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

Okay. Good morning, everyone. Thanks for joining us for the fireside chat for BridgeBio. I'm joined here by Neil Kumar, who is the CEO and Founder of the company. Just before we get started, the disclosure -- for important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.comresearchdisclosures. If you have any questions, please contact your Morgan Stanley sales representative. So why don't we get started? Neil, maybe just for people that don't know the company as well, maybe give a few minute overview of the company, what you're up to, maybe the philosophy and maybe we'll start there?

Yes, sure. Well, first of all, thanks so much for the opportunity to present here and thanks to the entire Morgan Stanley team. BridgeBio, for those of you that don't know, is a company that was founded about 6.5 years ago to primarily target well-described genetic diseases that they're sourced. That means both Mendelian or monogenic diseases, as well as somatic cancers with clear genetic drivers. And over the course of those 6.5 years, we've developed a late-stage pipeline that has some five programs that will read out its Phase II or Phase III over the course of the next 18 months. And then, really a barbell-shaped early discovery stage research program that's highlighted by our RAS franchise that will head into the clinic sometime in the next 12 months or so. And so over the course of the last 12 months, for a variety of different reasons that I'm sure we'll get into, we've done some pipeline pruning. We've done some cost pruning. And we've really focused in on what we think are large market drivers. And when I say large market drivers, you can think about our late-stage pipeline as delivering something like $9 billion in peak year sales -- in non risk-adjusted peak year sales by 2030 and about $4 billion on a risk-adjusted basis. So that's a pretty late-stage pipeline in some pretty large markets. And it's really driven by Phase III that we'll get into in three large markets that will read out in the next 12 months or so. One is in ATTR cardiomyopathy. The other is in ADH1, which is a subset of hypoparathyroidism. And the other is in limb-girdle muscular dystrophy type 2E. So those are three Phase IIIs that will read out by the end of next year, early the year after. And then two big Phase IIs in congenital genal hyperplasia and achondroplasia. There's a lot of words salad for those of you that aren't monogenic disease. But I think the important thing is we'll go through is those are all best-in-class or potentially first-in-class molecules that target really well-described diseases at their source. So the therapeutic hypotheses are simple, and we think the probability of technical success is reasonable. So yes, that's the company at the high level and happy to dive into any of the specific programs or...

Yes. Let's go into some of these specific programs. So maybe we'll start with ATTR, obviously. Do you want to just talk about why you think this could be a best-in-class molecule as well as stabilizers versus silencers, and how that kind of gets wound into this? And then maybe we'll go through some of the data and what we're expecting from it after that. But why don't we start with the first part of that.

Yes, sure. So this is an ever-evolving field that you see our cardiomyopathy for those of you that don't know is one of the largest genetic or genetic-oriented marketplaces out there, some 13% of heart failure with preserved ejection fraction. Patients actually have ATTR cardiomyopathy. There's a commercial drug in the space called tafamidis, which is a multibillion-dollar franchise. And there are really two design principles associated with our efforts within this space. Design principle number one is that every time you do better in managing what's toxic here, which is a monomer deposits in your heart, you do better for patients. And that's been shown across several different clinical trials, including some recent data that came out. So I don't think we've seen anything over the course of the last couple of years that changes our understanding of the molecular pathophysiology of this disease. And then secondly, that we wanted to, using a small molecule approach, preserve an important protein called transthyretin, which is really the driver of the disease. And I think, again, there's nothing in the datasets that thus far suggest anything other than the fact that this could be a long-term and interesting protein to keep around. And so we have a program in Phase III, that's a 95% stabilizer as compared to the competing products, which is around 50% stabilizer or knockdowns, which you could think about knockdown efficiency and small molecule stabilization is tantamount to each other. Knockdown efficiency is around 86%, 87% for the next nearest competitor. And what we're reading out is against the hard outcomes of mortality and CVH sometime early next year. And there's been some minimum reads in the context of 6-minute walk that I think have been confusing in the context of how they pertain to mortality. And I think there's been some big wins for patients, which we can get into. But I think the best-in-class principle here is that we believe that with the highest degree of monomer elimination or stabilization, we should be able to provide the best mortality data, which in turn, we think is going to win the day commercially.

Right. Let's spend a second on the data because I think there is a lot of -- people are asking questions about it. And so maybe describe what we saw in December, what that means? And then why -- what we think the mortality next year, mid next year could still be -- could be a significant benefit for patients? Yes.

