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

I'm Ellie Merle. I'm one of the biotech analysts here at UBS. Thanks so much for joining us at the UBS Healthcare Conference. Very happy to have Neil Kumar, CEO and Founder of BridgeBio here with us today for a fireside chat. And with that, I'll turn it over to Neil.

Maybe taking a step back, can you sort of frame for us the business model and philosophy of BridgeBio's structure and how this could sort of increase R&D returns? And then kind of high-level, sort of what your key priorities are over the next couple of years?

Sure. Well, first of all, thanks so much for having me here. It's great to speak with you. Can you hear me okay, by the way, is it crystal clear to -- okay. Wonderful. So the BridgeBio business model is actually quite simple. It's something that we set up to really maximize the number of meaningful medicines that we could create that wouldn't otherwise have been created for patients with genetic disease. And to accomplish that, what we wanted to do was build a company with a couple of different attributes. Number one is we wanted to preserve what we think is really remarkable about biotech R&D, which is focus the level of each asset or each disease, an expert in a specific cardiomyopathy or a specific inherited dermatologic disease or a specific germline cancer, they're all likely to be different, and you want them really incented to get what they're working on right. But we wanted to marry that with cost and, more importantly, time efficiency, and we wanted to marry that in turn with the ability to take on a multiplicity of programs, so that we could take the best of what we were learning from 1 program and port it into the next and port it into the next so that we had a broad diversified platform that ultimately would allow us to maximize our contributions to patients with genetic disease. So that's kind of the overarching business model. I know much has been made about how we decentralize it and the affiliates and things of that nature, but really it is that simple. We view ourselves as a decentralized genetic medicines company. And the way that I think it improves returns in terms of R&D are as follows. I think, number one, if you think about probably a technical success, we are really playing in a privileged area, which is that of genetic medicines, partly because we've used human clinical genetics to decrease target risk, and we're trying to target the causal drivers. So across all of our programs, we're targeting well described genetic diseases at their source. So we've increased POTS that way. And then the second way we've done it is we're diversified enough so that we can shut things down when they're not working. So we don't chase bad data, and we double down in the areas where we think the data is strongest. So that I think is the first of the drivers for return. Second of drivers for return is cost. And as I mentioned, in having a centralized infrastructure where each program can take what they need, when they need it and give it back, variabilizing a lot of the fixed costs, that would be true if you were to run each one of these programs as a separate company, and you're making it such that these programs can move very quickly out of the gates from early stages to IND, in remarkably efficient ways. So I think like we're limiting cost through that. And then the final piece of it is what we call the minimum viable corporation, super small teams, very focused, try to strip out the bureaucracy. So that's all part of the cost game. And then I think the other ways one might think about overall return or maybe taking a step back, overall, EV maximization would be also looking at Gs or growth. And that comes from the new programs that we're continually adding. And then finally, the cost of capital piece where I think having this number of programs helps us to be diversified enough to bring in other types of investors that may require a lower cost of capital just given our risk profile. So I think against all those levers, which we're trying to pull, so that our R&D ROI is high and that the gap between that and its cost of capital is meaningfully higher or greater as well. Sorry, long-winded but...

No, I love it. Great. Maybe just starting with TTR, which is clearly a huge near-term potential value driver. It was an upcoming readout from Part A of the Phase III study. Could you talk a little bit about the endpoints, your powering assumptions? And what drives your confidence and success, particularly with the Part A data analysis?

