrine and Spruce can look at because not only should we rectify 17 OHP, we should also start to see cortisol levels come up endogenously in these children. So that will be a home run hit much more profound than the work that they're doing, although we're rooting for that work, too.

CAH is a condition that's obviously identified in most major economies by child screening at birth. And so you have a fairly captive or well-identified patient population. But as you've been obviously stating here, Neil, it's a pretty young pediatric population here. So can you maybe just talk us through some of the considerations of using gene therapy in this kind of population? They are young, they are still growing, of course. And just what are sort of the puts and takes, both from a clinical perspective and from a regulatory perspective?

Yes. Great question. So I think as you mentioned, the prevalent population since this doesn't end life, is varied in terms of age. And I think the way I've been thinking about this marketplace is, for sure, as we study this, my understanding would be given the severity of the disease, again, if we're able to under a stim test get up to, let's say, 7 microgram per deciliter or better in terms of endogenous cortisol, that you'd be using this in most young children. Certainly, that would be the use case that I would imagine. And then as you get older and older, you're probably going to use it in more women than men, and you're going to use it in a reducing manner. I think, for instance, aged males with the disease may not use as much gene therapy as -- and certainly it wouldn't use as much gene therapy as you would see in the childhood setting. So that's kind of how I think about it, there's still tens of thousands of patients that would need the drug, so it's still a very large market. And I think if you do get endogenous cortisol production and you rectify that, I'd be hard pressed to imagine a future where most children who are born with the condition aren't getting gene therapy shortly after [ evolution ] and cell turnover is steady.

Okay. That's a helpful context. Maybe the other asset we can talk about in our time remaining here is Encaleret. You had some initial data at the ENDO meeting earlier this year. This is maybe one of your programs that gets -- is a little bit under the radar. Again so can you maybe frame for us what is the opportunity here? And how are you approaching the hypocalcemia here versus the current standard of care?

Yes. So just -- I mean, as a reminder, there is no real effective standard of care for this disease, which is uniformly caused by hyper activating mutations in like calcium sensing receptor. And those mutations result in low serum calcium and high urine calcium levels, which together are effectively the drivers of all the symptomatology you see downstream. And the unmet need is large any way you sort of cut it, number one, in terms of number of patients. For us, again, this is 3,500 or so already identified patients, carrier frequency of between 8,000 to 10,000 patients in the U.S. alone. So it's a very large disease population. Really, you can think of it as a subpopulation for hyperthyroidism that hasn't really been explored as much because there hasn't been much to do for these patients. And so calcium supplements, vitamin D is effectively what's used. And what we showed in that data that we read out a little earlier this year is actually something pretty profound, I thought, it's 100% responder rate in terms of being able to normalize both serum and urine calcium for these patients. And so obviously, we got FTD on it. We're in discussion with regulators as to what that Phase III would look like, which will take off early next year. But I think this is a really nice example of how targeting the disease at its source might do something great for patients. And I actually think it's a reasonably sized market as well with -- as far as I can tell, no one else really playing there.

Maybe just on the Phase III part that you mentioned here, Neil. I know you're still working on finalizing it. But I guess you did also show relatively quick activity in terms of evidence of normalization, both for serum and urine calcium. So I guess, is this something that could be a relatively short path to development in your mind, depending on the sizing of course, of the trial and so forth?

Yes. I think the sizing will be the key. It's hard to power a trial of about 100% response rate. So you'll be back and forth with the agency to figure out exactly what they'd like to see. And then, of course, the drug will be used in the outpatient setting, so making sure that you can find and keep patients on the right dose and what evidence base that they would want to see there. But yes, by and large, I think it can be a quick trial. Obviously, we believe that like HP, the endpoint would be something around both rectification of serine and urine calcium as well as being able to go off those supplements. So I think if you were able to do that, yes, hopefully, we can get into the marketplace a great medicine.

Okay. Great. We're coming off on time here. So maybe just a bigger picture question and a strategy one for you, Neil, which is you have a lot of programs that are -- will have major readouts in the next year, 1.5 years or so. And so you'll be advancing some late-stage assets to the regulatory stage and so forth. So I guess, as you think about capital allocation and priorities in the '22 and beyond time frame, can you maybe rank order for us how you're thinking about that? Is it the commercial piece? Is it thinking about finding new assets and so forth? And just how you're thinking about the capital piece in '22 and beyond?

Yes. I mean obviously, we do have an internal ranking of the IRR of various programs of where we can put dollars. Again, the objective function is to create as many new and meaningful medicines as possible. That wouldn't have otherwise been created. So if we find new opportunities that are early even though it might be a higher IRR, for instance, to buy back our stock because we're bullish, and we think the modal return is high on -- and the expensive return is high on TTR, we might well take on a new program that could help a new population of patients as long as it tends to be positive. I think in terms of capital ranking, we were able to do everything we need to do based on the cash we have on the balance sheet. So we try to take on everything in our universe, given the fact that we're modeling our cost of capital at where it is, which is a little bit higher than we would like it to be. But I think that will change over time, too. As TTR becomes commercial, we'll have access to different types of dollars, which will continue to help reduce that cost of capital. I don't think it's a trade-off. I mean the fact is we can do early stage discovery work quite cheaply, and that's where most of our programs fail anyway. So the fact that we might add on 5 new programs the year-to-year spend on each one of those programs might be something like a couple of million bucks. So that doesn't preclude us for building out a best-in-class commercial infrastructure nor might it preclude us from doing other things that could help buttress our overall sustainable competitive advantage. So yes, like although we're constantly ranking these things, unless it falls below cost of capital or becomes NPV negative, we tend to be able to finance it and move it forward. Maybe the easy way to say that is I don't think we're capitally constrained against the opportunities that we have on our plate right now.

Yes, definitely makes sense. We're up on time here, Neil, so we'll have to end it on that note. Thanks to Neil and BridgeBio for joining us today.

Thanks, Paul. Appreciate the opportunity. See you. Bye.