Yes. So just as a reminder, our Phase III in ATTR cardiomyopathy is effectively a nested trial design, where we had 12 months and then a readout against a 6-minute walk distance and then another 18 months for a total of 30 months where we read out the final and most important endpoint of mortality in hierarchical analysis with CVH as well. And what happened in that interim read at the end of December, as most of you know, is unfortunately, the drug did not show a statically significant difference as compared to placebo. But it was interesting because we saw no placebo decline whatsoever. So on treatment, the drug did about approximately what a healthy volunteer would do. But that is also what happened with the placebo. And we can talk about reasons for why that might have been. Against everything else, Kansas City questionnaire, which is the quality of life questionnaire against BNP, which is perhaps the most profound univariate predictor of mortality and everywhere else, we could see any sort of decline in 6-minute walk, for instance, in the Varian population. We saw a statistically significant impact of the drug and biochemically, we saw high levels of stabilization and increases in serum TTR that were beyond our expectation. So the drug seemed to be safe, biochemically active, doing what it could do, whenever there was a deteriorating baseline. But unfortunately, against the 6-minute walk, we saw no deterioration in that baseline. So our whole goal over the subsequent couple of months was to understand whether or not there was actually a baseline of deterioration on mortality against which the drug could show something. And just as a reminder, the mean age in these trials tend to be late 70s. For us, it's 77. So the death per annum is something like 1.5%. The blended death rates as of January, February in our trial were 13%, 14%, and they've crept up to 18% now with some 6 months to go left in the trial. So long story short, we believe there is a baseline of deterioration. And if our drug is active, we should have enough mortality events in the trial to show a statistically significant impact. So we feel good and confident in that endpoint, and we'll just have to see in first half next year.

Great. And maybe just back to that placebo response for a second. When you unpack that? Or is there a reason why you think that might happen? Or...

Yes. So the plot thickens a bit with, obviously, Alnylam is a wonderful for patients data that was delivered, I guess, a couple of weeks ago now. I guess the theory of the case is that we had a healthier population, and that's true as compared to ATTRACT. I think every trial that's going to run now has a healthier population. We didn't have a healthier population as compared to Alnylam's clinical trial population. We had more Class III patients, for instance. Our mean and medium BNPs were higher. Our death rate on placebo were higher. And our quality of life questionnaire declined more meaningfully over 12 months. So it's not immediately obvious that we're capturing the right descriptors of severity at baseline. I think they had much more of was they had doubled the number of variants that we had. And they had a category of so-called tafamidis progressors, where they were on top of tafamidis and that might have made some sort of a difference. But again, until we see those subpopulation analyses, it's hard for me to exactly understand why their placebo went down more meaningfully than ours. But again, I just -- when I think about mortality, I think about the fact that Class III tends to be worst in Class II that the higher the BNP and the more significant the change from baseline of BNP over the first 12 months, the greater the rates of mortality, and this has been well published, I think, since our study and in natural history studies prior to our study. So the 6-minute walk, there could have been a training bias, context bias. There could have been something around the way we baselined. That was a little different than Alnylam, but hard to tell right now still.

Great. Okay. Thank you. Why don't we move on to achondroplasia and maybe talk just to orient people on the size of the market and who can get treated and maybe some of those types of things?

Yes. So achondroplasia for those of you that don't know is the most common form of dwarfism. It's a very large unmet need in the area of skeletal dysplasias. And it's probably the simplest of the diseases we go after in the sense that there's one mutation in a receptor called FGFR3 gain of function mutation that drives the disease. And our therapeutic approach is simple. Again, we're inhibiting that FGFR3 receptor with a small molecule. And the marketplace itself as described is some 55,000 people affected by the condition. There's maybe 10,000 or slightly fewer kiddos that would actually be available for treatment because you probably can't treat after the gold plate closes. But still altogether, that's a multibillion dollar market. And I think what you've seen from our commercial competitor, BioMarin is a pretty healthy launch. That drug is tracking to be well over a $1 billion franchise for BioMarin. And I think there has been some dialogue around the importance of treatment and how early and how parents might think about it. But remember that 80% of these mutations are de novo mutations. And so most parents of normal stature are faced with this condition and thinking, well, what's the best thing for my child. And certainly, it's not just stature that's a big issue here. It's proportionality, it's spinal stenosis, it's infection. It's all of those things, but I think people are keen for solutions, and that's why you've seen a healthy launch for a month or so ago.