Yes. So great question. I think fundamentally, what gets us excited about this program is that it's a very well described disease. Again, about 140 odd mutations that do the same thing. Destabilized as tetramer transthyretin. Every time you do worse in terms of stabilization, you do worse as a patient, generally, if you line up thermodynamic stability and penetrants or pathogenicity. And every time we're able to do better in terms of stabilization or limiting the amount of toxic monomer, we seem to do better for patients. So we get excited about our compound as it relates to the competing compounds out there because it number one, sees more target; number two, has a superior KD2; and number three, does a better job of gluing that target together when it meets it. So how you resolve that is obviously a part and parcel what we're trying to do here in the clinical trial, number one through Part A with the 6-minute walk test and number two through mortality and cardiac rehospitalization. So 6-minute walk, specifically, what's interesting about that endpoint is lots of standard deviation, obviously, even within ATTR-ACT, we saw about a 70-meter standard deviation. But what gives us some confidence here is that if you look at both the natural history study that was done and ATTR-ACT, it's remarkably similar in terms of starting points around 350 to 360 meters or so and that the decrement looks pretty remarkably similar, around 60 meters in terms of decrement over the course of 12 months. So that feels pretty good and totally different than, let's say, healthy volunteer studies. Or even within the context of PAH, some of the deviation we saw there. And what's very interesting also is if you look at the starting data in and around what the ATTR-ACT study looked like and what we looked at, we're all around 355 meters at start point. So over time, over 12 months on drug, their patients were getting to something like the 325 or so. And I think if we were able to drive up into that 335, 340, getting close to what a normal person would look like, which is about 10-meter decrement over those 12 months. That's when we start to get really excited, especially if you can line that up with serum TTR levels, levels of stabilization, you know the drug is working. So I think that's the first part, and that's kind of how we're thinking about Part A. And then on Part B, 10% to 15% relative risk reduction against mortality really is what we're going to be keeping an eye on there. And so yes, [indiscernible] you asked, answers your question.

Yes, sure. And maybe just sort of diving into the variability a bit around 6-minute walk. Maybe -- Clearly, the powering assumes some sort of standard deviation. What's your expectation for the impact potentially of COVID around that? And your thoughts around potential missed visits and how those could be treated from a statistical perspective?

Yes. It's a great question. So we did miss some visits within kind of that first 1.5 months post the shutdown in the March-April timeframe, but things have come back quite nicely. Because of that, we dramatically over enrolled. So the powering assumptions in and around the trial, we're effectively assuming that we would do the same as tafamidis and taking about a 10% increase on standard deviation. So we tried to be conservative. And even then we overenrolled the trial by about 100 patients. So we feel pretty good about the powering of the trial and maybe put it another way now that -- and we've been keeping an eye obviously on missed visits. The missed visit rate looks good right now in terms of how low missed visit rate and a high actual rate at 12 months of being able to take the measurement. So I think, ultimately, this trial will allow us to measure whether or not we're doing as good or better than tafamidis against these key endpoints.

Absolutely. And how should we think about, I guess, the path to market? I know that you guys are sort of left the potential open for filing on Part A, whereas we might potentially need to wait for the full study? How should we think about sort of the puts and takes in the various scenarios and what might be meaningful enough from Part A in your view to Bio?

Yes, great question. Our base case is definitely filing on the data in Part A. Obviously, it's a nested trial design that we're excited about continuing to drive the trial forward to gather the mortality and rehospitalization data as well. Look, I think that we'll have to look at the totality of the data. But as I said, if we do better in terms of how much people -- how many meters people are walking at the end of this on treatment and if we do better in terms of serum TTR levels. That, coupled with the fact that we really do understand the mechanism of disease well. And that we are a superior stabilizer. I think all of those come together to make it pretty -- I think it would be an interesting launch just on Part A. And obviously, the sNDA would be coming about 6 months after our launch since it will take some time to file and get on market should we be lucky enough to have that data. So I think all of that is consistent with your launch. I think it will be an interesting treatment option even just given, a, and then with b, it will reinforce, hopefully, its value proposition for patients.

Absolutely. And then maybe could you talk a little bit about some of the patient populations enrolled and particularly why this drives your confidence that you'll see sort of a larger effect size on some of these key endpoints like 6-minute walk and hospitalizations?

I mean, yes, the patient population was designed to effectively be similar to ATTR-ACT. What we know is that the ATTR-ACT population, we know what the different categories of class of heart failure, we know kind of how many mutants versus how many non-mutants. So we're -- so we roughly desired our trial to track that. I think the important piece here is, are we going to be meaningful for both the wild-type population and the hereditary population, and I think the trial is designed to ascertain both those. And our hope is similar to tafamidis, that we would be able to serve both patient populations.