Great. And then when you're giving therapeutics to kids, can you talk for, in this condition, oral versus other forms of delivery and what that means for a parent and compliance, et cetera?

Look, our belief, first and foremost, is that efficacy and safety are going to rule the day here about that ROA, especially for a condition like this. Route of administration is going to be a very large deal for any of you who are parents injecting your child every day from the moment of diagnosis to the time the growth plate closes is quite onerous. And we have a sachet formulation that allows one to mix the drug in with food. And we demonstrated an interim look out in our Phase II that it's also a very safe drug. So I think that's going to be very, very appealing to physicians. And I think already, actually, if you go out and survey physicians, some 70%, 80% would prefer an oral of similar efficacy even what you see with BioMarin. On the efficacy side, it stands to reason that directly targeting FGFR3 should lead to better efficacy than what we've seen with the CMPs, both the Ascendis approach and BioMarin because they're getting only 1 of 2 of the effector pathways. The number that we delivered was 1.52 in terms of average growth velocity or annualized growth velocity, and that was slightly higher than what BioMarin has shown against baseline, which is 1.35. Look, I think AGV like 6-minute walk distance is a pretty variable metric. So I'm not out there saying we're definitively better then. But certainly, the efficacy is at least the same as Boomer with a safe daily oral versus a daily injectable. And we've got a cohort reading out in late June. That's one of those big Phase II studies -- late January, sorry, of next year, that is at double the dose of our fourth cohort. So we continue to expect that we should have best-in-class efficacy, benign safety profile. And with the once-daily oral, we'd imagine this would take the majority of the market.

Right. And let's go to that data that you released just a few weeks ago. You had a few different dose cohorts. So maybe describe how you started, where you ended up seeing efficacy and then why you added the fifth cohort?

Yes. So this drug, the FGFR3 inhibitor, it's actually an FGFR1/2/3 inhibitor that we have is used at very high dose in oncology. And whenever you have a drug that's used a high dose in oncology, regulators, patients, physicians are concerned, first and foremost, about safety. You can see that in the neuropharmatosis story with MEK inhibitors as well. So we started at extraordinarily low doses, about 150 -- AEL GVToXmodel that was wild-type. So effectively homeopathic dosing. And then we doubled the dose just to make sure since we had never inhibited FGFR in the context of kiddos before that this would be safe. The obvious safety signal that we were looking out for was hyperphosphatemia, which is driven by FGFR1 inhibition but we were also looking for things that sort of unknowns as well. And so the first three doses were well under what you would expect in terms of the AUC that drives efficacy in mouse models, which have been fairly faithful in this condition to date. The fourth actually got us right in the range, maybe about 15% lower than where we would like to have had equivalent efficacy to BioMarin in the mouse model. And so again, doubling the dose from there should put us firmly in where the dose looked like we were getting three to fourfold increases against BioMarin and Ascendas in terms of long bone growth and some effect on things like L4, L6 and spinal stenosis in the mouse.

Great. Okay. Why don't we switch for a second to oncology? And perhaps just describe for the audience your precision oncology strategy and your team and what the things you have in your portfolios? And then we can dive into some of the specific programs.

Yes. So we've been active in precision oncology from the get go. One of our founders is Frank McCormick, who founded Onex and was a close collaborator of ours at Third Rock overall there. And primarily, our efforts have been focused on the MAPK signaling pathway and primarily within that, within RAS. And our leaders there are Eli Wallace, who many of you know as CSO at Peloton prior to that, at Array for a long time and then a wonderful group he's assembled, including Pedro Beltran, and did a lot of important work at Amgen and the PI3K space and others. So it's a wonderful group of scientists that have been knocking away at various approaches to RAS and shift to over the course of the last 6 years. Our shift to compound, which we believe has the potential to be best-in-class mostly from a safety profile side is partnered with BMS and is entering a series of Phase IIs in combination with importantly, the KRAS, G12C, GDP inhibitors, but a few others. And then I think something that people don't really pay a lot of attention to, but I think is important is we believe we have a best-in-class direct inhibitor of G12C GTP-bound KRAS, which we can talk about in a moment, and that should head into the clinic in less than 12 months. And there are some important reasons to believe that what we've seen thus far with the GDP-bound class, which includes Amgen's drug, it includes Mirati's drug, is wonderful, but can be further improved on again, with a much more potent inhibitor and one that takes out both inactive and active forms of that. Right behind that, we have a pan-KRAS approach and a PI3K breaker approach as well, both of which should be in the clinic in the next 24 months.

Right. And actually, let's just go to the G12C because obviously, a lot of people are paying attention to that. And what kind of evidence do we have right now for some of the potency and potential differentiation versus the agents that a lot of people are focused on right now, given where it's at?

Yes. So maybe I'll focus on three different areas there. I mean, one is the hypothesis. The second is the preclinical data and the third is the clinical data that we have seen to date. The hypothesis is that, in general, when one is inhibiting KRAS, there's a couple of different drivers that would make it more potent to inhibit the GTP bound form #1, there's a wide variety of resistance mutations that occur upstream associated with RTKs or upstream map case signaling that are more potently shut down in the context of a GTP-bound inhibitor. In fact, if there is a GTP-bound population, and you inhibit the GDP-bound population, there's still going to be leakage to that GTP population, and you can see that both clinically as well as preclinically. And you can see that GDP inhibitors are -- completely abrogate that signaling and shut it down and drive cell death, where Amgen and Mirati's compounds would not. So that's number one. Number two is there are several important research papers published in the last 12 months that suggest that GTP-bound synthesis is one of the ways the cell reacts to GDP inhibition. And so this is basically targeting one of the resistant pathways out of source. There is also resistance mutations that occur in the binding pocket. This is the different binding pocket that the drug is active against and we've published data on that. And then third and final piece is that GTP is obviously a much higher concentrations than GDP. And the size is also millimolar concentration. So you'll have active reengagement as GDP comes unbound and GTP becomes rebound of KRAS and you would have a labeling only in the context of a drug like ours or Rev Med. So I think going to the preclinical data, what's most profound is you can see that the responses are deeper and more potent with a drug like ours. Just to give you some sense, most tenfold more potent than Amgen's drug close to 500x more potent when you look at the KI over Kant. And if you look at the IC50 around fossil work, you're getting down to almost full inhibition within 20 minutes or so with the drug. So it's a quicker, deeper response in the cellular model. And in the PDX models, I think importantly, what we've seen is in areas where the Amgen compound is only able to ameliorate but not fully regress tumors, we're getting 100% tumor regression. And that owes in a bit, again, that deeper, more potent challenge. And I think we put out some of that data with our Q, and we'll have a fulsome review of that data in the October KRAS conference upcoming October 17 or so. So that's the preclinical. And then on the critical side, I think every time we do a little bit better in terms of potency, we seem to be doing better for patients. And the recent Genentech data, I think, showed us that an ever greater more GDP inhibitor alone can get you better and better ORRs. And again, we'd expect given the fact that RAS is a clear driver in many of the conditions we're going after that the ORRs that we've seen to date can be surpassed. And you've seen that in other targeted areas. So I'd sort of think about this like a sumburginib-like play where we're really trying to be best-in-class, obviously, not first-in-class. And we'll just have to see how that plays out in the clinic care.

Yes. And maybe just walk us through the timelines for -- you mentioned October 17 for some of the preclinical, but just maybe how the rest of the program will unfold there?

Yes. So the program right now is in IND-enabling studies. I think October will be the right time for us to kind of unwrap the development candidate package. And then I'd expect it to be in the clinic somewhere 9 months from now or so. And then you're probably looking at a trial with sort of a 50-50 split of naive patients and refractory patients. And so another 18 months or so before you get real data out of that in terms of whether or not you have a differentiated ORR, I guess enough patients that you can hang your head on it.

Great. Okay. And then maybe just for oncology, anything else in the Precision portfolio that you want to just mention?

Yes. So behind the G12C GTP-bound program there is, as I mentioned, a pan-KRAS program, that's about 6 months from development candidate. And I think importantly, we have a very novel approach that stems from a research in RAS, which is a PI3K breaker approach. So as you probably know, RAS and PI3K alpha come together as a part of the effector pathway in many cancers. And instead of directly inhibiting either on a mutant selective basis or on a just PAN basis, PI3K alpha, which has its issues, what we've demonstrated is the ability to actually inhibit that interface between RAS and PI3K, alpha. And that compound is pretty close to development candidate. There's a wide variety of uses there, both in RAS-driven cancers, as well as outside of that and PI3K-driven cancers. So that's a very exciting compound that we hope to show more on sometime late this year in terms of the development candidate package.