Got it. And maybe just -- yes, to that point, I mean, there's a lot of data around sort of the finding of TTR sort of aggregate postmortem and a lot of people. How should we think about if these aggregates are found and certain people, if this was sort of a driver in their cardiovascular sort of health overall? And how should we think about this like long term, what proportion of the population theoretically has wild-type TTR?

Right. Yes. So I mean you can get into some goofy large numbers if you look at potential amyloidotic deposition in 80-plus year olds, for instance, there's some anecdotal evidence suggesting that population numbers are quite large. I think the ones that we think about are the people, the 13% to 15% of the HFpEF population that does have a pathogenic deposition of amyloidotic plaque. And in those cases, you want to treat the disease, you want to treat the disease as early as possible. ATTR-ACT showed that the earlier you can pick this up, the more prominent an effect you can have. And it is a mass action disease. So that couples nicely with our understanding of if you can deplete that deposition of toxic monomer earlier. And over time, you should be able to do better for these patients. So that is -- that was what we'd be looking to do, is pick up those HFpEF patients early. And we are, to that point, thinking about running a prevention trial as well. We've been trying to design that and put that together. Because I think it will be important to continue to move these medicines earlier and earlier in the treatment algorithm. So if you can suspect ATTR cardiomyopathy, there's a wide variety of things that might allow us to suspect it outside of the hereditary form even, but certainly even within the hereditary form mutations. And I would guess that the penetrance of some of these mutations are higher than what's been reported to date. And I think that if we could pick up the disease earlier, we should be able to do something even more profound for patients than what we're seeing in these clinical trials.

Got it. And maybe just starting with the clinical and then we can go to commercial. But from a clinical perspective, what do you see is the biggest risk to the Phase III? Whether it's tafamidis usage sort of longer-term in the study or COVID, anything around sort of the design and if something were to go wrong, what it would be? Sorry, I know it's a very typical question.

No, it's -- no, it's a great question. And I think the risk is what you cited right out of the gates, which is the standard deviation against the 6-minute walk endpoint is high. It's not that high within the populations that we've seen in ATTR cardiomyopathy. But if you ask me what keeps me up at night, we're pulling from 2 data sets there versus a triple, from 30 data sets across the universe of measured 6-minute walk, including just amongst healthy people, you see standard deviations well in excess of 70 meters. So I think that's probably the largest risk here. I think mortality is a tighter band. And I think, ultimately, the mechanism seems to work. I mean, I was just remarking with someone the other day, in cardiology, when you have a mechanism that seems to be working like big statins, all the statins work to 1 degree or another, and we were able to show that. So I'm heartened for patients and physicians that they're going to have a new tool here alongside tafamidis pretty soon. But certainly, that variance on 6-minute walk is something that we're keeping an eye on.

And then maybe...

By the way, to that point, we were working with that [indiscernible] that does nothing else than 6-minute walk. I mean they really focus in on making sure that those 6-minute walk measurements are standardized, the physicians that we have the privilege of working with. And the sites have been very, very good at keeping the integrity of the measurement high. I was worried for some time based on COVID, if we were going to do these at home, 6-minute walk test, that would be difficult and introduced quite a bit more variance as some of the studies on that had shown, but we haven't had to go there. So yes, I think overall, that's how I would answer that question.

Got it. No, that's helpful. It seems like you're doing a lot and everything you cam to kind of mitigate that variability. And then, I guess, just from a commercial perspective, obviously, there's many -- this is further out, but there's many potential levers that could be pulled in terms of either -- gaining share either through switches or new starts. Maybe how are you thinking about potential pricing scenarios?

I think it's too early to tell right now on pricing for us. Obviously, right now, our focus is really trying to see as the market evolves, how many people have access to this drug, and you're hearing about a lot of challenges. So our focus there would be, certainly, I think we think the market is big enough to tolerate a lower price point. And we also think that access for patients worldwide, it's going to be something that we're going to be very much focused on. So I can say that. I can say that right now, it's not a perfect access story. So I think you can solve some of that through price and solve others potentially through other types of reform and patient health and patient hub services. And I think we'll be looking at all those levers.

Got it. That's helpful. And I guess turning to the large pipeline beyond TTR. I'm going to ask you another very typical question, which you probably won't answer. But are there any programs in particular that you want to call out that you think deserve more attention or that you're particularly excited about?

Yes, I think for us, right now, what's on the line are these big 4 value drivers we've been talking about that are delivering in the next 12 months, except for ADH1, which came a little earlier than we thought. But it's ADH1, TTR, achondroplasia and CAH. And I think that we've traditionally had trouble trying to get people to concentrate on anything beyond TTR or maybe TTRNA achondroplasia. And I think as hopefully, the pipeline delivers great data as we saw with ADH1, people will start to understand the power of the platform, which isn't 1 technology or 1 set of IP, but it's this method of targeting well described diseases at their source and working broadly with academics and really best-in-class innovators to translate and engineer therapies as quickly as possible. So my hope is as people start to see a totality of success if we're able to deliver that, if we're lucky enough to deliver that, that will start to open things up and open eyes up to the next wave of programs and the next wave of programs after that.

Got it. Well, maybe let's start with achondroplasia then.

Okay.

In terms of the data later this year, I mean, we'll just, I guess, thinking high level in terms of a achondroplasia. I know I've asked you this a ton of time from the past. But what do you think the treatment goal should be? I guess if you're maybe in a patient in the older years, say, like, say, above 10 or what should be the growth or goal in terms of annual growth velocity increase from baseline. If it's between catch up or just normalizing? How are you thinking about sort of what the long-term treatment goal should be?

Yes. It's a great question. And I think for these kiddos, AGV is just 1 part of a broader puzzle. And what got us excited about this program is, obviously, for this very common disease, almost 55,000 patients, the ability to target the disease added source, which is unique as compared to what BioMarin and Ascendis are doing. Could potentially allow us not only to impact AGV, but some of the other key aspects of disease like proportionality, final stenosis, et cetera. So that's what gets us excited fundamentally. In terms of AGV and catch up just to specifically talk about that. I think the obvious bogey is the 1.35 centimeters per year that BioMarin delivered, I think we need to deliver in excess of that. I think that allows us, if you're thinking about between 1.5 centimeters and 2 centimeters per year. If you're thinking about those ranges, one might start to get into the cash up regime, which might allow some younger patients to get up to that 58th percentile of what some of the younger kiddos to get up into that range where people who are unaffected would otherwise get to. So I think there is a possibility there that you might be able to deliver a catch-up growth, but we'll just have to see.

Okay. Got it. And when you talk about this 1.3 increase in AGV, are you talking about for the data later this year?

Yes. I think that when we look at -- so just as a reminder, this trial is a 6-month run in to understand the baseline of AGV, and then we're going to be looking to see what the AGV looks like on treatment. And I think as we start to step into doses that we think are going to be meaningful, that's exactly the bogey that we'll be looking to beat. I think there's some variance against that endpoint, but it's pretty well-established, AGV. So we should be able to learn a lot. We'll also be looking at Collagen X, and we'll be looking at as best as we can. Well, safety will be a big issue since this is oral. So if it's oral and safe, then that's obviously an advantage over a daily injection. But long story short, I think we have to do better and should do better than 1.35.

Got it. And just in terms of -- to the extent that you can comment where you are in sort of the dose escalation and maybe which cohorts we can expect to get data on this year and how you're thinking about sort of the optimal dose in terms of efficacy?

Yes. It's a good question. We were delayed a little bit on the trial. We're in the second phase of dosing. I'm not sure that we've disclosed exactly what cohort we're in, but I would expect the efficacious cohort to be cohorts 3 or 4 based on the modeling and the mouse work that we did. So we should get those by end of year or Q1 of next year. And if nothing is happening there, I would be very surprised just because the amount of MAPK suppression at those doses, as we model it, given the present F and what's available to target should be at or in excess of what you're seeing with BioMarin's drug and you're also shutting down the STAT1 pathway at those's concentrations. So we should see something. Otherwise, I think there's an issue.

The study is open label?

Yes, that's right.