Great. Okay. Let's move to ADH1 and maybe as we did for Aecon, maybe an overview of the condition and the total addressable market, I think would be helpful for people to hear about.

Yes, sure. So this disease, I think, is one of the more overlooked diseases in our portfolio because there really is no competition here. And that's a good thing, I think, commercially, but perhaps a harder thing in terms of education. This is a disease that's quite prevalent for our portfolio. At least, 10,000 to 12,000 patients affected, some 3,500 patients alone that are diagnosed in the U.S. today. And the unmet need stems from the pathophysiology of the disease, which is effectively hyper-activating mutations in what's called the calcium sensing receptor, which you can think of as a thermostat for calcium in your body. And what these hyper-activating mutations result in or low serum calcium levels and high urine calcium levels, all of which directly result in the diaspora of symptomatology that one sees here, both in terms of muscle cramps, tetany seizures in the case of low serum calcium and nephrolithiasis and downstream kidney disease in terms of high urine calcium. So it's a bad disease. It's a well-described disease, some 70-odd hyperactivated mutations have been described to date in the CASR. And once again, a very simple therapeutic approach. We're taking a small molecule that's an allosteric inhibitor of the hyper activating mutations. And what we demonstrated in our Phase II results that we released, I guess, at Endo now, 4 months ago, is an extraordinarily high responder rate, above 80% in terms of urine and serum calcium levels. You have about a 2% responder rate on standard of care, which is vitamin D and calcium. Obviously, calcium is going to exacerbate urine calcium levels. So there's nothing obvious that one -- that allows one to go after this disease right now. So a pretty poor standard of care, very high responder rate. And I think the really good news on this one is that the endpoints are basically response rate against serum and urine calcium and that Phase III reads out towards the end of next year. So if I put down all that together, it's, I think, a high probability of technical success because the endpoints are understood that the renins greater than the standard deviation, it's not measuring growth or 6-minute walk or things that can have a higher standard deviation. And I think it's a large market with no other players that we can see so far. So that's kind of a it.

That's great. Why don't we go to the muscle dystrophy program? And just maybe give an overview of that program and we can go there.

Yes, sure. So this is the final -- we haven't done CAH yet, but this is the fourth of our main value drivers that should be reading out its Phase III sometime first half of 2024. Limb-girdle muscular dystrophy 2E is one of the largest -- it is the largest of the limb-girdle muscular dystrophies. LGMDs, I think many people are familiar with based on Sarepta's great work in 2B, 2D and 2E. This one is uniformly driven by loss of function in an enzyme called FKRP, which is responsible for the glycosylation of a complex called the alpha-dystroglycan complex. And we're taking a very, very simple approach once again, which is we're providing substrate back to the enzyme that's not actually fully loss of function but has a lower productivity. And so with the substrate replacement therapy, we should be able to get back to normal levels of glycosylation of that alpha-dystroglycin complex. And the disease presents like a muscular dystrophy typically diagnosed sometimes in adolescence and leads to progressive loss of ambulation as well as in about 1/4 of patients cardiovascular manifestations as well. So it's a devastating disease. And what we showed in our Phase II data that we read out, I think, in March of this year, was that we were able to increase the glycosylation of the alpha dystroglycan complex, some 40%. The goal was about 10% based on genotype, phenotype in mouse models. So we're well within the range of where we want it to be in terms of therapeutic efficacy. We were able to reduce creatinine kinase levels markedly over 70%. It's a good -- I mean, that's a noisy endpoint, but the good news is if you put increases in alpha-dystroglycan glycosylation against decreases in CK levels, it was very highly correlated. So it seems like something real was happening there. And then with all the appropriate caveats here, we had a natural history running on 10-meter walk time as well as modified North Star. And you can see against both of those, you would expect to see a decline for patients, and you actually saw an improvement -- a slight improvement on drug. So that's really where we're at now. I was talking to the agency about trying to do an accelerated approach, looking at just alpha DG levels over the course of 12 months or so and then going out for a longer period of time against the modified North Star test.

Okay. I think we're actually out of time. So Neil, thanks for joining us today, and thanks for being here at the conference.

Yes. Thanks for having me. Appreciate it.

Great. Thanks.