Okay. Got it. Just confirming. And just in terms of safety, I mean, you alluded to this. But can you talk bit about your safety margin versus the dose that's being used in the oncology setting, and then also some of kind of the safety, I guess, monitoring triggers that are kind of put in place in the study, both, I guess, from a growth perspective, but also maybe from a potential toxicity perspective?

Yes. It's a good question. So the paradigm of using low dose oncologic agents has already even established as you likely know, in some of the other indications. Like neurofibromatosis type 1 in the Mendelian space. This is actually even more marked because we're starting at a 130th -- the dose of the adult oncology dose. As a reminder, obviously, as you know, in oncology, we're trying to get up to concentrations where you're cytotoxic and you're shutting down the signaling. Here, what we're trying to do is ameliorate the excess signaling and bring it back down to normal levels of signaling. So in the context of that, what we found is that the starting dose of probably somewhere between, I would guess, 140th and 130th of the adult oncology dose will be plenty of efficacy to get there. And we're 10x to 20x cleared against where we start to see the adult tox, which is hyperphos and reversible hyperphos. So that's a lab value. It's reversible. I don't expect that we'll get anywhere close to that in these kiddos. So then the question is, what might there be otherwise in terms of a development oriented tox signal. Obviously, we're running the trial, so we'll see. But our NOAEL from juvie tox studies won't be exceeded even at high dose here. So that gives you confidence as well. And there's nothing obvious from any genetic disease in terms of a loss of function that would strike me as worrisome either. So I think -- so I think we've done all the requisite experiments both on experiments in terms of the lab and now the key is to just monitor these kiddos really closely to make sure we're not doing anything untoward.

Got it. And then maybe from a growth perspective, at what point is it too much as -- it's too much growth. I mean, I know that you have the percentile cutoff...

Yes, the 90th percentile, I think, is -- I have to look back exactly at the protocol, but it's 2 or above, I think, it's in that range. I think that's where you start to get -- if you're at the 90th percentile AGV, I can't remember exactly how it was defined. I'll get back to you on that. That's the kind of like -- that's when we stop on therapy.

Got it. And then maybe just from a mechanistic perspective, I know you mentioned sort of the benefits versus CMP. Outside of just increased growth, are there different sort of mechanisms that you can comment on that could help with things like proportionality? Or just how are you thinking about the mechanistic benefits?

Yes. Well, the stenosis [Audio Gap] those, the dual pathways are what's affecting the proliferation of the differentiation. So in showing both of those, we're not shutting them down, but bringing them back down or normalizing signaling flux there. One would hope to have in the long term, effects on spinal stenosis as well as proportionality. I think it will take a little bit longer to show, but certainly, that is the hope here. And I think we're the only agent in mouse models, which have been fairly predictive thus far to have effect on things like foramen magnum area and things of that nature. So that gives us hope that we can do something special for this patient population.

Got it. And then, I guess, assuming that we see all this, like, theoretically, or a year from now, and we've seen this level of growth and across the cohorts and safe what would be the next steps? And how are you thinking about maybe the fastest potential path to market and what the regulatory requirements might be?

That's a good question. I think we'll learn more from vosoritide as to whether or not 1 or 2-year Phase III is required. I think AGV will be the right endpoint. Because it's well defined. We understand its variance, and we understand that it's a reasonable starting point for understanding if we're helping patients here. So I would expect a conversation with the regulators. One can't predict. But to the best of our knowledge would be a 1- to 2-year trial focused on AGV as the primary endpoint.

Got it. That's helpful. Maybe just pivoting to CAH. Can you talk a bit about the treatment landscape, unmet need? And I guess, why gene therapy for this indication?

Yes. Sure. So just as a reminder, this is a large disease. It's a new disease, almost 75,000 patients between the U.S. and EU and it's uniformly driven by a loss of 21 hydroxylase, which is a siP enzyme, which is in part responsible for endogenous cortisol production. And so when you lose it, what happens is you get shunting on the upstream part of the pathway to androgen production and then you lose endogenous cortisol so what people do as they come in with high-dose synthetic steroid, which effectively is warding off adrenal crisis by putting people into almost like a Cushingoid symptomatology. And so the treatment landscape right now outside of steroid and in the pipeline, effectively, is focused on the CRF1 programs at Neurocrine and Spruce have. And what they will do, and they've shown to be effective here is reduction in 17OHP, which is the upstream intermediate. So one might be able to rectify some of that androgen flux. They're not going to have any effect on endogenous cortisol levels, obviously. And it has yet to be seen if there's any effect on the ability to steroid spare based on that mechanism. We -- this is the only game in town that I think could potentially resolve endogenous cortisol production. And that's precisely what we're going to be looking at, obviously, in addition to 17OHP and some of these other markers in our clinical trial, really hoping to show that we can massively elevate production from whatever the baseline is, probably 0 to 2 microgram per deciliter, up well past 5 and hopefully, into that 8 to 10-microgram per deciliter range. If we can get there, I think we'll have significant steroid sparing, and the dream would be obviously to get high enough such that children wouldn't need to take steroid or could massively limit the amount of steroid they're taking.

Got it.

That's also exciting about it. And the other thing that's cool about the program, I think, is there's not that much -- I mean, from the genotype phenotype, this is actually quite different than TTR and that you get this -- in TTR, you have the sort of linear response regime. Here, that's much more of a threshold regime. If you have above 10% of wild-type enzyme, you should be able to be or effectively operate close to normal. So we don't have to put that much back to do something profound for these patients. So that makes me feel like the -- it's addressable.

Yes, absolutely. And just in terms of the Phase I/II design and where you guys are, I know the IND was recently approved and you guys are working on site activation. Have you dosed the first patient? And I guess, should we think about what we could be getting from a data perspective at the initial update, I guess, in the coming months or towards the end of the year?

Yes. I think FPI will be second half of this year, the IND is cleared and the sites are being activated. So -- but we don't have FPI yet. And I would say that first half of next year [Audio Gap] there is the second or third cohort, would be the cohort where I expect, based on nonhuman primate studies, we start to see increases in endogenous cortisol. And the data would be precisely the reads, as I mentioned, against the biomarkers as well as actual cortisol levels, which will be pretty neat if we're able to do something there.

So I mean, just to take it a step further, say you are able to generate this sort of -- in the levels that clearly, you only need around 10% to really modify the phenotype. What's the next step in terms of clinical studies and particularly on the manufacturing front and how you're thinking about building that out given the potential large capital investment and the size of the indication?

Yes. It's a great question. I think in terms of the clinical trial, we would obviously -- that would be at an end-of-Phase II meeting there, and we have a discussion with the agency. I do think that steroid-sparing is a clear endpoint here. And so I think if we've got endogenous cortisol increases, that's the obvious one to go with. In terms of manufacturing, to the best of our models, we're talking about a [indiscernible] to the 13 range here. Obviously, lots of patients. But so -- and we have a partnership with Catalent that is serving us quite well. They're great partners thus far. The real hope for us is that the industry catches up in terms of CDMO activity to the potential that the therapeutic side has for building things out. I'm not sure that we would want to burden ourselves yet with the fixed cost of building on our own manufacturing. But we'll have to take a call on that after we start to see some early data here.

Got it. And how are you thinking about the 75,000 patients? Are there particular subsets that maybe are more severe that you would sort of initially target before you go broader? Or how are you thinking about sort of the potential segmentation across the population?

Yes. I think that there's a sliding scale probably of uptake, if you will, although I think all patients could potentially benefit here the 2 relevant parameters would be age and gender. And I think that early for the younger patients, 0 to 12, I think there would be quite a bit of demand against both genders. I think as you get older and older, the demand would likely dwindle faster for males than females. And so of the 75,000 patients, I think, maybe the addressable patient population for us, at least initially, would be somewhere in that 30,000 to 40,000 range.

Got it. That's helpful. And how should we think about things like durability? And how are you thinking about it from a development perspective?

That's a great question. Obviously, no one's studied durability in the context of the adrenal cortex. So if you look at AAV5, durability has probably been most closely followed in the context of the BioMarin data, which -- and it looks durable to ROI in terms of especially if we can get at low VEC levels, we can have a profound effect for patients. So I think from that standpoint, we're heartened, but a lot of durability comes down the cellular turnover and cellular turnover in the adreno gland has really not been studied to the quantitative effect that one would like. So the best we have is non-human primate data, and that builds out now for 6 months, but no longer than that. So I think if durability were a year only, that we'd be in trouble. Our suspicion is that we'll be able to get multiyear durability, but we'll have to see and prove that out.

Got it. All right. That's helpful. Excited to see that data there. And then maybe just pivoting to ADH1. Can you talk a bit about this indication? I think investors are less familiar in sort of the unmet need there? And also maybe what you saw in the recent data at endo?

Yes. This is an exciting one. I mean, I think it was like some of the most profoundly positive data. I've had the opportunity to be a part of in my biotech career. So ADH1 is a subpopulation of HP. It's actually remarkably a common disease for what we go after with a carrier frequency of 10,000 to 12,000 people in the U.S., a couple of thousand people at least already diagnosed. And just as a reminder, this is a disease that's uniformly driven by gain of function mutations in the calcium sensing receptor. And again, our approach is simple. Target disease at its source, it's gain of function mutations. We're inhibiting that gain of function and bringing it back down to normal. And the disease is well-defined in terms of what's driving it. You get the hypocalcemia and you get the increased urine calcium. And both of those are effectively the drivers of what you see in terms of symptomatology, in terms of low serum calcium levels. You get the tetany, you get, in many cases, hypocalcemic seizures. In terms of the increased urine calcium, we have downstream kidney disease, nephrocalcinosis and the like. And so what we were aiming to do was to have effect on both urine and serum calcium levels. And in 6 of 6 patients in the Phase II data that we reported out for a suite of mutations that included both transmembrane and extracellular mutations, we showed complete normalization of urine calcium levels as well as serum calcium levels. So super exciting data. We have fast track on the program. We're excited to take this forward into a Phase III. And I think it will be a good drug for the patients with a fair bit of unmet need here.

Got it. And what should we expect for the rest of the year, both in terms of further data from the ongoing study as well as your maybe conversations with the regulators around what a pivotal study could look like?

Yes. I think so. The rest of the Phase II is focusing on use of drug in the outpatient setting. As one might imagine, there may be some titration that's required here. And then we'll have our end of Phase II meeting sometime second half of this year. And then I think we'll kick off a Phase III next year. So it will really be -- I do believe the regulators understand the unmet need here. It's been a really nice conversation with them and including Mike Collins, whose idea this was, who's our partner at the NIH. And I think that I do believe that analogous to HP, some of the endpoints, which is effectively being able to reduce supplements, which in this case is obviously calcium and vitamin D and normalization of serum calcium and urine calcium. I think those will be the right endpoints. So I think it's fairly a straightforward plan, but we look forward to talking with the agency and learning more.

And I mean, just -- I know you to finalize the design, but I mean, how should we think about just in terms of like the scale and size of the study and potential time lines for the program? I mean, it seems like a relatively rare orphan disease, I guess, ballpark, how should we think about the size of the Phase III and maybe patient and physician interest in terms of uptake in clinical studies?

Yes. I mean, I think the physician interest has peaked and the patient interest, should you go talk to patient foundations, I think, is heartening, meaning I think there's a real unmet need here, and I think people are excited for a new opportunity. So -- and it's hard to power a trial when you have 100% response rate. So a little bit of it will just come down to a discussion with the agents. There are a number of patients out there, as I mentioned, already diagnosed. So I don't know what the exact number will be. But I don't imagine it's going to be a super long or super populous trial just because, obviously, the response can come very quickly.

Got it. And with a couple of minutes left, I'm going to open it up to the audience and see if anyone has any questions. But in the meantime, I'll turn it to you Neil. And we touched on a couple of programs. I know you have a lot more. Anything else in the pipeline that you're particularly excited about that we didn't cover.

Yes, I'm excited about a lot of the pipeline. I mean I think about the shape of the pipeline as interesting because we've got these 2 derisked programs at 1 approved drug and hopefully another to come here in the near-term with our second line cholangiocarcinoma FGFR Inhibitor that targets FGFR2 fusions. And then we've got the big 4 that we talked about. And then we've sort of got 2 interesting buckets, I think, of upside opportunity. Number one, are the already in the clinic of reasonable-sized Mendelian disease opportunities that we're prosecuting. And those include pantothenate kinase efficiency and the organic acidemias where we have a PANK agonist, which has shown remarkable efficacy in mouse models. And I think it's going to be a really exciting, really exciting set of clinical trials here. And we'll know the data sometime next year in terms of -- is it increasing acetyl-CoA levels? And do we see drug in the brain, which is important because some of the other approaches didn't get any drug to the brain. So that's one that I think is exciting. The second of the big ones, that's kind of the next wave on the Mendelian side is the Limb Girdle Muscular Dystrophy Type 2i program that we're running where we've got a Phase II that's ongoing, where we're looking for glycosylation of that alpha-dystroglycan complex. And the hope is, given the fact that this is effectively substrate replacement, if you will, that we should see, in a straightforward manner, increases there. And then the quandary is how do we resolve that clinically. So that's a good exciting trial, and then we've got 2 of our derm trials ongoing in venous malformations and dystrophic epidermolysis. So that's 1 bucket of upside. The second bucket of upside, I think, is kind of an interesting SHP2 inhibitor in as much as what we learned from ASCO and what we're seeing generally is that the SHP2 inhibitors that were ahead of us seem to have very long half-life. That can be very tough because you're basically using those SHP2s in combination as a monotherapy. Clearly, SHP2 is not interesting. And so in combination with, say, G12C, we think a lower half-life, but still potent drug could be quite interesting. And so we've got that program in Phase II. I think that could be really exciting, especially given the fact that we can probably couple it with an approved G12C from Amgen. And then the second is our FGFR3 adjuvant urothelial carcinoma program that's ongoing, which -- where we've shown really nice data. We had well in excess of 35% ORRs in UTUC, FGFR3 driven, we're up against placebo. So I think the POTS of that trial is quite high. And the population is not insignificant for us, 7,000 to 10,000 patients. So again, a large marketplace where we're at least a leading game in town. So those are 2 -- and then we've got the RAS programs that are preclinical and a lot of other cool things that are preclinical, maybe just to talk about 2 really interesting things, I think, we've really expanded our efforts in the cardio -- in the genetic cardiovascular disease space. We have 2 undisclosed programs, 1 was Maze Therapeutics, one on our own in the gene therapy space, but there's no question in CV between MyoKardia, which a number of us played a role in between IDOs and tafamidis there's a wide variety of very striking genetic signals in the CV space, CV disease being obviously tantamount to cancer and the unmet need, broadly in society. And I think there's a lot of cool ways that one can go about it. And I think the Rocket data, too, showing us that AAV9 approaches can help us to put back what's missing potentially in the heart in -- relative to sharing for worse. So that's one thing. And then second is, we've been looking at porphyria associated with PP9, which is -- which targets a couple of diseases. Including EPP that affect probably 5,000 to 6,000 people between the U.S. and the EU. And there, we're straightforwardly inhibiting the transporter of PP9, which is ABCG2 and again, I think a really exciting program, early small molecules fine along. It could be a big opportunity. It could be in the clinic fairly soon. So anyway, yes, I love a lot of my kids. So I don't know. I'll stop there.

I know I always like to see which ones you pick. Maybe just 1 on follow-up in terms of the SHP2. You mentioned the advantage of a potentially shorter half-life. Where are you in monotherapy dose escalation? And I mean, how should we think about the time lines for potential data maybe sooner now? Yes, just...

Yes. I think by end of the year, we should have that model. And I think that's consistent with how we've guided. And then you'll start to see us open up combination studies pretty quickly. So yes, I think of that -- I don't think we've mentioned which cohort we're in, but it's going along. Yes, there's pretty -- there's a reasonable amount of interest in the target despite the 0% ORR that was recently read out by the TNL molecule. I think it's going to be interesting in combination.

Got it. Well, with that, I think we're out of time. But Neil, thank you so much for joining us and everyone on the line, thanks so much for attending, and we'll talk to you all soon.

Yes. Thanks for having me. Appreciate it.

Thanks so much.